Materiały źródłowe

• #1 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Sarcomas are infrequent malignant mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting molecular alterations that provide diagnostic, prognostic or predictive information. […] We will address five major molecular alterations frequent in sarcoma, including 1) the presence of chimeric transcription factors, in vascular tumors; 2) abnormal kinase signaling, in gastrointestinal stromal tumor; 3) epigenetic deregulation, either by oncometabolites, as a result of metabolic enzyme mutations, or as primary events, in chondrosarcoma, chondroblastoma, and other tumor types; 4) deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma; and 5) extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.

• #2 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. […] This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. […] This review, therefore, focuses on the key molecular mechanisms identified to be associated with sarcomagenesis and their potential as novel targets for sarcoma therapy.

• #3 Sarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519533/

  Soft tissue sarcomas (STS) are a group of neoplasms that can affect individuals at the extremes of age and can originate from any location throughout the human body. […] The majority of STS occurs spontaneously. However, germline mutations, radiation, and environmental exposure(s) have been causative. […] Sarcomas are connective tissue tumors, and thus the tumors may occur in bone, cartilage, fat, muscle, or vascular or hematopoietic tissues. […] Several causative factors have been identified. […] A chronic lymphatic blockage is thought to stimulate the proliferation of lymphatics and vessels or lead to local immunodeficiency causing the development of malignancy. […] The effects are dose-dependent, and they typically occur at the periphery of the radiation field. […] Tumor-promoting pathways MET, RET, and PI3K/Akt are thought to be activated.

• #4 Pathogenetic factors in soft tissue and bone sarcomas – UpToDate

  https://www.uptodate.com/contents/pathogenetic-factors-in-soft-tissue-and-bone-sarcomas

  Pathogenetic factors in soft tissue and bone sarcomas […] Sarcomas are malignant tumors arising from skeletal and extraskeletal connective tissues, including the peripheral nervous system. Approximately 76 percent arise in soft tissue, the remainder in bone. […] There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified. These include a genetic predisposition, gene mutations, radiation therapy (RT), chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, an association between viral infection and sarcoma has been shown for human herpesvirus 8 (HHV-8) in Kaposi sarcoma, and for Epstein-Barr virus (EBV) and smooth muscle tumors in immunocompromised patients. […] Some patients with bone and soft tissue sarcomas, particularly children, have a genetic predisposition to cancer. In some cases, individuals are from families with a defined inherited predisposing condition, such as Li-Fraumeni syndrome (LFS) or retinoblastoma, but many cases do not fit recognized inherited cancer syndromes. […] The major genetic syndromes are briefly outlined below. […] Mutations in TP53 are the most common germline mutations that predispose to pediatric sarcomas, including osteosarcoma, undifferentiated pleomorphic sarcoma, rhabdomyosarcoma, leiomyosarcoma, and liposarcoma. As many as 7 percent of children with soft tissue sarcomas may have LFS.

• #5 Sarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK519533/

  Soft tissue sarcomas (STS) are a group of neoplasms that can affect individuals at the extremes of age and can originate from any location throughout the human body. […] The majority of STS occurs spontaneously. However, germline mutations, radiation, and environmental exposure(s) have been causative. […] Sarcomas are connective tissue tumors, and thus the tumors may occur in bone, cartilage, fat, muscle, or vascular or hematopoietic tissues. […] Several causative factors have been identified. […] A chronic lymphatic blockage is thought to stimulate the proliferation of lymphatics and vessels or lead to local immunodeficiency causing the development of malignancy. […] The effects are dose-dependent, and they typically occur at the periphery of the radiation field. […] Tumor-promoting pathways MET, RET, and PI3K/Akt are thought to be activated.

• #6 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  The molecular correlates of these cytogenetic presentations are recurrent genomic rearrangements and activating gene mutations for sarcomas with relatively simple karyotype, and multiple, diverse genomic events including gene amplifications and non-recurrent rearrangements, for those with complex karyotype. […] Biologically, oncogenic mechanisms are better understood for sarcomas with simple karyotype, and fall typically into two broad categories: transcriptional deregulation or deregulated signaling. […] This is in contrast to sarcomas with highly complex karyotypes, which typically do not harbor single driver genetic alterations, and rather display non-specific molecular changes that promote oncogenic traits, such as cell cycle de-regulation or genomic instability. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting those alterations that provide diagnostic, prognostic or predictive information (the so-called clinically-actionable alterations).

• #7 Pathogenesis of Sarcomas

  https://www.omicsonline.org/open-access/pathogenesis-of-sarcomas-DPO-1000e103.php?aid=63313

  Based on genetic alterations, sarcomas can be roughly divided into two major categories; one characterized by complex karyotypes with non-specific chromosomal rearrangements, gains and losses, e.g. myxofibrosarcoma, leiomyosarcoma, and chondrosarcoma and the second characterized by simple karyotypes with specific chromosomal translocation events, e.g. synovial sarcoma, alveolar rhabdomyosarcoma and myxoid liposarcoma, or mutations, e.g. activating KIT mutations in Gastrointestinal Stromal Tumor (GIST). […] A large-scale integrated sequencing, copy number and mRNA expression study of six major soft tissue sarcoma subtypes by Barretina et al. has demonstrated recurrent mutations in a subset of cases within each subtype including some targetable pathways. […] As the next generation sequencing technology has been utilized more frequently in elucidating the mutational landscape of cancer genomes, the same strategy should be applied to a wider range of sarcoma subtypes to facilitate identification of potential therapeutic targets as well as molecular signatures for sarcoma pathogenesis. […] Additional molecular data will also likely translate into new prognostic parameters and therapeutic targets.

• #8 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  The molecular correlates of these cytogenetic presentations are recurrent genomic rearrangements and activating gene mutations for sarcomas with relatively simple karyotype, and multiple, diverse genomic events including gene amplifications and non-recurrent rearrangements, for those with complex karyotype. […] Biologically, oncogenic mechanisms are better understood for sarcomas with simple karyotype, and fall typically into two broad categories: transcriptional deregulation or deregulated signaling. […] This is in contrast to sarcomas with highly complex karyotypes, which typically do not harbor single driver genetic alterations, and rather display non-specific molecular changes that promote oncogenic traits, such as cell cycle de-regulation or genomic instability. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting those alterations that provide diagnostic, prognostic or predictive information (the so-called clinically-actionable alterations).

• #9 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomagenesis is driven by fusion oncoproteins and/or mutations and amplifications that result in activation of oncogenes or loss-of-function of tumor suppressors, leading to unrestrained cell proliferation, invasion, and metastasis. […] Sarcomas with simple karyotypes are defined by chromosomal translocations which lead to oncogenic fusion proteins which play a central role in their pathogenesis. […] The upregulation of positive cell-cycle regulators such as the TFs c-Myc, Forkhead Box F (FoxF1/FoxF2), and T-box transcription factor 3 (TBX3) has also been implicated in sarcomagenesis. […] Most sarcoma subtypes are associated with mutations that result in constitutive activation of pro-survival and growth-factor signaling pathways. […] The vascular endothelial growth factor (VEGF) family members VEGF-A, -B, -C, -D and placental growth factor (PGLF) are master regulators of angiogenesis and mediate their biological effects via the surface receptors VEGFR1, VEGFR2, and VEGFR3.

• #10 Recent advances in the molecular pathogenesis of Ewing’s sarcoma | Oncogene

  https://www.nature.com/articles/onc2010205

  Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. […] Ewing’s sarcoma serves as an excellent paradigm for understanding tumorigenesis because it exhibits some very useful and important characteristics. […] These two features suggest that EWS/FLI is the primary mutation that drives the development of this tumor. […] Thus, improved understanding of the pathogenesis of this tumor will not only be of academic interest, but may also lead to new therapeutic approaches for individuals afflicted with this disease. […] The purpose of this review is to highlight recent advances in understanding the molecular pathogenesis of Ewing’s sarcoma, while considering the questions surrounding this disease that still remain and how this knowledge may be applied to developing new treatments for patients with this highly aggressive disease.

• #11

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #12

  https://www.orthobullets.com/pathology/8052/synovial-sarcoma

  Synovial Sarcoma is a malignant, soft tissue sarcoma caused by a t(X;18) chromosomal translocation mutation ( SS18:SSX fusion protein) most commonly found near joints but rarely within the joint. […] Mechanism: mesenchymal soft tissue sarcoma with unknown cellular origin; synovial sarcoma is a misnomer due to the tumor’s microscopic resemblance to mature synovium. […] Chromosomal translocation t(X;18) is observed in more than 90% of cases. […] Translocation forms the SYT-SSX1, 2, or 4 fusion protein. […] Fusion proteins bind to BAF complex, which displaces the tumor suppressor BAF47; new BAF complex activates Sox2, which leads to tumor formation. […] Synovial sarcoma typically shows high histologic grade. […] Metastasis may develop in 30-60% of patients; like other sarcomas, the lung is most common site of metastasis. […] Synovial sarcoma has been shown to have similar rates of lymph node metastasis compared to other soft tissue sarcomas. […] Metastasis is more common with large, deep, and high grade sarcomas. […] SYT-SSX fusion type is most important prognostic factor; SYT-SSX2 better survival.

• #13 Sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Sarcoma

  Dermatofibrosarcoma protuberans often is associated with a chromosomal translocation in which the COL1A1 gene becomes fused to the PDGFRB gene. […] This results in over-active PDGF signaling, which is thought to promote cell division and ultimately lead to tumor development. […] Inflammatory myofibroblastic tumor often is associated with rearrangements of the ALK gene, and occasionally with rearrangements of the HMGA2 gene. […] Many liposarcomas are associated with amplification of part of chromosome 12, which results in extra copies of known cancer-promoting genes („oncogenes”) such as the CDK4 gene, the MDM2 gene and the HMGA2 gene.

• #14 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  The molecular correlates of these cytogenetic presentations are recurrent genomic rearrangements and activating gene mutations for sarcomas with relatively simple karyotype, and multiple, diverse genomic events including gene amplifications and non-recurrent rearrangements, for those with complex karyotype. […] Biologically, oncogenic mechanisms are better understood for sarcomas with simple karyotype, and fall typically into two broad categories: transcriptional deregulation or deregulated signaling. […] This is in contrast to sarcomas with highly complex karyotypes, which typically do not harbor single driver genetic alterations, and rather display non-specific molecular changes that promote oncogenic traits, such as cell cycle de-regulation or genomic instability. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting those alterations that provide diagnostic, prognostic or predictive information (the so-called clinically-actionable alterations).

• #15 Pathogenesis of Sarcomas

  https://www.omicsonline.org/open-access/pathogenesis-of-sarcomas-DPO-1000e103.php?aid=63313

  Based on genetic alterations, sarcomas can be roughly divided into two major categories; one characterized by complex karyotypes with non-specific chromosomal rearrangements, gains and losses, e.g. myxofibrosarcoma, leiomyosarcoma, and chondrosarcoma and the second characterized by simple karyotypes with specific chromosomal translocation events, e.g. synovial sarcoma, alveolar rhabdomyosarcoma and myxoid liposarcoma, or mutations, e.g. activating KIT mutations in Gastrointestinal Stromal Tumor (GIST). […] A large-scale integrated sequencing, copy number and mRNA expression study of six major soft tissue sarcoma subtypes by Barretina et al. has demonstrated recurrent mutations in a subset of cases within each subtype including some targetable pathways. […] As the next generation sequencing technology has been utilized more frequently in elucidating the mutational landscape of cancer genomes, the same strategy should be applied to a wider range of sarcoma subtypes to facilitate identification of potential therapeutic targets as well as molecular signatures for sarcoma pathogenesis. […] Additional molecular data will also likely translate into new prognostic parameters and therapeutic targets.

• #16 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Deregulation of cellular signaling driving sustained proliferation is a major hallmark of cancer and, as such, contributes to the biology of most sarcoma types. […] In certain sarcoma types, however, signaling alteration due to kinase activation is the main oncogenic driver and, most likely, the initiating oncogenic event. […] Mutations in metabolic enzymes lead to deregulated cellular energetics in cancer cells and, more importantly, result in the production of metabolites that may alter tightly-regulated physiological processes such as gene expression and epigenetic regulation. […] Epigenetic deregulation is emerging as a very prevalent oncogenic mechanism in a wide variety of tumors, beyond the effects of metabolic enzymes and oncometabolites. […] The majority of sarcomas show complex genomic profiles, with inconsistent, nonspecific molecular alterations. […] These high grade sarcomas often harbor aberrations in the Rb or p53 pathway.

• #17 Pathogenesis of Sarcomas

  https://www.omicsonline.org/open-access/pathogenesis-of-sarcomas-DPO-1000e103.php?aid=63313

  Based on genetic alterations, sarcomas can be roughly divided into two major categories; one characterized by complex karyotypes with non-specific chromosomal rearrangements, gains and losses, e.g. myxofibrosarcoma, leiomyosarcoma, and chondrosarcoma and the second characterized by simple karyotypes with specific chromosomal translocation events, e.g. synovial sarcoma, alveolar rhabdomyosarcoma and myxoid liposarcoma, or mutations, e.g. activating KIT mutations in Gastrointestinal Stromal Tumor (GIST). […] A large-scale integrated sequencing, copy number and mRNA expression study of six major soft tissue sarcoma subtypes by Barretina et al. has demonstrated recurrent mutations in a subset of cases within each subtype including some targetable pathways. […] As the next generation sequencing technology has been utilized more frequently in elucidating the mutational landscape of cancer genomes, the same strategy should be applied to a wider range of sarcoma subtypes to facilitate identification of potential therapeutic targets as well as molecular signatures for sarcoma pathogenesis. […] Additional molecular data will also likely translate into new prognostic parameters and therapeutic targets.

• #18 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Sarcomas are infrequent malignant mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting molecular alterations that provide diagnostic, prognostic or predictive information. […] We will address five major molecular alterations frequent in sarcoma, including 1) the presence of chimeric transcription factors, in vascular tumors; 2) abnormal kinase signaling, in gastrointestinal stromal tumor; 3) epigenetic deregulation, either by oncometabolites, as a result of metabolic enzyme mutations, or as primary events, in chondrosarcoma, chondroblastoma, and other tumor types; 4) deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma; and 5) extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.

• #19 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomagenesis is driven by fusion oncoproteins and/or mutations and amplifications that result in activation of oncogenes or loss-of-function of tumor suppressors, leading to unrestrained cell proliferation, invasion, and metastasis. […] Sarcomas with simple karyotypes are defined by chromosomal translocations which lead to oncogenic fusion proteins which play a central role in their pathogenesis. […] The upregulation of positive cell-cycle regulators such as the TFs c-Myc, Forkhead Box F (FoxF1/FoxF2), and T-box transcription factor 3 (TBX3) has also been implicated in sarcomagenesis. […] Most sarcoma subtypes are associated with mutations that result in constitutive activation of pro-survival and growth-factor signaling pathways. […] The vascular endothelial growth factor (VEGF) family members VEGF-A, -B, -C, -D and placental growth factor (PGLF) are master regulators of angiogenesis and mediate their biological effects via the surface receptors VEGFR1, VEGFR2, and VEGFR3.

• #20 Epigenetic Mechanisms underlying Ewing Sarcoma Pathogenesis – SFA

  https://curesarcoma.org/funded-research/epigenetic-mechanisms-underlying-ewing-sarcoma-pathogenesis/

  Rationale: Ewing sarcoma, the second most common pediatric bone cancer, is a highly lethal malignancy. […] It has been proposed that its refractory nature arises in part from resistance of a cancer stem cell (CSC) subpopulation to chemotherapy. […] We have found that the epigenetic modifier drug, JQ1, is highly toxic to Ewing sarcoma cells in vitro, and is especially efficacious in targeting the CSC subpopulation. […] JQ1 functions by inhibiting BET proteins, factors that bind to acetylated histones. […] Microarray and additional analyses reveal that JQ1 rapidly reverses the EWS-FLI1-dependent gene expression, indicating that EWS-FLI1 requires BET proteins for function. […] We hypothesize that EWS-FLI1 requires BET proteins to induce target genes that control proliferation, survival, and “stemness”.

• #21 Recent advances in the molecular pathogenesis of Ewing’s sarcoma | Oncogene

  https://www.nature.com/articles/onc2010205

  Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. […] Ewing’s sarcoma serves as an excellent paradigm for understanding tumorigenesis because it exhibits some very useful and important characteristics. […] These two features suggest that EWS/FLI is the primary mutation that drives the development of this tumor. […] Thus, improved understanding of the pathogenesis of this tumor will not only be of academic interest, but may also lead to new therapeutic approaches for individuals afflicted with this disease. […] The purpose of this review is to highlight recent advances in understanding the molecular pathogenesis of Ewing’s sarcoma, while considering the questions surrounding this disease that still remain and how this knowledge may be applied to developing new treatments for patients with this highly aggressive disease.

• #22 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Deregulation of cellular signaling driving sustained proliferation is a major hallmark of cancer and, as such, contributes to the biology of most sarcoma types. […] In certain sarcoma types, however, signaling alteration due to kinase activation is the main oncogenic driver and, most likely, the initiating oncogenic event. […] Mutations in metabolic enzymes lead to deregulated cellular energetics in cancer cells and, more importantly, result in the production of metabolites that may alter tightly-regulated physiological processes such as gene expression and epigenetic regulation. […] Epigenetic deregulation is emerging as a very prevalent oncogenic mechanism in a wide variety of tumors, beyond the effects of metabolic enzymes and oncometabolites. […] The majority of sarcomas show complex genomic profiles, with inconsistent, nonspecific molecular alterations. […] These high grade sarcomas often harbor aberrations in the Rb or p53 pathway.

• #23 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomagenesis is driven by fusion oncoproteins and/or mutations and amplifications that result in activation of oncogenes or loss-of-function of tumor suppressors, leading to unrestrained cell proliferation, invasion, and metastasis. […] Sarcomas with simple karyotypes are defined by chromosomal translocations which lead to oncogenic fusion proteins which play a central role in their pathogenesis. […] The upregulation of positive cell-cycle regulators such as the TFs c-Myc, Forkhead Box F (FoxF1/FoxF2), and T-box transcription factor 3 (TBX3) has also been implicated in sarcomagenesis. […] Most sarcoma subtypes are associated with mutations that result in constitutive activation of pro-survival and growth-factor signaling pathways. […] The vascular endothelial growth factor (VEGF) family members VEGF-A, -B, -C, -D and placental growth factor (PGLF) are master regulators of angiogenesis and mediate their biological effects via the surface receptors VEGFR1, VEGFR2, and VEGFR3.

• #24

  https://haematologica.org/article/view/9319

  In this issue of Haematologica, Egan et al. performed genomic profiling of 21 primary histiocytic sarcomas, and in addition to confirming frequent alterations in the RAS/MAPK pathway, identified a novel intra-chromosomal transcript between exon 12 of TTYH3 and exon 8 of BRAF on chromosome 7. […] This group was characterized by loss of gene sets related to cellular proliferation and the cell cycle. […] Further data suggest that a subset of these cases involve co-occurring NF1 and PTPN11 mutations, suggesting that activating mutations of PTPN11 may synergize with NF1 mutations to potentiate oncogenesis. […] In contrast, cases with wild-type NF1/PTP11 had RAS/MAPK pathway activating mutations, and were unrelated to site of presentation, and had activating mutations involving KRAS, NRAS, BRAF, and MAP2K1. […] This molecular profile offers an intriguing insight into the relationship between histiocytic sarcoma and B-cell lymphoma.

• #25

  https://haematologica.org/article/view/9319

  In this issue of Haematologica, Egan et al. performed genomic profiling of 21 primary histiocytic sarcomas, and in addition to confirming frequent alterations in the RAS/MAPK pathway, identified a novel intra-chromosomal transcript between exon 12 of TTYH3 and exon 8 of BRAF on chromosome 7. […] This group was characterized by loss of gene sets related to cellular proliferation and the cell cycle. […] Further data suggest that a subset of these cases involve co-occurring NF1 and PTPN11 mutations, suggesting that activating mutations of PTPN11 may synergize with NF1 mutations to potentiate oncogenesis. […] In contrast, cases with wild-type NF1/PTP11 had RAS/MAPK pathway activating mutations, and were unrelated to site of presentation, and had activating mutations involving KRAS, NRAS, BRAF, and MAP2K1. […] This molecular profile offers an intriguing insight into the relationship between histiocytic sarcoma and B-cell lymphoma.

• #26

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant clinical problem. […] A better understanding of sarcomas pathogenesis may help develop more effective therapies in the future. The Sonic hedgehog (Shh) signaling pathway is involved in both embryonic development and mature tissue repair and carcinogenesis. […] Its increased activity has been demonstrated in many sarcomas, including osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant rhabdoid tumor. […] In vitro studies have demonstrated the effectiveness of inhibitors of the Hedgehog pathway in inhibiting proliferation in those sarcomas in which the components of the pathway are overexpressed.

• #27 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Deregulation of cellular signaling driving sustained proliferation is a major hallmark of cancer and, as such, contributes to the biology of most sarcoma types. […] In certain sarcoma types, however, signaling alteration due to kinase activation is the main oncogenic driver and, most likely, the initiating oncogenic event. […] Mutations in metabolic enzymes lead to deregulated cellular energetics in cancer cells and, more importantly, result in the production of metabolites that may alter tightly-regulated physiological processes such as gene expression and epigenetic regulation. […] Epigenetic deregulation is emerging as a very prevalent oncogenic mechanism in a wide variety of tumors, beyond the effects of metabolic enzymes and oncometabolites. […] The majority of sarcomas show complex genomic profiles, with inconsistent, nonspecific molecular alterations. […] These high grade sarcomas often harbor aberrations in the Rb or p53 pathway.

• #28 Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02125-z

  Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated. […] Class I HDACs are constitutively expressed in EwS. Patients with high levels of individual class I HDAC expression show decreased overall survival. […] Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi is an interesting new treatment opportunity for this malignant disease. […] The expression of EWS-FLI1 in EwS leads to large-scale epigenetic alterations that result in global modifications of histone H3K27-acetylation as well as H3K27-trimethylation in conjunction with altered histone deacetylase (HDAC) activity.

• #29 Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02125-z

  HDAC class I genes are strongly expressed in various pediatric sarcomas and other pediatric and adult tumor entities. EwS are very susceptible to HDAC inhibition. […] Genetic analysis of the role of individual HDAC class I genes by CRISPR/Cas9 knockouts showed that both HDAC1 and 2 expression are essential for proliferation, invasiveness and local tumor growth of EwS cells. […] Our results suggest that HDAC1, 2 and partly HDAC3 are important mediators of the EwS-typical expression profile and the malignant stemness phenotype.

• #30 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Deregulation of cellular signaling driving sustained proliferation is a major hallmark of cancer and, as such, contributes to the biology of most sarcoma types. […] In certain sarcoma types, however, signaling alteration due to kinase activation is the main oncogenic driver and, most likely, the initiating oncogenic event. […] Mutations in metabolic enzymes lead to deregulated cellular energetics in cancer cells and, more importantly, result in the production of metabolites that may alter tightly-regulated physiological processes such as gene expression and epigenetic regulation. […] Epigenetic deregulation is emerging as a very prevalent oncogenic mechanism in a wide variety of tumors, beyond the effects of metabolic enzymes and oncometabolites. […] The majority of sarcomas show complex genomic profiles, with inconsistent, nonspecific molecular alterations. […] These high grade sarcomas often harbor aberrations in the Rb or p53 pathway.

• #31 Cell Cycle Deregulation in Ewing’s Sarcoma Pathogenesis

  https://escholarship.org/uc/item/9sz8n057

  Ewing’s sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). […] This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. […] One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing’s sarcoma modulate the cell cycle to facilitate tumorigenesis. […] This paper will summarize current published data associated with deregulation of the cell cycle in Ewing’s sarcoma and highlight important questions that remain to be answered.

• #32 Sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Sarcoma

  Dermatofibrosarcoma protuberans often is associated with a chromosomal translocation in which the COL1A1 gene becomes fused to the PDGFRB gene. […] This results in over-active PDGF signaling, which is thought to promote cell division and ultimately lead to tumor development. […] Inflammatory myofibroblastic tumor often is associated with rearrangements of the ALK gene, and occasionally with rearrangements of the HMGA2 gene. […] Many liposarcomas are associated with amplification of part of chromosome 12, which results in extra copies of known cancer-promoting genes („oncogenes”) such as the CDK4 gene, the MDM2 gene and the HMGA2 gene.

• #33 Clinical activity and exploratory resistance mechanism of milademetan, an MDM2 inhibitor, in intimal sarcoma with MDM2 amplification: an open-label phase 1b/2 study | Twist Bioscience

  https://www.twistbioscience.com/resources/publication/clinical-activity-and-exploratory-resistance-mechanism-milademetan-mdm2

  Clinical activity and exploratory resistance mechanism of milademetan, an MDM2 inhibitor, in intimal sarcoma with MDM2 amplification: an open-label phase 1b/2 study […] Intimal sarcoma is an extremely rare life-threatening malignant neoplasm. […] Murine double minute 2 (MDM2) amplification is observed in 70% of intimal sarcomas. […] Milademetan, an MDM2 inhibitor, may provide a clinical benefit in this patient population. […] These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma.

• #34 Molecular Pathogenesis, Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4988391/

  Sarcomas are infrequent malignant mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. […] In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting molecular alterations that provide diagnostic, prognostic or predictive information. […] We will address five major molecular alterations frequent in sarcoma, including 1) the presence of chimeric transcription factors, in vascular tumors; 2) abnormal kinase signaling, in gastrointestinal stromal tumor; 3) epigenetic deregulation, either by oncometabolites, as a result of metabolic enzyme mutations, or as primary events, in chondrosarcoma, chondroblastoma, and other tumor types; 4) deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma; and 5) extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.

• #35 A Novel Mechanism Inducing Genome Instability in Kaposi’s Sarcoma-Associated Herpesvirus Infected Cells | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004098

  Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. […] Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. […] Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. […] Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. […] Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. […] Specifically, lytic infection of cells has been shown to directly induce DNA double-strand breaks, a severe form of genome instability.

• #36 A Novel Mechanism Inducing Genome Instability in Kaposi’s Sarcoma-Associated Herpesvirus Infected Cells | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004098

  Our model proposes that aberrant hTREX levels, sequestered by ORF57, leads to the formation of R-loops, which in turn increases the number of DNA DSBs and the rate of mutation. […] Our work highlights a novel mechanism by which KSHV can induce genome instability in infected cells, an enabling characteristic of the hallmarks of cancer.

• #37

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #38

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #39

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #40

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #41

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #42

  https://www.orthobullets.com/pathology/8047/ewings-sarcoma

  Ewing’s Sarcoma is a malignant, distinctive small round cell sarcoma associated with a t(11:22) translocation which most commonly occurs in the diaphysis of long bones in patients 25 with regional pain, swelling and fevers. […] Diagnosis is made with a biopsy showing sheets of monotonous small round blue cells with prominent nuclei and minimal cytoplasm and immunostaining positive for CD99. […] Etiology […] cell biology […] cell of origin in Ewing’s Sarcoma unknown, however, thought to be of neuroectodermal origin. […] Genetics […] mutations […] t(11:22) translocation […] found in 85-95% of cases […] leads to the formation of a fusion protein (EWS-FLI1) […] can be identified with PCR/FISH and useful to differentiate Ewing sarcoma from other round cell lesions. […] less common translocations including t(21:22) with fusion protein EWS-ERG comprise remaining 10-15%. […] Molecular pathology […] p53 mutation in addition to t(11:22) translocation […] overexpression of cell proliferation antigen Ki-67 […] overexpression of HER-2/neu.

• #43 Cell Cycle Deregulation in Ewing’s Sarcoma Pathogenesis

  https://escholarship.org/uc/item/9sz8n057

  Ewing’s sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). […] This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. […] One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing’s sarcoma modulate the cell cycle to facilitate tumorigenesis. […] This paper will summarize current published data associated with deregulation of the cell cycle in Ewing’s sarcoma and highlight important questions that remain to be answered.

• #44 Tracking Ewing Sarcoma Origin by Developmental and Trans-species Genomics | Alex’s Lemonade Stand Foundation for Childhood Cancer

  https://www.alexslemonade.org/project/tracking-ewing-sarcoma-origin-developmental-and-trans-species-genomics

  Malignant bone tumors, mainly Ewing sarcoma and osteosarcoma, comprise about 6% of all cancers in children and adolescents. […] The genetic cause of Ewing sarcoma is a mutation that results in the expression of an oncogenic fusion protein called EWS-FLI1, with disastrous effects on the enigmatic Ewing sarcoma progenitor cell. […] There is evidence that Ewing sarcoma develops from some kind of mesenchymal stem cells from the bone marrow or the neural crest (as transient structure arising during fetal development). […] In this project, we will follow two complementary approaches to decipher the tissue and stage of origin for Ewing sarcoma and osteosarcoma to facilitate pre-clinical model development. […] We aim at elucidating bone sarcoma origin considering cell type and its developmental stage at the time of tumor initiation to better understand disease pathogenesis and to develop urgently needed disease models for pre-clinical drug testing.

• #45 Role of long non-coding RNAs in sarcoma pathogenesis – Eric Sweet-Cordero

  https://grantome.com/grant/NIH/R01-CA211657-01A1

  Role of long non-coding RNAs in sarcoma pathogenesis […] The primary goal of this proposal is to elucidate the molecular function of lncRNAs in Ewing sarcoma. […] This proposal uses both genomic and biochemical approaches to elucidate the role of long non-coding RNAs (lncRNAs) in the pathogenesis of Ewing sarcoma.

• #46 Discovered one of the mechanism that influences aggressiveness in Ewing’s Sarcoma – IDIBELL

  https://idibell.cat/en/2013/08/discovered-one-of-the-mechanism-that-influences-aggressiveness-in-ewings-sarcoma/

  Discovered one of the mechanism that influences aggressiveness in Ewings Sarcoma. […] Caveolin-1 participates in the formation of new blood vessels around the tumor, facilitating growth and proliferation. […] Researchers from the Bellvitge Biomedical Research Institute (IDIBELL) led by the head of the research group in sarcomas, Oscar Martinez-Tirado, have discovered one of the mechanisms that triggers angiogenesis (formation of new blood vessels) around tumor cells of Ewings sarcoma, a very aggressive childhood cancer. […] Angiogenesis is a key process in the growth, proliferation and migration of solid tumors. Tumor cells need new blood vessels that provide extra oxygen and nutrients they need to grow so quickly. […] The group of Oscar Martinez-Tirado has described in several studies the functions of caveolin-1 protein in Ewings sarcoma, We have seen that it plays a tumorogenic role in this type of tumor, which is involved in resistance to chemotherapy, which favors metastasis and in this paper we have shown it plays a critical role in the angiogenic process.

• #47 Kaposi’s sarcoma | Institut Pasteur

  https://www.pasteur.fr/en/medical-center/disease-sheets/kaposi-s-sarcoma

  Kaposis sarcoma (KS) is caused by infection with human herpesvirus-8 (HHV-8). […] The discovery of viral DNA sequences in the skin lesions of HIV-infected patients in 1994 confirmed that human herpesvirus-8 (HHV-8) is associated with Kaposis sarcoma. […] These arguments, associated with molecular data, have implicated HHV-8 as the causal agent of Kaposis sarcoma. […] Much still remains unknown about the pathogenesis of Kaposis sarcoma. While we know that the virus plays an essential role, its interaction with the immune system, especially the inflammatory cytokines, remains poorly understood. And little is known about exactly how KS spreads: what is the precise origin of the tumor cells, are the lesions really cancerous, does the disease involve clonal proliferation (i.e. is it derived from a single cell)?

• #48 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases. […] Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease. […] The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis. […] Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.

• #49 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases. […] Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease. […] The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis. […] Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.

• #50 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases. […] Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease. […] The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis. […] Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.

• #51 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Immune activation may also be a factor in Kaposi sarcoma, with a role for inflammatory cytokines such as gamma interferon and the initiation of HHV-8 infected cell proliferation by HIV-tat protein. […] This complex interaction of HIV, HHV-8, environmental factors, and the immune system requires further investigation to attempt to decipher the true pathogenesis of Kaposi sarcoma. […] Kaposi sarcoma is caused by an excessive proliferation of spindle cells that are thought to have an endothelial cell origin. […] KSHV contains a large genome with greater than 85 antigenically competent genes. […] Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions (including epidemic and endemic forms), suggesting a causative role for this DNA virus.

• #52 Kaposi’s sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma

  Kaposi’s sarcoma (KS) is caused by a combination of immune suppression (such as due to HIV/AIDS) and infection by Human herpesvirus 8 (HHV8 also called KS-associated herpesvirus (KSHV)). […] KSHV encodes oncogenes, microRNAs and circular RNAs that promote cancer cell proliferation and escape from the immune system. […] Despite its name, in general it is not considered a true sarcoma, which is a tumor arising from mesenchymal tissue. The histogenesis of KS remains controversial. […] KS may arise as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance. KSHV proteins are uniformly detected in KS cancer cells. […] The spindle cells of Kaposi sarcoma differentiate toward endothelial cells, probably of lymph vessel rather than blood vessel origin. The consistent immunoreactivity for podoplanin supports the lymphatic nature of the lesion.

• #53 Kaposi’s Sarcoma Pathogenesis: A Link between Immunology and Tumor Biology – Critical Reviews™ in Oncogenesis, Volume 9, 1998, Issue 2 – Begell House Digital Library

  https://www.dl.begellhouse.com/journals/439f422d0783386a,645806e9180c30e2,367b3b32051f534a.html

  Kaposi’s sarcoma (KS) was a rare disease in Europe and North America until a decade ago, when it became the most common neoplasm complicating the acquired immunodeficiency syndrome (AIDS), where it acquires an aggressive course. […] Clinical and experimental data suggest that, at least in early stage, KS may not be a true sarcoma, but an hyperplastic-proliferative lesion that may regress. […] At least three components characterize KS lesions: (1) neoangiogenesis and proliferation of spindle-shaped cells of endothelial and macrophage cell origin, some of which may originate from a circulating precursor; (2) a cellular infiltrate represented by macrophages, lymphoid cells, mast cells, and neutrophils; and (3) the infection of spindle cells and mononuclear cells with a new virus of the Herpesvirinae family defined KS-associated herpesvirus or human herpesvirus-8 (HHV-8).

• #54 Kaposi’s Sarcoma Pathogenesis: A Link between Immunology and Tumor Biology – Critical Reviews™ in Oncogenesis, Volume 9, 1998, Issue 2 – Begell House Digital Library

  https://www.dl.begellhouse.com/journals/439f422d0783386a,645806e9180c30e2,367b3b32051f534a.html

  KS lesions are highly responsive, in terms of growth, to inflammatory cytokines (IC) and many lesional cell components are able to secrete cytokines and chemokines, which induce paracrine-autocrine mechanisms of growth, angiogenesis, and promote further cellular recruitment. […] The association between HHV-8 and KS is close; however, the role of the virus in KS development is yet unknown. […] Nevertheless, the virus has the potential to encode for homologs of cellular cytokines and some chemokines and its reactivation is sensitive to stimuli provided by IC. […] This review focuses on these aspects of KS pathogenesis, trying to reconcile many of the clinical and experimental observations. […] Finally, the role of the HIV-1 Tat protein as a factor of progression in AIDS-KS as well as the role of cellular and HHV-8 encoded proto-oncogenes as factors and markers of progression of KS to a true malignancy is reviewed.

• #55 Angiosarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/276512-overview

  Angiosarcomas arising at different sites and in different organs have some distinct features. Angiosarcomas may occur in any region of the body but are more frequent in skin and soft tissue. Angiosarcomas also can originate in the liver, breast, spleen, bone, or heart. […] The Angiosarcoma Project performed whole-exome sequencing of 47 tumors and found recurrent mutations of genes including KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, while angiosarcoma of the head, neck, face, and scalp was associated with a high tumor mutation burden and a dominant ultraviolet damage mutational signature, suggesting that ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. […] The etiology of most cases of angiosarcoma is unknown. The tumors may develop as a complication of a preexisting condition.

• #56 Angiosarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/276512-overview

  Angiosarcomas arising at different sites and in different organs have some distinct features. Angiosarcomas may occur in any region of the body but are more frequent in skin and soft tissue. Angiosarcomas also can originate in the liver, breast, spleen, bone, or heart. […] The Angiosarcoma Project performed whole-exome sequencing of 47 tumors and found recurrent mutations of genes including KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, while angiosarcoma of the head, neck, face, and scalp was associated with a high tumor mutation burden and a dominant ultraviolet damage mutational signature, suggesting that ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. […] The etiology of most cases of angiosarcoma is unknown. The tumors may develop as a complication of a preexisting condition.

• #57 Angiosarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/276512-overview

  Angiosarcomas arising at different sites and in different organs have some distinct features. Angiosarcomas may occur in any region of the body but are more frequent in skin and soft tissue. Angiosarcomas also can originate in the liver, breast, spleen, bone, or heart. […] The Angiosarcoma Project performed whole-exome sequencing of 47 tumors and found recurrent mutations of genes including KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, while angiosarcoma of the head, neck, face, and scalp was associated with a high tumor mutation burden and a dominant ultraviolet damage mutational signature, suggesting that ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. […] The etiology of most cases of angiosarcoma is unknown. The tumors may develop as a complication of a preexisting condition.

• #58 Angiosarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/276512-overview

  Chronic lymphedema is the most widely recognized risk factor, especially in angiosarcomas of the skin and soft tissue. […] Radiation-induced angiosarcomas occur in the absence of chronic lymphedema after radiotherapy for carcinoma of the cervix, ovary, endometrium, or breast and Hodgkin lymphoma. […] The Finnish Cancer registry suggests that although an increased risk of angiosarcoma in cancer patients is evident, especially with breast and gynecologic cancer, the excess does not appear to be strongly related to radiotherapy. […] Approximately 3% of primary angiosarcomas are associated with hereditary diseases. […] All angiosarcomas tend to be aggressive and are often multicentric. These tumors have high rates of local recurrence and metastasis because of their intrinsic biologic properties and because they are often misdiagnosed, leading to a poor prognosis and a high mortality rate. […] Angiosarcoma of the viscera (particularly liver and heart) and retroperitoneal disease are especially associated with poor outcome. […] High-grade angiosarcomas exhibit extremely aggressive behavior with rapid local growth and early disseminated metastasis.

• #59 The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

  https://www.mdpi.com/2073-4409/9/4/972

  YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. […] As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. […] The adaptation to microenvironments of different tissue architecture plays a particularly important role in bone cancers which tend to metastasize through the hematogenous route and home primarily to bone and lungs, which are organs of completely different stiffness, extracellular matrix composition and oxygen supply. It is therefore not unexpected that the YAP/TAZ signaling pathway is prominently involved in bone cancer pathogenesis and metastatic spread.

• #60 The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

  https://www.mdpi.com/2073-4409/9/4/972

  YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. […] As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. […] The adaptation to microenvironments of different tissue architecture plays a particularly important role in bone cancers which tend to metastasize through the hematogenous route and home primarily to bone and lungs, which are organs of completely different stiffness, extracellular matrix composition and oxygen supply. It is therefore not unexpected that the YAP/TAZ signaling pathway is prominently involved in bone cancer pathogenesis and metastatic spread.

• #61 The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

  https://www.mdpi.com/2073-4409/9/4/972

  YAP and TAZ are frequently overexpressed in many cancers, and there is a growing interest in YAP and TAZ as potential prognostic factors and therapeutic targets. […] In human bone cancers, YAP and TAZ are variably expressed in the cytoplasm and the nucleus. YAP/TAZ nuclear activation may be assigned to epigenetic silencing or the loss of YAP/TAZ negative regulatory proteins (RASSF family members, NF2, AMOT and MOB1) or to the activation of receptor tyrosine kinases (SRC, FGFR, FAK, etc.) or of chemokine receptor CXCR4 and/or of GPCRs (RHO/RAC). […] These findings identify YAP and TAZ as very promising therapeutic targets in cancer in general and particularly for the treatment of bone cancer.

• #62

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant clinical problem. […] A better understanding of sarcomas pathogenesis may help develop more effective therapies in the future. The Sonic hedgehog (Shh) signaling pathway is involved in both embryonic development and mature tissue repair and carcinogenesis. […] Its increased activity has been demonstrated in many sarcomas, including osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant rhabdoid tumor. […] In vitro studies have demonstrated the effectiveness of inhibitors of the Hedgehog pathway in inhibiting proliferation in those sarcomas in which the components of the pathway are overexpressed.

• #63

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  However, until now, the efficacy of sarcomas treatment with Shh pathway inhibitors has not been established in clinical trials. […] In this review, we present the Shh signaling pathway’s role in the pathogenesis of sarcomas, including both canonical and non-canonical signaling. […] The Hedgehog (Hh) pathway plays an important role in embryogenesis and in the upkeep of mature tissues and stem cells. […] Mutations leading to dysregulation of the Hh pathway are consistently observed in basal cell carcinoma (BCC) and medulloblastoma and sporadically in other cancers. […] Previous studies have shown that both the canonical and non-canonical Hh pathways may be involved in osteosarcoma tumorigenesis. […] Osteosarcoma patients with higher levels of Gli1 are more likely to respond better to chemotherapy.

• #64

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Other evidence suggests a correlation between overexpression of Gli-2 and poor clinical outcomes. […] Data report that Gli2 significantly promotes the proliferation, migration, and invasion of mesenchymal stem cells and osteosarcoma cells. […] The interaction of the Hh pathway with other signaling pathways can also be an essential factor in osteosarcoma progression, including metastasis formation. […] The Notch pathway has also been shown to influence the Hh pathway in the pathogenesis of osteosarcoma. […] The role of the Hh pathway in the pathogenesis of osteosarcoma has also been shown in several studies assessing the preclinical efficacy of the Hh pathway inhibitors. […] The efficacy of saridegib (Smo inhibitor) in the treatment of chondrosarcoma in primary xenografts was also evaluated.

• #65

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Other evidence suggests a correlation between overexpression of Gli-2 and poor clinical outcomes. […] Data report that Gli2 significantly promotes the proliferation, migration, and invasion of mesenchymal stem cells and osteosarcoma cells. […] The interaction of the Hh pathway with other signaling pathways can also be an essential factor in osteosarcoma progression, including metastasis formation. […] The Notch pathway has also been shown to influence the Hh pathway in the pathogenesis of osteosarcoma. […] The role of the Hh pathway in the pathogenesis of osteosarcoma has also been shown in several studies assessing the preclinical efficacy of the Hh pathway inhibitors. […] The efficacy of saridegib (Smo inhibitor) in the treatment of chondrosarcoma in primary xenografts was also evaluated.

• #66 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  Sarcoma is a malignant tumor that originates from mesenchymal tissue. […] Ferroptosis is an iron-dependent nonapoptotic type of regulated programmed cell death that is closely related to the pathophysiological processes underlying tumorigenesis. […] Recent studies have shown that the induction of ferroptosis is an effective way to kill sarcoma cells and reduce their resistance to chemotherapeutic drugs. […] Ferroptosis represents a distinctive type of cell demise induced by erastin, which is a kind of oncogenic RAS-selective lethal small molecule (RSL). […] Ferroptosis has the potential to be a new and highly effective treatment for sarcoma. […] This comprehensive review meticulously delineates the molecular mechanisms that underlie ferroptosis. […] Ferroptosis, a relatively recent discovery in the realm of cell biology, represents a unique form of regulated cell death.

• #67 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  Sarcoma is a malignant tumor that originates from mesenchymal tissue. […] Ferroptosis is an iron-dependent nonapoptotic type of regulated programmed cell death that is closely related to the pathophysiological processes underlying tumorigenesis. […] Recent studies have shown that the induction of ferroptosis is an effective way to kill sarcoma cells and reduce their resistance to chemotherapeutic drugs. […] Ferroptosis represents a distinctive type of cell demise induced by erastin, which is a kind of oncogenic RAS-selective lethal small molecule (RSL). […] Ferroptosis has the potential to be a new and highly effective treatment for sarcoma. […] This comprehensive review meticulously delineates the molecular mechanisms that underlie ferroptosis. […] Ferroptosis, a relatively recent discovery in the realm of cell biology, represents a unique form of regulated cell death.

• #68 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  This tightly regulated cell death mechanism operates at multiple hierarchical levels, spanning epigenetic, transcriptional, posttranscriptional, and posttranslational tiers of control. […] When dysregulation of intracellular iron leads to abnormal accumulation of free iron, excessive amounts of lipid peroxide are produced, triggering ferroptosis. […] Iron-dependent lipoxygenase (LOX) serves as a catalyst in the enzymatic pathway, facilitating the production of lipid peroxides, thereby increasing the sensitivity of cells to ferroptosis. […] The mechanism governing the storage of iron within cells holds significant importance in the context of ferroptosis. […] Hence, the development of ferroptosis can be influenced by interventions at various stages of cellular iron metabolism. […] In conclusion, intracellular iron is involved in the formation of lipid peroxides and free radicals through the Fenton reaction or functions at the active sites of enzymes.

• #69 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  This tightly regulated cell death mechanism operates at multiple hierarchical levels, spanning epigenetic, transcriptional, posttranscriptional, and posttranslational tiers of control. […] When dysregulation of intracellular iron leads to abnormal accumulation of free iron, excessive amounts of lipid peroxide are produced, triggering ferroptosis. […] Iron-dependent lipoxygenase (LOX) serves as a catalyst in the enzymatic pathway, facilitating the production of lipid peroxides, thereby increasing the sensitivity of cells to ferroptosis. […] The mechanism governing the storage of iron within cells holds significant importance in the context of ferroptosis. […] Hence, the development of ferroptosis can be influenced by interventions at various stages of cellular iron metabolism. […] In conclusion, intracellular iron is involved in the formation of lipid peroxides and free radicals through the Fenton reaction or functions at the active sites of enzymes.

• #70 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  Lipid peroxidation constitutes a fundamental process in ferroptosis and represents a potential target for clinical intervention. […] Among the identified ferroptosis-regulating mechanisms, the three primary pathways include the system Xc()-glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, the nicotinamide adenine dinucleotide phosphate (NADPH)-ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathway, and the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway. […] The first regulatory pathway discovered and harnessed for inducing ferroptosis is the system Xc()-GSH-GPX4 pathway. […] The synthesis of GSH plays a critical role in cellular ferroptosis. […] Different from the effects of erastin, RSL3-induced ferroptosis doesn’t significantly alter intracellular GSH levels.

• #71 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. […] This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. […] This review, therefore, focuses on the key molecular mechanisms identified to be associated with sarcomagenesis and their potential as novel targets for sarcoma therapy.

• #72 Clinical activity and exploratory resistance mechanism of milademetan, an MDM2 inhibitor, in intimal sarcoma with MDM2 amplification: an open-label phase 1b/2 study | Twist Bioscience

  https://www.twistbioscience.com/resources/publication/clinical-activity-and-exploratory-resistance-mechanism-milademetan-mdm2

  Clinical activity and exploratory resistance mechanism of milademetan, an MDM2 inhibitor, in intimal sarcoma with MDM2 amplification: an open-label phase 1b/2 study […] Intimal sarcoma is an extremely rare life-threatening malignant neoplasm. […] Murine double minute 2 (MDM2) amplification is observed in 70% of intimal sarcomas. […] Milademetan, an MDM2 inhibitor, may provide a clinical benefit in this patient population. […] These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma.

• #73

  https://link.springer.com/article/10.1007/s00432-023-05441-3

  Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant clinical problem. […] A better understanding of sarcomas pathogenesis may help develop more effective therapies in the future. The Sonic hedgehog (Shh) signaling pathway is involved in both embryonic development and mature tissue repair and carcinogenesis. […] Its increased activity has been demonstrated in many sarcomas, including osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant rhabdoid tumor. […] In vitro studies have demonstrated the effectiveness of inhibitors of the Hedgehog pathway in inhibiting proliferation in those sarcomas in which the components of the pathway are overexpressed.

• #74 Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-02125-z

  HDAC class I genes are strongly expressed in various pediatric sarcomas and other pediatric and adult tumor entities. EwS are very susceptible to HDAC inhibition. […] Genetic analysis of the role of individual HDAC class I genes by CRISPR/Cas9 knockouts showed that both HDAC1 and 2 expression are essential for proliferation, invasiveness and local tumor growth of EwS cells. […] Our results suggest that HDAC1, 2 and partly HDAC3 are important mediators of the EwS-typical expression profile and the malignant stemness phenotype.

• #75 TAZVERIK® (tazemetostat) | Mechanism of Action | HCP

  https://www.tazverik.com/hcp/epithelioid-sarcoma/mechanism-of-action

  Overactive EZH2 causes dysregulated gene expression by inappropriately silencing target genes and locking cells in a proliferative state. This can lead to tumor growth. […] Uniquely designed to target and inhibit EZH2 activity, TAZVERIK can help unlock gene expression to allow target genes to be appropriately expressed.

• #76 Soft Tissue Sarcoma Update, Issue 1, 2017 (Video Program) | Research To Practice

  https://www.researchtopractice.com/index.php?q=STSU117/Video/11

  Mechanism of action, efficacy and tolerability of olaratumab 3:10 minutes. […] This is a monoclonal antibody against PDGFR alpha. And it was tested in a Phase II study that had about 60-something patients on each arm. And patients were randomized to receive either doxorubicin alone or doxorubicin plus olaratumab. And the results were really striking. […] Unlike your typical trial where the progression-free survival benefit is usually strong and then maybe youll see something in overall survival, in this case there was a trend toward an improved response rate and a progression-free survival benefit in the olaratumab arm, but they werent statistically significant. But there was a huge benefit in terms of overall survival. […] So the overall survival in the olaratumab arm was 26 months versus about 14 months in the doxorubicin-alone arm. And this was highly statistically significant. And thats what led to the conditional approval of olaratumab for soft tissue sarcoma in combination with doxorubicin.

• #77 Soft Tissue Sarcoma Update, Issue 1, 2017 (Video Program) | Research To Practice

  https://www.researchtopractice.com/index.php?q=STSU117/Video/11

  Its really confusing, because they actually did a correlative analysis where they looked at PDGFR alpha in the tumors to see if that would predict who responded to olaratumab or not. And they didnt really see an increased benefit in the patients that had strong PDGFR alpha expression, right? That pretty much didnt make a difference. […] Im not really sure how this drug works without causing a progression-free survival benefit but having this big increase in overall survival. Some people think that maybe its changing the biology of the tumor, that its making the tumor less aggressive so that even as you go on to future lines of treatment, the tumor is just not being as aggressive. […] And theres a Phase III trial thats coming that has finished accruing. Were waiting to see what the data is. […] For sure, Im using this in the patient that Im treating off protocol in the up-front setting in the metastatic setting that hasnt received chemotherapy before or hasnt received an anthracycline before. But I think that we want to see what the Phase III trial result is.

• #78 Mechanism-Driven Science Informs Novel Treatments in Soft Tissue Sarcoma

  https://www.targetedonc.com/view/mechanism-driven-science-informs-novel-treatments-in-soft-tissue-sarcoma

  These results also suggest that a longer lead-in time with chemotherapy helps prime the tumor for immunotherapy. […] The immune micro environment is highly variable in STS, with some subtypes having strong immune presence, which offers a promise for immunotherapy in those malignancies, whereas other subtypes are classified as cold tumors. […] Wilky emphasized that we dont really know how to sequence these therapies for STS yet. […] The rarity and the heterogeneity contribute to the challenges faced by experts in the field, a fact that both Wilky and Van Tine highlighted. […] Evidence from preclinical studies suggests that TTI621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as LMS. […] The primary end point was progression-free rate (PFR) at 12 weeks for cohort 1 (uterine and nonuterine LMS), which was 45.9%, with a median PFS of 6.4 months.

• #79 Afami-cel’s Mechanism of Action and Role in Synovial Sarcoma

  https://www.targetedonc.com/view/afami-cel-s-mechanism-of-action-and-role-in-synovial-sarcoma

  Afami-cel is a T-cell receptor therapy. What we do is we harvest the cell to the patient and then we modify the receptor to target a cancer protein called MAGE-A4. Once the T-cell receptor is genetically modified, we can re-infuse the T cells back into the cancer patient. […] In theory, these T cells can now target the tumor because they are attracted to the MAGE-A4 target. […] You have to detect the tumor for MAGE-A4. […] Similarly, we will look at synovial sarcoma as a MAGE-A4-expressing tumor that is amenable to this type of therapy. […] I think MAGE-A4 will be tested almost right off the bat by pathology.

• #80 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  GPX4 emerges as a pivotal factor in the regulation of ferroptosis. […] The role of mitochondria in ferroptosis is significant, with experimental evidence indicating a substantial increase in nonheme iron accumulation and lipid peroxidation specifically within mitochondria. […] The complete process of ferroptosis, including cell lysis, might be necessary for its propagation. […] Ferroptosis can affect the whole TME, not just tumor cells, and it can also serve as a bridge between tumor cells and related immune cells. […] Ferroptosis holds significant promise for overcoming the resistance of sarcoma cells to chemotherapeutic agents, particularly cisplatin. […] The synergistic combination of ferroptosis inducers with conventional chemotherapeutic agents represents a potentially transformative approach in the treatment of sarcoma.

• #81 Mechanism-Driven Science Informs Novel Treatments in Soft Tissue Sarcoma

  https://www.targetedonc.com/view/mechanism-driven-science-informs-novel-treatments-in-soft-tissue-sarcoma

  These results also suggest that a longer lead-in time with chemotherapy helps prime the tumor for immunotherapy. […] The immune micro environment is highly variable in STS, with some subtypes having strong immune presence, which offers a promise for immunotherapy in those malignancies, whereas other subtypes are classified as cold tumors. […] Wilky emphasized that we dont really know how to sequence these therapies for STS yet. […] The rarity and the heterogeneity contribute to the challenges faced by experts in the field, a fact that both Wilky and Van Tine highlighted. […] Evidence from preclinical studies suggests that TTI621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as LMS. […] The primary end point was progression-free rate (PFR) at 12 weeks for cohort 1 (uterine and nonuterine LMS), which was 45.9%, with a median PFS of 6.4 months.

• #82 Mechanism-Driven Science Informs Novel Treatments in Soft Tissue Sarcoma

  https://www.targetedonc.com/view/mechanism-driven-science-informs-novel-treatments-in-soft-tissue-sarcoma

  Data from a number of studies showing impressive efficacy vs historical efficacies in soft tissue sarcomas (STS) caused both Brian A. Van Tine, MD, PhD, and Breelyn A. Wilky, MD, to say, It’s an exciting time to be a sarcoma doctor, in separate interviews with Targeted Therapies in Oncology. […] Van Tine, a professor of medicine and sarcoma program director at Washington University School of Medicine in St Louis, Missouri, explained that the field is moving toward mechanism-driven science, with preclinical exploration of the biology of STS, including immune system biology and genomics, informing clinical trials. Were no longer just throwing darts at a board, he said. […] The hypothesis is that the targeted agents and the chemotherapy can prime the tumors, allowing the ICIs to act afterward, explained Van Tine.

• #83 Molecular mechanisms underpinning sarcomas and implications for current and future therapy | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-021-00647-8

  Sarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. […] This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. […] This review, therefore, focuses on the key molecular mechanisms identified to be associated with sarcomagenesis and their potential as novel targets for sarcoma therapy.

• #84 Mechanism-Driven Science Informs Novel Treatments in Soft Tissue Sarcoma

  https://www.targetedonc.com/view/mechanism-driven-science-informs-novel-treatments-in-soft-tissue-sarcoma

  These results also suggest that a longer lead-in time with chemotherapy helps prime the tumor for immunotherapy. […] The immune micro environment is highly variable in STS, with some subtypes having strong immune presence, which offers a promise for immunotherapy in those malignancies, whereas other subtypes are classified as cold tumors. […] Wilky emphasized that we dont really know how to sequence these therapies for STS yet. […] The rarity and the heterogeneity contribute to the challenges faced by experts in the field, a fact that both Wilky and Van Tine highlighted. […] Evidence from preclinical studies suggests that TTI621 may enhance the response to doxorubicin in macrophage-rich tumors that express CD47, such as LMS. […] The primary end point was progression-free rate (PFR) at 12 weeks for cohort 1 (uterine and nonuterine LMS), which was 45.9%, with a median PFS of 6.4 months.

• #85 Soft Tissue Sarcoma Update, Issue 1, 2017 (Video Program) | Research To Practice

  https://www.researchtopractice.com/index.php?q=STSU117/Video/1

  Because different agents are shown to have different activity in different diseases. […] And so I think the statement in the NCCN Guidelines about sarcoma is important, which is that and these words are carefully chosen the guidance for the treatment of sarcoma should come from a multidisciplinary group with an extensive experience in sarcoma. […] Now theres this cascade where an epithelioid sarcoma is probably the cascade of things you do by line. […] Because this is a large group of diseases where if you see it all the time, you really do treat it a little bit differently than if youre looking it up.

• #86 Tracking Ewing Sarcoma Origin by Developmental and Trans-species Genomics | Alex’s Lemonade Stand Foundation for Childhood Cancer

  https://www.alexslemonade.org/project/tracking-ewing-sarcoma-origin-developmental-and-trans-species-genomics

  We focus on the disruptive effect of the EWS-FLI1 oncogene and link disrupted differentiation to Ewing sarcoma. […] Our long-term objectives are to better understand disease pathogenesis resulting from perturbed cell differentiation, and to develop urgently needed disease models for pre-clinical drug testing. […] We will establish a molecular reference atlas of human mesenchymal stem cell development and use it to chart different aspects of bone sarcoma pathogenesis. […] Eventually our innovative combinatorial approach will identify equivalent cell types across vertebrate species that serve as bone sarcoma precursors in humans and characterize developmental cell states susceptible to sarcomagenesis.

• #87 Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00498-3

  The expression of FRGs has been strongly associated with the development of several types of cancer, including hepatocellular carcinoma, glioma, esophageal adenocarcinoma, and lung adenocarcinoma. […] The first prognostic model for soft tissue sarcoma (STS) based on FRGs was developed by Huang W and colleagues. […] These findings suggest that FRG-encoded proteins can influence tumor prognosis by modulating the immune system, and further support the relationship between ferroptosis and tumor immune system.

• #88 Tracking Ewing Sarcoma Origin by Developmental and Trans-species Genomics | Alex’s Lemonade Stand Foundation for Childhood Cancer

  https://www.alexslemonade.org/project/tracking-ewing-sarcoma-origin-developmental-and-trans-species-genomics

  We focus on the disruptive effect of the EWS-FLI1 oncogene and link disrupted differentiation to Ewing sarcoma. […] Our long-term objectives are to better understand disease pathogenesis resulting from perturbed cell differentiation, and to develop urgently needed disease models for pre-clinical drug testing. […] We will establish a molecular reference atlas of human mesenchymal stem cell development and use it to chart different aspects of bone sarcoma pathogenesis. […] Eventually our innovative combinatorial approach will identify equivalent cell types across vertebrate species that serve as bone sarcoma precursors in humans and characterize developmental cell states susceptible to sarcomagenesis.

• #89 Role of long non-coding RNAs in sarcoma pathogenesis – Eric Sweet-Cordero

  https://grantome.com/grant/NIH/R01-CA211657-01A1

  Role of long non-coding RNAs in sarcoma pathogenesis […] The primary goal of this proposal is to elucidate the molecular function of lncRNAs in Ewing sarcoma. […] This proposal uses both genomic and biochemical approaches to elucidate the role of long non-coding RNAs (lncRNAs) in the pathogenesis of Ewing sarcoma.

• #90 Dissertation or Thesis | Mechanisms of Ewing sarcoma development and therapeutic resistance | ID: ks65hd12b | Carolina Digital Repository

  https://cdr.lib.unc.edu/concern/dissertations/ks65hd12b

  Many large scale consortia have begun to use high-throughput sequencing technologies to identify key mutations and pathways involved in the etiology of cancers. […] Recent evidence implicates the insulin-like growth factor pathway in development of Ewing Sarcoma, a highly malignant bone and soft tissue tumor that primarily affects children and young adults. […] All cases of Ewing sarcoma are characterized by a translocation between EWSR1 and an ETS-family transcription factor where 85% of the cases result in the EWSR1-FLI1 t(11;22)(q24:q12). […] This novel transcription factor is retargeted to a subset of repetitive elements in a cell-type specific manner by a previously unknown mechanism. […] We demonstrate that Ewing sarcoma cells with PTEN loss exhibited increased transformative properties, as well as reciprocal sensitivity to IGF-1R and mTOR inhibition, therapies currently undergoing testing in clinical trials. […] Strikingly, a subset of accessible repetitive elements in stem cells is associated with Ewing Sarcoma development. […] Taken together, these studies expand our knowledge of Ewing sarcoma etiology and provide a potential mechanism for therapy resistance.

• #91 Pathogenesis of Sarcomas

  https://www.omicsonline.org/open-access/pathogenesis-of-sarcomas-DPO-1000e103.php?aid=63313

  Based on genetic alterations, sarcomas can be roughly divided into two major categories; one characterized by complex karyotypes with non-specific chromosomal rearrangements, gains and losses, e.g. myxofibrosarcoma, leiomyosarcoma, and chondrosarcoma and the second characterized by simple karyotypes with specific chromosomal translocation events, e.g. synovial sarcoma, alveolar rhabdomyosarcoma and myxoid liposarcoma, or mutations, e.g. activating KIT mutations in Gastrointestinal Stromal Tumor (GIST). […] A large-scale integrated sequencing, copy number and mRNA expression study of six major soft tissue sarcoma subtypes by Barretina et al. has demonstrated recurrent mutations in a subset of cases within each subtype including some targetable pathways. […] As the next generation sequencing technology has been utilized more frequently in elucidating the mutational landscape of cancer genomes, the same strategy should be applied to a wider range of sarcoma subtypes to facilitate identification of potential therapeutic targets as well as molecular signatures for sarcoma pathogenesis. […] Additional molecular data will also likely translate into new prognostic parameters and therapeutic targets.

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