Materiały źródłowe

• #1 The Molecular Pathogenesis of Osteosarcoma: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3087974/

  Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management. […] However, recent developments in molecular biology have provided insight into the molecular pathogenesis of osteosarcoma. Through the identification of tumour pathways and specific mediators of osteosarcoma progression, novel approaches for targeting osteosarcoma are being developed.

• #2 Biology and pathogenesis of human osteosarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6955653/

  Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. […] The origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines.

• #3 Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

  https://www.mdpi.com/2077-0383/10/6/1182

  Osteosarcoma is the most common primary malignant bone tumor in children and young adults. […] The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. […] Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. […] Given the complex heterogeneity of osteosarcoma tumors, we explore the development of novel therapeutics for osteosarcoma that encompass a series of molecular targets. This analysis of pathogenic mechanisms will shed light on promising avenues for future therapeutic research in osteosarcoma. […] The various genetic, epigenetic, and environmental factors that drive mesenchymal stem cells to differentiate into bone precursor cells also play a role in the development of osteosarcoma.

• #4 Osteosarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1256857-overview

  Osteosarcoma is thought to arise from primitive mesenchymal bone-forming cells, and its histologic hallmark is the production of malignant osteoid. Other cell populations may also be present, as these types of cells may also arise from pluripotential mesenchymal cells, but any area of malignant bone in the lesion establishes the diagnosis as osteosarcoma. […] The exact cause of osteosarcoma is unknown. However, a number of risk factors have been identified. Rapid bone growth appears to predispose persons to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt, the high incidence among large-breed dogs (eg, Great Dane, St Bernard, German shepherd), and osteosarcoma’s typical location in the metaphyseal area adjacent to the growth plate (physis) of long bones.

• #5 What Is Osteosarcoma? | Types of Osteosarcoma | American Cancer Society

  https://www.cancer.org/cancer/types/osteosarcoma/about/what-is-osteosarcoma.html

  Osteosarcoma (also called osteogenic sarcoma) is the most common type of cancer that starts in the bones. The cancer cells in these tumors look like early forms of bone cells that normally help make new bone tissue, but the bone tissue in an osteosarcoma is not as strong as that in normal bones. […] Based on how the cancer cells look under the microscope, osteosarcomas can be classified as high grade, intermediate grade, or low grade. The grade of the tumor tells doctors how likely it is that the cancer will grow quickly and spread to other parts of the body. […] These are the fastest growing types of osteosarcoma. When seen with a microscope, they do not look like normal bone, and many of the cancer cells are in the process of dividing into new cells. Most osteosarcomas that occur in children and teens are high grade. […] The grade of the tumor plays a role in determining its stage and the type of treatment used. […] Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology.

• #6 Biology and pathogenesis of human osteosarcoma (Review)

  https://www.spandidos-publications.com/10.3892/ol.2019.11229

  Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines. […] Different studies point to pre-osteoblasts and osteoblasts being the cells which give rise to tumors. […] The occurrence of mutations is not the most common event in this type of tumor. Rather, it is best characterized by deregulation of the expression of tumor suppressor genes such as retinoblastoma (RB1) and TP53, aneuploidy, chromosome structure disruption and uncontrolled cell cycles. This suggests the possibility of a defect in surveillance or DNA repair mechanisms as one of the possible causes of the tumor’s genesis. […] Epigenetic events are also identified as risk factors for OS, since the DNA methylation pattern of specific genes or gene regions and histone modifications may be involved in tumor development.

• #7 Biology and pathogenesis of human osteosarcoma (Review)

  https://www.spandidos-publications.com/10.3892/ol.2019.11229

  Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. […] Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of noncoding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters.

• #8 Biology and pathogenesis of human osteosarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6955653/

  However, the occurrence of mutations is not the most common event in this type of tumor. Rather, it is best characterized by deregulation of the expression of tumor suppressor genes such as retinoblastoma (RB1) and TP53, aneuploidy, chromosome structure disruption and uncontrolled cell cycles. This suggests the possibility of a defect in surveillance or DNA repair mechanisms as one of the possible causes of the tumor’s genesis. […] Epigenetic events are also identified as risk factors for OS, since the DNA methylation pattern of specific genes or gene regions and histone modifications may be involved in tumor development. […] The initiation and progression of cancer, traditionally considered as a genetic disease, is now understood as a complex process involving epigenetic abnormalities along with genetic alterations.

• #9 The Molecular Pathogenesis of Osteosarcoma: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3087974/

  Osteosarcoma has a predilection for developing in rapidly growing bone. A number of studies have established a correlation between the rapid bone growth experienced during puberty and osteosarcoma development. […] The chemical agents linked to osteosarcoma formation include methylcholanthrene and chromium salts, beryllium oxide, zinc beryllium silicate, asbestos, and aniline dyes. […] A recent study of pretherapeutic biopsy specimens has identified amplifications of chromosomes 6p21, 8q24, and 12q14, as well as loss of heterozygosity of 10q21.1, as being among the most common genomic alterations in osteosarcoma. […] The p53 gene is mutated in 50% of all cancers and 22% of osteosarcomas. […] Recently, p53 mutations have been shown to result in impaired DNA repair mechanisms and disrupted antiangiogenesis activity.

• #10 Biology and pathogenesis of human osteosarcoma (Review)

  https://www.spandidos-publications.com/10.3892/ol.2019.11229

  Current knowledge indicates that OS exhibit a wide range of genetic, epigenetic, and molecular changes, including gains, losses, or arrangements of chromosomal regions; inactivation of tumor suppressor genes; and deregulation of cell signaling pathways. […] The TP53 gene plays a critical role in the regulation of both the cell cycle and apoptosis, and its product (the p53 protein) is synthesized in response to stress situations due to tensions such as DNA damage, hypoxia, and oncogene activation. […] It has been demonstrated that p53 not only regulates the genomic stability of MSCs, but also regulates the cell differentiation program including osteogenesis and bone remodeling to prevent the onset of bone tumor. The absence of the p53 function in the regulation of the differentiation of MSCs in osteoblasts due to mutational events or silencing can start the tumor as a result of changes in osteogenesis, bone homeostasis, and bone remodeling.

• #11 Researchers uncover what drives aggressive bone cancer | EMBL

  https://www.embl.org/news/science-technology/researchers-uncover-what-drives-aggressive-bone-cancer/

  This finding explains the unique biology that makes this tumour type so aggressive and the high levels of genomic instability observed in osteosarcoma cancer cells. […] LTA chromothripsis starts when a double-strand break in DNA leads to the loss of a crucial tumour suppressor gene known as TP53, which normally helps prevent cancer initiation. […] The loss of TP53 triggers the DNA to rearrange and amplify incorrectly, causing multiple copies across different chromosomes of genes that drive cancer growth. […] As a result, normal bone cells rapidly transform into aggressive cancer cells. This leads to fast tumour development and progression.

• #12 Breakthrough in Osteosarcoma Research: New Mutation Mechanism Identified, Offering Hope for Targeted Therapies – CheckOrphan

  https://checkorphan.org/news/breakthrough-in-osteosarcoma-research-new-mutation-mechanism-identified-offering-hope-for-targeted-therapies/

  Osteosarcoma is a type of aggressive bone cancer that most commonly affects children and young adults between the ages of 10 and 20, during times of rapid bone growth. […] New research, published in the journal Cell, solves the mystery of what drives the genomic rearrangements causing the aggressive development and evolution of osteosarcoma tumours. […] By analysing the largest collection of whole-genome data from osteosarcoma patients, the researchers identified a new mutation mechanism, called loss-translocation-amplification (LTA) chromothripsis, which is present in approximately 50% of high-grade osteosarcoma cases. […] This finding explains the unique biology that makes this tumour type so aggressive and the high levels of genomic instability observed in osteosarcoma cancer cells.

• #13 The Molecular Pathogenesis of Osteosarcoma: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3087974/

  In addition to p53, the Rb tumour suppressor has also been implicated in the tumorigenesis of osteosarcoma. […] Both germ-line and somatic mutations of Rb confer an increased risk of osteosarcoma. […] Transcription is the process of forming single-stranded messenger RNA (mRNA) sequences from double-stranded DNA. […] The activator protein 1 complex (AP-1) is a regulator of transcription that controls cell proliferation, differentiation, and bone metabolism. […] Osteosarcoma cells produce a range of growth factors that exert autocrine and paracrine effects. Dysregulated expression of growth factors such as transforming growth factor (TGF), insulin-like growth factor (IGF), and connective tissue growth factor (CTGF) leads to the accelerated proliferation of cells. […] Tumour angiogenesis is essential for sustained osteosarcoma growth and metastasis.

• #14 Osteosarcoma and UPS of Bone Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/bone/hp/osteosarcoma-treatment-pdq

  The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection. […] Prognostic considerations for the axial skeleton and extraskeletal sites are as follows: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas. Survival rates for patients with pelvic primary tumors are 20% to 47%. […] The number of structural variants observed for osteosarcoma is high, at more than 200 structural variants per genome. Thus, osteosarcoma has the most chaotic genome among childhood cancers. […] Genomic alterations in TP53, leading to loss of TP53 function, are present in most osteosarcoma cases. A distinctive form of TP53 inactivation occurs through structural variations in the first intron of TP53 that lead to disruption of the TP53 gene.

• #15 Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

  https://www.mdpi.com/1422-0067/22/2/813

  Several chromosomal and genetic syndromes, like Li-Fraumeni or hereditary retinoblastoma, have been linked to OS as well as 6p21, 8q24, and 12q14 chromosome amplifications and loss of heterozygosity of 10q21.1, described as the most common genomic alteration in OS. […] Transcription factors such as the activator protein 1 complex, found to be significantly upregulated in high-grade OS and associated with propensity to metastatic development, may play a future role as potential therapeutic targets. […] OS cells have the capacity to develop and secrete a range of growth factors that exert autocrine and paracrine effects. Abnormal production and expression of these factors can lead to accelerated cell proliferation. […] Another relevant factor in OS molecular pathogenesis is the resistance of OS cells to anoikis. Anoikis consists of a type of apoptosis that specifically takes place when cells lose their attachment to a basement membrane or matrix. It is particularly important in OS given the propensity of this tumor’s clones to detach from the matrix components and metastasize.

• #16 Mutation Mechanism Found That Drives the Aggressive Development and Evolution of Osteosarcoma

  https://www.genengnews.com/topics/cancer/mutation-mechanism-found-that-drives-the-aggressive-development-and-evolution-of-osteosarcoma/

  The researchers also analyzed whole-genome sequencing data from over 5,300 tumors from diverse cancer types. Through this broader analysis, the team identified that complex chromosomal abnormalities in various cancers arise because chromosomes affected by chromothripsis are highly unstable. […] Predicting the prognosis for osteosarcoma patients remains a major unmet need. As part of this study, the team also presented a novel prognostic biomarker for osteosarcoma: loss of heterozygosity (LOH). LOH occurs when one copy of a genomic region is lost. In osteosarcoma, a high degree of LOH across the genome predicts a lower survival probability. […] These discoveries go a long way towards improving our understanding of what drives the progression of this aggressive type of bone cancer and how it may develop in a patient.

• #16 Mutation Mechanism Found That Drives the Aggressive Development and Evolution of Osteosarcoma

  https://www.genengnews.com/topics/cancer/mutation-mechanism-found-that-drives-the-aggressive-development-and-evolution-of-osteosarcoma/

  Scientists identified a new mutation mechanism, called loss-translocation-amplification (LTA) chromothripsis, which is present in approximately 50% of high-grade osteosarcoma cases. […] Researchers published a new study, “Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution,” in Cell that they say solves the mystery of what drives the genomic rearrangements causing the aggressive development and evolution of osteosarcoma tumors. […] These research findings explain the unique biology that makes bone cancer so aggressive and the high levels of genomic instability observed in osteosarcoma cancer cells, noted the team of scientists. […] This study analyzed multiple regions from each osteosarcoma tumor using long-read sequencing. This approach was crucial in identifying the LTA chromothripsis mechanism and discovering that chromosomes rearranged in cancer cells continue to acquire additional abnormalities as cancer progresses, explained the scientists, and that this helps tumors evade treatment.

• #17

  https://journals.lww.com/cmj/fulltext/2023/10200/research_progress_in_the_mechanism_and_treatment.3.aspx

  Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. […] High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. […] The tumor microenvironment plays a key role in the proliferation, invasion, and metastasis of OS, and therapies targeting the tumor microenvironment can have a good effect. Additionally, several studies have also demonstrated an essential role of dysregulation of genetic signaling pathways in the development of OS. […] The typical Wnt signaling pathway is the Wnt/-catenin signaling pathway. Several studies have shown that abnormal activation of Wnt signaling and high expression of -catenin are associated with abnormal histomorphology and abnormal cell proliferation and differentiation in OS, ultimately leading to the development of OS.

• #18 Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

  https://www.mdpi.com/2077-0383/10/6/1182

  Furthermore, the cellular pathways that contribute to the pathogenesis of the tumor are explored, and this information is used to describe the avenues for novel treatment development for osteosarcoma. […] Osteosarcomagenesis was originally classified as occurring only from mesenchymal stem cells, though more recent data suggest that osteosarcomas can form at multiple points in bone development, from both mesenchymal stem cells and osteoblasts, as well as dysregulated osteoclasts. […] It is widely understood that alterations to TP53 and RB1 tumor suppressor genes play a role in osteosarcoma, as in the development of several other cancers. […] Genes that relate to osteoblast development have also been associated with osteosarcomagenesis. […] Aberrant activation of Wnt family members can drive the further progression of osteoblasts into osteosarcoma.

• #19

  https://journals.lww.com/cmj/fulltext/2023/10200/research_progress_in_the_mechanism_and_treatment.3.aspx

  Dysregulated PI3K/AKT pathway was shown to promote the proliferation and metastasis of OS cells. […] Activation of the HH pathway mediated by multiple genes significantly promotes OS invasion and metastasis. […] In particular, activation of the Notch signaling pathway is closely associated with the migration and metastasis of OS. […] Abnormal activation of this pathway is closely related to cell transformation and carcinogenesis. […] The mechanisms of OS development are complex and involve multiple biomolecular and genetic signaling pathways. Therefore, further research is required to clarify the mechanisms to provide precise treatments and improve the prognosis of patients with OS.

• #20

  https://link.springer.com/article/10.1134/S0006297916040027

  This review summarizes data on microRNA (miRNA) genomic organization, biogenesis, and functions in carcinogenesis. […] The roles of key genes and regulatory miRNAs in molecular mechanisms and signaling pathways involved in the development of osteosarcoma, the most aggressive type of bone tumor striking mainly in adolescence and early adulthood, are discussed in detail. […] The most critical pathways in osteosarcoma pathogenesis are the Notch, Wnt, NF-B, p53, PI3K/Akt, and MAPK pathways. […] Several miRNAs (miR-21, -34a, -143, -148a, -195a, -199a-3p, -382) regulate multiple target genes, pathways, and processes essential for osteosarcoma pathogenesis. […] Data on the key genes and regulatory miRNAs involved in metastasis and tumor cell response to drug treatment are presented. […] Possible applications of miRNA in osteosarcoma diagnostics and treatment are discussed.

• #21 Osteosarcoma | Oncohema Key

  https://oncohemakey.com/osteosarcoma-4/

  There is convincing evidence that abnormal TP53 function is one of the central events in osteosarcomagenesis. […] Structural chromosomal alterations, loss of tumor suppressor function, and oncogene amplification have all been described in osteosarcoma. […] Multiple genomic techniques have been applied to the assessment of copy number alterations in osteosarcoma. […] The phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is a central signaling pathway contributing to proliferation and survival in many cancers.

• #22

  https://journals.lww.com/md-journal/fulltext/2024/01190/effect_of_traditional_chinese_medicine_in.23.aspx

  The TGF-/Smad signaling pathway is widely involved in a variety of biological functions, including cell proliferation, differentiation, survival, angiogenesis and immune surveillance, and plays an important role in the growth and metastasis of multiple tumors. […] Numerous studies have shown that propagation and survival of OS cells are also closely related to the TGF-/Smad signaling pathway. […] The NF-B signaling pathway can also induce biological reactions in related factors, such as IL-6, tumor necrosis factor- (TNF-), chemokines, inflammatory mediators nitric oxide (NO), prostaglandin E2, inducible cyclooxygenase-2, adhesion factors, inflammatory enzymes, immune receptors, apoptotic genes, proliferation-regulating genes, signal transduction genes, anti-oxidative stress-related genes, so as to further amplify the inflammatory response.

• #23 Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

  https://www.mdpi.com/2077-0383/10/6/1182

  Interestingly, osteosarcoma tumors tend to express higher amounts of TGFβ1 and TGFβ3, which have been associated with disease progression. […] The elevated expression of Runx2, one of the main drivers of osteoblast formation from osteochondroprogenitor cells through the coordinated activation of osteocalcin, Type I collagen, and ALP, has been shown to drive osteosarcomagenesis. […] Gli1 expression has also been shown to drive osteosarcoma development and has been associated with enhanced tumorigenesis, along with other members of the Shh signaling pathway. […] Several additional pathways may also contribute to the enhanced capacity for migration and invasion and the common incidence of pulmonary metastases in osteosarcoma. […] The signaling components of the bone microenvironment play a critical role in osteosarcoma development.

• #24 Osteosarcoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Osteosarcoma_pathophysiology

  Expression of the TGF-1 is significantly higher in high-grade osteosarcomas. […] Recent studies revealed an association between increased susceptibility and metastasis of osteosarcoma with TGFR1 variants, TGFBR1*6A, and Int7G24A. […] IGF-I and IGF-II are growth factors usually overexpressed by osteosarcomas. […] The ability of osteosarcoma cells to metastasise by such a pathway completely depended on the complex cell-cell and cell-matrix interactions. […] Osteosarcoma invasion of bone relies on interactions between the bone matrix, osteosarcoma cells, osteoblasts, and osteoclasts. […] The PTHrP as an important GF and the IL-11 also act on osteoblasts enhancing the expression of receptor activator of nuclear factor B ligand (RANKL). […] Previous studies have revealed a positive significant correlation between the osteosarcoma development and the rapid bone growth occurs during puberty.

• #25

  https://journals.lww.com/md-journal/fulltext/2024/01190/effect_of_traditional_chinese_medicine_in.23.aspx

  The MAPK pathway is an important central link in multiple signaling pathways, which is mainly involved in regulating cell proliferation, differentiation, apoptosis, cycle arrest, immunity and inflammation. […] The active ingredients in TCM can also cooperate with multiple mechanisms to regulate the occurrence and development of OS.

• #26 Molecular mechanisms and microRNAs in osteosarcoma pathogenesis – SEARCH

  https://primo.qatar-weill.cornell.edu/discovery/fulldisplay/cdi_proquest_miscellaneous_1796684595/974WCMCIQ_INST:VU1

  This review summarizes data on microRNA (miRNA) genomic organization, biogenesis, and functions in carcinogenesis. The roles of key genes and regulatory miRNAs in molecular mechanisms and signaling pathways involved in the development of osteosarcoma, the most aggressive type of bone tumor striking mainly in adolescence and early adulthood, are discussed in detail. The most critical pathways in osteosarcoma pathogenesis are the Notch, Wnt, NF-κB, p53, PI3K/Akt, and MAPK pathways. The balance between cell survival and apoptosis is determined by the Wnt and NF-κB pathways, as well as by the ratio between the activities of the MAPK and PI3K/Akt pathways. Several miRNAs (miR-21, -34a, -143, -148a, -195a, -199a-3p, -382) regulate multiple target genes, pathways, and processes essential for osteosarcoma pathogenesis. Data on the key genes and regulatory miRNAs involved in metastasis and tumor cell response to drug treatment are presented. Possible applications of miRNA in osteosarcoma diagnostics and treatment are discussed.

• #27 Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

  https://www.mdpi.com/1422-0067/22/2/813

  Tumor angiogenesis is essential for sustained OS growth and metastatic development. Vascular endothelial growth factor (VEGF) is a very well characterized pro-angiogenic factor, promoting endothelial cell proliferation, migration, and blood vessel maturation. […] Ultimately, bone invasion relies on interactions between osteoblasts and osteoclasts. Osteoclasts play a main role as bone-resorbing cells, and significant osteolysis exhibited in some OS cases is the direct consequence of the increased osteoclastic activity. […] Several signaling pathways have been associated with tumorigenesis in OS such as the Wnt and Notch pathways. […] OS immunogenicity is closely linked with the intrinsic immunogenic properties of cancer clones, while the activity patterns of different immune cells that are part of the OS microenvironment influence the nature of the elicited immune response.

• #28 The Molecular Pathogenesis of Osteosarcoma: A Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3087974/

  The immature and inefficient nature of the vessels so produced facilitates feedback loops for further vessel formation. […] Osteosarcoma is a highly metastatic tumour, and pulmonary metatases are the most common cause of death. […] Matrix metalloproteinases (MMPs) are principally involved in the breakdown of the extracellular matrix, although roles in tumour angiogenesis have also been established. […] Osteosarcoma invasion of bone relies on interactions between the bone matrix, osteosarcoma cells, osteoblasts, and osteoclasts. […] Osteoclast pathways of differentiation, maturation, and activation have potential as therapeutic targets.

• #29 The Growth and Aggressive Behavior of Human Osteosarcoma Is Regulated by a CaMKII-Controlled Autocrine VEGF Signaling Mechanism | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121568

  We discovered that the levels of VEGF are augmented with increased aggressiveness of human OS cell lines. Furthermore, we show that -CaMKII positively regulates the levels of VEGF mRNA and protein in OS cells. We demonstrate that the inhibition of both -CaMKII and VEGF dramatically decreases the aggressiveness of OS in vitro and in vivo. Taken together, our findings show that -CaMKII-induced VEGF is crucial for the growth and aggressiveness of human OS. Furthermore, the combinatorial use of compounds that inhibit both CaMKII and VEGF might be developed into a novel therapeutic approach for the treatment of this devastating childhood tumor. […] The paracrine effect of tumor-secreted VEGF on its surrounding endothelial cells is well established. Interestingly, evidence continues to emerge suggesting an additional autocrine effect of VEGF on tumor, which may contribute to a more severe tumor pathogenesis. An increasing number of primary tumors have been shown to express functional VEGF receptors and respond directly to increases in extracellular VEGF by increasing free intracellular Ca2+ [Ca2+]i. In order to examine if OS cells are capable of responding to extracellular VEGF, we first examined the levels of VEGFRs in OS cells. Western blot analyses were performed using antibodies directed against VEGFR-1, VEGFR-2 or -Actin. Here we show that VEGFR-1 is highly expressed in all four of the examined human OS cell lines while VEGFR-2 is only expressed in the more aggressive cell lines (MNNG/HOS and 143B), suggesting that aggressive OS cells are potentially more capable of responding to extracellular VEGF.

• #30 Biology and pathogenesis of human osteosarcoma (Review)

  https://www.spandidos-publications.com/10.3892/ol.2019.11229

  The high expression of CircTADA2A was found in both OS tissue and tumor-derived cell lines. The inhibition of circTADA2A expression attenuated tumor cell proliferation, migration and invasion in vitro, as well as tumorigenesis and metastasis in vivo. […] Cytokine is a generic term used to denote a large group of signaling proteins secreted by specific cells in response to stressful conditions which mediate and regulate immunity, inflammation, and hematopoiesis. […] IL-6 is among the possible cytokines involved in OS development, and is a pro-inflammatory cytokine which activates Janus kinase (JAK), promoting the phosphorylation of transcription activator 3 (STAT3), which in turn signals for increased cell proliferation and inhibits apoptosis of the MSCs and of OS-derived cells. […] TGF is linked to the dedifferentiation of MSCs in OS, a dynamic population of cells associated with tumor invasion and radio-and chemoresistance with poor prognosis. […] TNF- is a pro-inflammatory cytokine produced by lymphocytes and macrophages which, although it can induce apoptosis of tumor cells, is associated with progression of several types of tumors, including OS.

• #31 Osteosarcoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Osteosarcoma_pathophysiology

  Environmental factors known as carcinogens for osteosarcoma include: Physical agents, Chemical agents, Biological agents. […] Any type of exposure to previously-mentioned environmental insults causes a significant damages on the somatic DNA. […] It’s been reported that the mutations in both the p53 and Rb genes have been proven to be involved in osteosarcoma pathogenesis. […] Tumour angiogenesis is essential for sustained osteosarcoma growth and metastasis. […] Invasion of the surrounding tissues by osteosarcoma also involves degradation of the extracellular matrix using the Matrix metalloproteinases (MMPs). […] Malignant cells such as osteosarcoma cells are mostly resistant to apoptosis. […] Osteosarcoma cells are resistant to anoikis and proliferate despite deranged cell-cell and cell-matrix attachments.

• #32 Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

  https://www.mdpi.com/2077-0383/10/6/1182

  Dysregulation of RANKL expression and ligand binding by osteoblasts and other cells in the bone microenvironment can limit bone resorption by osteoclasts and allows bone to form unchecked. […] The cytokines secreted by mesenchymal stem cells in the bone microenvironment, including TGFβ and tumor necrosis factor α (TNFα), can inhibit lymphocyte proliferation and block the response of the immune system, allowing the tumor to escape the inflammatory response. […] The transformation of normal functioning bone cells into osteosarcoma has been demonstrated to occur at multiple levels in mesenchymal stem cell differentiation, whereby mesenchymal stem cells can transform directly into osteosarcoma, or can undergo various stages of differentiation into osteoblasts before becoming tumorigenic. […] Numerous factors that are involved in osteoblast differentiation can be overexpressed or dysregulated to drive abnormal bone production and osteosarcomagenesis.

• #33 Biology and pathogenesis of human osteosarcoma

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6955653/

  It is believed that epigenetic mechanisms act individually or together to change the expression of tumor suppressor genes and/or oncogenes, activating or deactivating the transcription of these genes, resulting in the deregulation of cell signaling pathways which, in some way, triggers the tumor initiation and progression process.

• #34 Roles of microRNA-206 in Osteosarcoma Pathogenesis and Progression

  https://journal.waocp.org/article_27853.html

  MicroRNA-206 has proven to be down-regulated in many human malignancies in correlation with tumour progression. […] We found that miR-206 was down-regulated in the osteosarcoma cell line MG63 and primary tumor samples, and decreased miR-206 expression was significantly associated with advanced clinical stage, T classification, metastasis and poor histological differentiation. […] These findings indicate that miR-206 may have a key role in osteosarcoma pathogenesis and development.

• #35 A Review of Osteosarcoma Therapeutics

  https://www.cancertreatmentjournal.com/articles/a-review-of-osteosarcoma-therapeutics.html

  Proto-oncogenes such as c-fos, c-jun, myelocytomatosis proto-oncogene protein (c-myc) have been associated with osteosarcoma. […] Myc overexpression has also been correlated with osteosarcoma pathogenesis and chemotherapeutic resistance. […] Signaling pathways for cell proliferation and anti-apoptotic factors become overactive in several tumor cells including osteosarcoma. […] Several miRNAs have been observed specifically as chemo-resistant and radiation resistant factors in treating osteosarcoma by targeting tumor suppressor genes that allow apoptosis of the cell, inhibit cell proliferation and migration from the tissue. […] Some miRNA sequences are known to increase chemo-resistance of osteosarcoma cell lines.

• #36 Advances on immunotherapy for osteosarcoma | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02105-9

  The TME of osteosarcoma is distinctly suppressive, with immune cells exhibiting complex and diverse functions. […] Understanding the roles and mechanisms of different immune cells within it, and developing corresponding therapeutic strategies targeting specific elements, can help improve the prognosis for patients with osteosarcoma. […] The presence and functional state of M2-type TAMs are closely related to the prognosis and therapeutic responsiveness of osteosarcoma. […] Given the critical role of MDSCs in immune suppression and tumor progression, they have become potential targets for immunotherapy. […] Treg cells not only help tumor cells evade immune surveillance but also participate in promoting tumor angiogenesis. […] The cellular components infiltrating the tumor microenvironment are diverse, and their functions are not singular but also varied.

• #37 Advances on immunotherapy for osteosarcoma | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02105-9

  The TME of osteosarcoma is immunosuppressive, as increased expression of immunosuppressive molecules such as PD-1 and PD-L1 has been detected, especially in metastatic lesions. […] Therefore, combination strategies to improve the immunogenicity of osteosarcoma and then administering immunotherapy may have stronger anti-tumor effects. […] The immunosuppressive TME of osteosarcoma, especially the lung metastatic foci, is infiltrated with a variety of cells that promote immunosuppression and express numerous immunosuppressive molecules, providing opportunities for the application of immunotherapy in osteosarcoma. […] The immune checkpoint blockers treatment only showed a limited therapeutic effect on osteosarcoma. […] CAR-T therapy in osteosarcoma is still in early stages of research.

• #38 T cell exhaustion drives osteosarcoma pathogenesis

  https://atm.amegroups.org/article/view/79957/html

  Osteosarcoma (OS) is a rare cancer with a bimodal age distribution that peaks in children and young adults. It has been shown that the expression of programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells negatively correlates with prognosis of OS patients. […] Recent studies have highlighted the importance of the tumor microenvironment (TME) in OS pathogenesis and progression, especially the role of tumor-infiltrating macrophages, which express an M2-like phenotype. […] OS cells can control the balance between M1 and M2 macrophages, in turn regulating the T cell response within the TME via programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1). […] The expression of both PD-L1 and PD-1 negatively correlates with prognosis in OS patients.

• #39 T cell exhaustion drives osteosarcoma pathogenesis

  https://atm.amegroups.org/article/view/79957/html

  The tumor-infiltrating immune cells in OS are enriched with macrophages and T cells, with disproportionately higher numbers of CD4+ T cells compared with CD8+ T cells. […] Given that the enhanced expression of ICRs can induce T cell exhaustion and prior literature reports high expression of ICRs in OS, we determined the expression of inhibitory receptors on tumor-infiltrating CD8+ T cells in OS. […] CD8+ T cells infiltrating the TME of OS patients showed higher expression of the inhibitory receptors TIM3 and PD-1. […] The tumor-infiltrating effector T cells exhibit increased expression of the ICRs, TIM3, and PD-1, and are functionally exhausted. […] Blockade of TIM3 can restore the alloreactivity of these effector T cells ex vivo, whereas in vivo it inhibits tumor progression and increases infiltration of functionally active effector T cells within the TME.

• #40 Molecular pathogenesis and therapeutic strategies of human osteosarcoma

  http://www.jbr-pub.org.cn/en/article/doi/10.7555/JBR.30.20150075

  Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. […] As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. […] In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

• #41 An overview of resistance to chemotherapy in osteosarcoma and future perspectives

  https://www.oaepublish.com/articles/cdr.2022.18

  Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. […] This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

• #42 Therapeutic Mechanism of Osteosarcoma | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/60792/therapeutic-mechanism-of-osteosarcoma

  Ferroptosis plays a critical role in the treatment of OS, in particular chemotherapy resistance OS cells. Immunogenic cell death (ICD) is considered one of the most promising ways to achieve total tumor cell elimination. […] Both ferroptosis and ICD can be triggered by many anticancer treatment modalities, including optical therapy (PDT, PTT). […] Nanoparticles-based drug delivery systems (NDDSs) are designed to induce ferroptosis and ICD by incorporating photosensitizers (PSs) for photodynamic therapy (PDT), and photothermal conversion agents for photothermal therapy (PTT).

• #43 The Molecular Pathogenesis of Osteosarcoma: A Review – Open Access Library

  https://www.oalib.com/paper/3080985

  Osteosarcoma is the most common primary malignancy of bone. […] As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. […] However, recent developments in molecular biology have provided insight into the molecular pathogenesis of osteosarcoma. […] Through the identification of tumour pathways and specific mediators of osteosarcoma progression, novel approaches for targeting osteosarcoma are being developed. […] This paper will review our current understanding.

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