Materiały źródłowe

• #1 The pathogenesis of bone metastasis in solid tumors: a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8275949/

  Owing to its frequent occurrence and severe clinical picture, bone metastasis is an important problem in the clinical course of tumor diseases. Bone metastasis develops when the physiological remodeling process is disrupted by tumor cells via the same molecular mechanisms used by native bone cells. […] All known mechanisms taking part in bone metastasis process are related to the disorders of physiological bone remodeling. […] Tumor affects the bone marrow microenvironment via exosomes, soluble factors, and membrane-bound ligands. In this way, an initial lesion is established, which after a variable duration of disseminated tumor cells dormancy progresses to an overt condition. […] An important part of the bone microenvironment are osteocytes, the most abundant bone cells. They attract tumor cells to the bone tissue by secreting CXCL12, an already mentioned chemotactic and adhesion molecule.

• #2 Mechanisms, Diagnosis and Treatment of Bone Metastases

  https://www.mdpi.com/2073-4409/10/11/2944

  Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. […] A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. […] The evolution of solid tumor metastasis is a complex process. Metastatic dissemination of tumor cells involves pre-metastatic niche formation, tumor cell dissemination through the circulation and chemotactic attraction and homing of tumor cells to the metastatic site of a target organ, as well as reciprocal interactions with local stromal cells and immune cells within the new microenvironment.

• #3 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. […] Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. […] This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions. […] Greater than 50% of patients with advanced breast or prostate cancer show bone metastases. […] Importantly, once tumors metastasize to bone, they are virtually incurable and result in significant morbidity prior to a patient’s death. […] Bone metastases can lead to pain, pathological fractures, nerve compression syndromes, and hypercalcemia.

• #4 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. […] In this review, we summarize the current understanding of the mechanism of bone metastases. […] Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases. […] The distant metastasis of cancer cells has long been known to have characteristic preferences. Bone is one of the most common metastatic sites for malignancies, such as breast, prostate, and lung cancer. […] Bone metastases can be categorized into osteolytic metastases with bone resorption, osteoblastic metastases with excessive bone formation, and a mixed phenotype of both.

• #5 Bone Metastasis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507911/

  Bone metastases occur mostly through the hematogenous spread. However local invasion from soft tissue tumors is also possible. Hematogenous spread through the venous system is the predominant process of spinal metastasis. […] A pivotal occurrence in the pathogenesis of bone metastases involves the cellular interaction between the receptors on the tumor cells (e.g., CXCR4, RANKL) and the stromal cells of the bone marrow and bone matrix. These interactions subsequently lead to the release of growth factors, cytokines (IL-6, IL-8), and angiogenic factors (VEGF) leading to tumor growth and osteoclast activation and resultant osteolysis. […] Secondary bony involvement can be largely classified as osteoblastic (prostate cancer) and osteolytic (breast, lung, renal cancers) or mixed (breast cancer).

• #6 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. […] In this review, we summarize the current understanding of the mechanism of bone metastases. […] Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases. […] The distant metastasis of cancer cells has long been known to have characteristic preferences. Bone is one of the most common metastatic sites for malignancies, such as breast, prostate, and lung cancer. […] Bone metastases can be categorized into osteolytic metastases with bone resorption, osteoblastic metastases with excessive bone formation, and a mixed phenotype of both.

• #7 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  The type of metastasis is a reflection of the local interaction between tumor cells and the bone remodeling system. […] As a result of the dynamic nature of bone remodeling and the potential heterogeneity of metastatic lesions, patients can have both osteolytic and osteosclerotic lesions or mixed lesions containing both elements. […] Osteolytic metastasis occurs in solid tumors including breast cancer, prostate cancer, thyroid cancer, lung cancer, and renal cancer. […] Most in vivo studies indicate that osteolysis is caused by osteoclast stimulation, not by the direct effects of cancer cells on bone. […] Osteolytic metastases are associated with increased osteoclast activity and reduced osteoblast activity that is uncoupled from bone resorption. […] It is becoming evident that osteolytic bone metastases are derived from a complex cycle of progressive interactions between tumor cells and the bone microenvironment, which has been called a viscous cycle.

• #8 Mechanisms, Diagnosis and Treatment of Bone Metastases

  https://www.mdpi.com/2073-4409/10/11/2944

  The main compartment affected by bone metastasis is the red bone marrow, found mainly in the central skeleton, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and to a variable extent in the proximal ends of long bones such as the femur and humerus. […] Current views on tissue tropism of metastasis are based upon specific properties of the metastatic niche. The “seed and soil” hypothesis, articulated by Stephen Paget more than 100 years ago, assumes that a particular tumor cell can settle and begin to proliferate only within a compatible microenvironment. […] In fact, increasing evidence suggests that primary tumors can prepare the microenvironment of a target organ to create a supportive, pre-metastatic niche for subsequent tumor cell colonization. […] Specific ligand/receptor interactions with osteoblasts in the bone marrow niche appear to play a major role for the induction of cancer cell dormancy.

• #9 Mechanisms of Bone Metastasis – G D Roodman – Discovery Medicine

  https://www.discoverymedicine.com/G-D-Roodman/2009/06/18/mechanisms-of-bone-metastasis/

  Cancer frequently spreads to bone, a process termed bone metastasis. […] The underlying molecular mechanisms are discussed as to why cancer transfers to bone. […] Multiple factors account for the frequency of bone metastases. Blood flow is high in areas of the bone marrow, accounting in part for the predilection of metastases for those sites. […] This seed and soil hypothesis for the mechanism of bone metastasis was first advanced by Stephen Paget in 1889 and is supported by findings in animal models of bone metastasis. […] The destruction of bone by cancer cells is caused by the tumor cells increasing the numbers of osteoclasts rather than by the tumor cells themselves. […] The tumor cells produce factors that either directly increase the number of osteoclasts in the area around the tumor or increase the amount of RANK ligand expressed by other bone cells.

• #10 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  According to the seed and soil hypothesis, bone metastasis is dependent on the interactions between tumor cells and the bone microenvironment. […] Several deleterious complications, such as ostealgia, fractures, serious hypercalcemia, and nerve compression syndromes, occur in bone metastasis. […] As recent advances in bone metastasis research have revealed various pathways involved in this process, both in the primary tumor site and in the resident bone microenvironment, we herein describe the current understanding of the mechanism for bone metastases. […] Tumor metastasis is a complex process that involves the reciprocal interactions between tumor cells and the bone microenvironment. […] The preferential tumor metastasis to bone is therefore probably attributed to the bone microenvironment, which corresponds to the seed and soil hypothesis described below.

• #11 Mechanisms, Diagnosis and Treatment of Bone Metastases

  https://www.mdpi.com/2073-4409/10/11/2944

  The main compartment affected by bone metastasis is the red bone marrow, found mainly in the central skeleton, such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and to a variable extent in the proximal ends of long bones such as the femur and humerus. […] Current views on tissue tropism of metastasis are based upon specific properties of the metastatic niche. The “seed and soil” hypothesis, articulated by Stephen Paget more than 100 years ago, assumes that a particular tumor cell can settle and begin to proliferate only within a compatible microenvironment. […] In fact, increasing evidence suggests that primary tumors can prepare the microenvironment of a target organ to create a supportive, pre-metastatic niche for subsequent tumor cell colonization. […] Specific ligand/receptor interactions with osteoblasts in the bone marrow niche appear to play a major role for the induction of cancer cell dormancy.

• #12 Molecular Mechanisms of Bone Metastasis | Cancer Genomics & Proteomics

  https://cgp.iiarjournals.org/content/13/1/1

  Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. […] We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. […] Bone metastases can be classified as osteolytic with significant bone destruction, osteoblastic due to excess bone formation or a mixed phenotype can occur. […] Metastasis to the bones is facilitated by the fenestrated structure of the bone marrow sinusoid capillaries, high blood flow in the areas of red marrow and adhesive molecules on tumor cells that bind to the bone marrow stromal cells such as osteoblasts and osteoclasts as well as the bone matrix. […] Disruption of this balance can convert normal niches into metastatic niches.

• #13 Bone Metastasis | Radiology Key

  https://radiologykey.com/bone-metastasis/

  Metastasis to bone is frequently observed in the most relevant types of solid tumors. […] Following primary tumor growth, cancer cells detach from this site and intravasate in adjacent blood vessels for hematogenous spread. After circulation via the blood stream and extravasation, disseminated tumor cells enter the stroma of various organs including bone. […] During the development of metastasis in the skeleton, two processes occur simultaneously or sequentially: tumor cell proliferation and bone destruction. Both processes are influenced by bone marrow stroma and bone cells that interact with tumor cells in a so-called vicious cycle. […] Thereby, metastatic cells stimulate osteoclasts and osteoblasts at the endosteal bone surface to resorb or produce bone matrix, leading to osteoclastic, osteoblastic, or mixed metastases.

• #14 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The bone matrix, BM sinusoid capillaries with a fenestrated structure that provides an abundant blood supply, and the cells in the BM stroma such as osteoblasts and osteoclasts all contribute to the bone microenvironment. […] The premetastatic niche refers to the supportive environment of potential metastatic sites before the arrival of cancer cells, providing a fertile soil to facilitate the invasion, localization, survival, and proliferation of the seeds, namely, metastatic tumor cells. […] The formation of a premetastatic niche relies on a suppressive immune system. […] Primary tumors recruit myeloid cells, which then allow tumor cells to evade immune surveillance, leading to metastasis. […] Compelling preclinical data have indicated that even before tumor cell migration, primary tumors can release soluble molecules into the circulation and prepare the soil for disseminating tumor cells.

• #15 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Prostate cancer is a particularly slow growing cancer, the early stage of the disease is not easy to detect, the some major clinical manifestations include low back pain, urgent and frequent urination, urinary pain, and other urethral symptoms. […] Bone metastasis is a continuous and complex pathological process regulated by tumor cells and bone microenvironment, in which epithelial-mesenchymal transformation, homing and dormancy, reactivation, and proliferation of tumor cells are closely related to its occurrence and development. […] Several cytokines such as Receptor activator of NF-B ligand (RANK-L) is overexpressed in bone microenvironment and prostate cancer. […] A variety of bone-targeting drugs such as bisphosphonates, RANKL inhibitors (denosumab) and radiotherapy drugs (radium-223, strontium-89, samarium-153), tyrosine kinase inhibitors, integrin-targeted drugs, etc. are approved for the prevention and treatment of skeletal related events caused by bone metastasis in prostate cancer patients.

• #16 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Bone metastasis of prostate cancer is completed in four steps, including colonization, dormancy, reactivation, and reconstruction. […] Studies have shown that a variety of cytokines are involved in the process of bone metastasis in prostate cancer. […] The relative balance between osteoblasts and osteoclasts in the bone microenvironment maintains the integrity of bone structure. […] The cytokines synthesized during bone matrix release and bone turnover promote the colonization of prostate cancer cells in the bone. […] Studies have demonstrated that chemokine and receptor interactions play an important role in bone metastasis of prostate cancer. […] The increase of chemokine ligand 12 (C-X-C motif chemokine ligand 12, CXCL12) in bone tissue is associated with tumor metastasis. […] Dormant diffuse tumor cells can often develop into secondary tumors of bone, and dormant cells are often resistant to conventional chemotherapeutic drugs, preventing drug clearance from tumor cells.

• #17 Current progress and mechanisms of bone metastasis in lung cancer: a narrative review – Wu – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/47783/html

  Lung cancer is one of the most common sites of distant metastasis, with bone being the second most common site of lung cancer metastasis. […] Among all lung cancer patients with bone metastasis, most of them are osteolytic metastasis. […] The process of bone metastasis in lung cancer could be roughly segmented into three steps: tumor invasion, tumor cell migration and invasion in bone tissue. […] The common metastasis sites are spine, pelvis, ribs and so on. […] Certain adhesion molecules, for instance, vascular cell adhesion protein-1, play an important role. They promote lung cancer cells joining with the bone cells, beginning to change the bone microenvironment. […] Osteolytic bone metastasis accounts for 70% and most lung cancer bone metastasis can be classified into this category.

• #18 Mechanisms, Diagnosis and Treatment of Bone Metastases

  https://www.mdpi.com/2073-4409/10/11/2944

  Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. […] A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. […] The evolution of solid tumor metastasis is a complex process. Metastatic dissemination of tumor cells involves pre-metastatic niche formation, tumor cell dissemination through the circulation and chemotactic attraction and homing of tumor cells to the metastatic site of a target organ, as well as reciprocal interactions with local stromal cells and immune cells within the new microenvironment.

• #19 Molecular Mechanisms of Bone Metastasis | Cancer Genomics & Proteomics

  https://cgp.iiarjournals.org/content/13/1/1

  The chemokine/chemokine receptor CXCL12/CXCR4 pathway has been shown to be involved in bone metastasis. […] Stromal cells secreting CXCL12 are able to attract CXCR4-overexpressing tumor cells. […] CXCL12/CXCR4 signaling was explored in the context of metastasis of prostate cancer cells to the skeleton. […] The role of CXCL12-induced integrin v3 activation in adhesion of prostate cancer cells to endothelial cells is further supported by inhibition experiments with an v3mAb. […] The involvement of the CXCL12/CXCR4 axis in invasion is supported by induction of MMP9 and decrease in tissue-inhibitor of metalloproteinases 2 (TIMP2) expression in prostate cancer cells by this pathway. […] miRNAs are small RNAs that regulate gene expression and can act as modulators of regulatory networks.

• #20 The pathogenesis of bone metastasis in solid tumors: a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8275949/

  Owing to its frequent occurrence and severe clinical picture, bone metastasis is an important problem in the clinical course of tumor diseases. Bone metastasis develops when the physiological remodeling process is disrupted by tumor cells via the same molecular mechanisms used by native bone cells. […] All known mechanisms taking part in bone metastasis process are related to the disorders of physiological bone remodeling. […] Tumor affects the bone marrow microenvironment via exosomes, soluble factors, and membrane-bound ligands. In this way, an initial lesion is established, which after a variable duration of disseminated tumor cells dormancy progresses to an overt condition. […] An important part of the bone microenvironment are osteocytes, the most abundant bone cells. They attract tumor cells to the bone tissue by secreting CXCL12, an already mentioned chemotactic and adhesion molecule.

• #21 The Molecule Mechanisms of Bone Metastasis in Breast Cancer | OMICS International

  https://www.omicsonline.org/open-access/the-molecule-mechanisms-of-bone-metastasis-in-breast-cancer-joo-1000102.php?aid=64956

  Breast cancer frequently spreads to the skeleton and causes destructive osteolytic bone metastases. […] Once breast cancer cells arrest in bone, bone is a storehouse of a variety of cytokines and growth factors and thus provides an extremely fertile environment for the cells to grow. […] Although the molecular mechanism of bone metastasis of breast cancer is of the highest importance, it has not yet been fully cleared. […] The process of bone metastasis of breast cancer was complex and was interrelated with many cytokines, growth factors and molecular signaling pathways. […] The interaction between the Stromal cell-derived factor-1(SDF1/CXCL12) and its receptor (CXCR4) played important role in the migration and adhesion of tumor cells to the endothelial cells of bone marrow. […] The osteoclasts express high levels of integrin av 3 which play important role in the osteolytic bone metastasis mediated by osteoclasts.

• #22 The pathogenesis of bone metastasis in solid tumors: a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8275949/

  Owing to its frequent occurrence and severe clinical picture, bone metastasis is an important problem in the clinical course of tumor diseases. Bone metastasis develops when the physiological remodeling process is disrupted by tumor cells via the same molecular mechanisms used by native bone cells. […] All known mechanisms taking part in bone metastasis process are related to the disorders of physiological bone remodeling. […] Tumor affects the bone marrow microenvironment via exosomes, soluble factors, and membrane-bound ligands. In this way, an initial lesion is established, which after a variable duration of disseminated tumor cells dormancy progresses to an overt condition. […] An important part of the bone microenvironment are osteocytes, the most abundant bone cells. They attract tumor cells to the bone tissue by secreting CXCL12, an already mentioned chemotactic and adhesion molecule.

• #23 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The bone matrix, BM sinusoid capillaries with a fenestrated structure that provides an abundant blood supply, and the cells in the BM stroma such as osteoblasts and osteoclasts all contribute to the bone microenvironment. […] The premetastatic niche refers to the supportive environment of potential metastatic sites before the arrival of cancer cells, providing a fertile soil to facilitate the invasion, localization, survival, and proliferation of the seeds, namely, metastatic tumor cells. […] The formation of a premetastatic niche relies on a suppressive immune system. […] Primary tumors recruit myeloid cells, which then allow tumor cells to evade immune surveillance, leading to metastasis. […] Compelling preclinical data have indicated that even before tumor cell migration, primary tumors can release soluble molecules into the circulation and prepare the soil for disseminating tumor cells.

• #24 Molecular Mechanisms of Bone Metastasis | Cancer Genomics & Proteomics

  https://cgp.iiarjournals.org/content/13/1/1

  Osteolysis is based on a self-perpetuating signaling system (vicious cycle) that is maintained by mitogenic factors for tumor cells such as transforming growth factor- (TGF-), insulin-like growth factor-1 (IGF-1), fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs) and Ca-ions released from demineralized bone as well as parathyroid hormone-related peptide (PTHrP) derived from tumor cells. […] A bone metastasis suppressive pathway was identified using a breast cancer in vivo system. […] Additionally, lung cancer-derived bone metastases are predominantly osteolytic. […] Osteoblastic bone metastases are preferentially associated with prostate cancer. […] Pre-metastatic niches in the bone marrow can be newly-induced as a result of tumor-secreted factors or they can be adapted from pre-existing physiological niches such as stem cell niches.

• #25 Molecular Mechanisms of Bone Metastasis | Cancer Genomics & Proteomics

  https://cgp.iiarjournals.org/content/13/1/1

  Interaction between activated stromal cells and other cells in the pre-metastatic niche enables survival of tumor cells. […] Genesis of an early bone metastatic niche was investigated in a breast cancer micrometastasis model after injection of tumor cells and stromal cells into the iliac artery of mice. […] In this model, the microenvironment is composed of cells abundantly secreting alkaline phosphatase and collagen-1 with low abundance of osteoclasts. […] Systemic induction of a metastatic niche in bone by the ECM-modifying enzyme LOX secreted by hypoxic ER-negative breast tumor cells was demonstrated. […] The formation of pre-metastatic lesions can act as a platform for circulating tumor cells (CTC) to colonize and form metastases. […] High expression of LOX in primary tumors or systemic delivery of LOX resulted in osteolytic lesion formation that could be inhibited by silencing or inhibition of LOX with small molecules.

• #26 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The best-characterized function of lysyl oxidase (LOX) is extracellular matrix (ECM) remodeling, which by strengthening the crosslinking of collagen and elastin, thereby improving the structural integrity of the ECM. […] LOX can prepare the premetastatic niche by activating bone resorption. […] Bone homeostasis is partly regulated by LOX activity, either directly through an RANKL-independent pathway BM stromal cells such as osteoblasts and osteoclasts or indirectly through RANKL-dependent mechanisms. […] The two major categories of bone metastases are osteolytic and osteoblastic, based on which type of cells exhibit the predominant activities, and the impaired balance between bone formation and resorption is frequently observed in both types of metastasis. […] Despite the excess occurrence of bone resorption and formation, growing evidence has suggested the coexistence of osteolytic and osteoblastic metastases, leading to mixed-type bone metastases.

• #27 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The bone matrix, BM sinusoid capillaries with a fenestrated structure that provides an abundant blood supply, and the cells in the BM stroma such as osteoblasts and osteoclasts all contribute to the bone microenvironment. […] The premetastatic niche refers to the supportive environment of potential metastatic sites before the arrival of cancer cells, providing a fertile soil to facilitate the invasion, localization, survival, and proliferation of the seeds, namely, metastatic tumor cells. […] The formation of a premetastatic niche relies on a suppressive immune system. […] Primary tumors recruit myeloid cells, which then allow tumor cells to evade immune surveillance, leading to metastasis. […] Compelling preclinical data have indicated that even before tumor cell migration, primary tumors can release soluble molecules into the circulation and prepare the soil for disseminating tumor cells.

• #28 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The modulation of immune responses plays a pivotal role in the progression and control of metastatic cancer. […] The activation of myeloid-derived suppressor cells (MDSCs) plays a significant role in the progression of bone metastases. […] The proliferation of tumor cells in the bone microenvironment disrupts the delicate balance of bone remodeling by releasing substances such as interleukins (ILs) and parathyroid hormone-related protein (PTHrP), which prompt osteoblasts to increase the synthesis of receptor activator of NF-κB ligand (RANKL). […] The process of osteoclast precursors developing into active, bone-resorbing osteoclasts is initiated by the binding of RANKL to the receptor RANK on osteoclasts. […] Enhanced osteoclast formation and heightened bone resorption lead to the release of substances from the deteriorating bone matrix that support tumor development, such as transforming growth factor-β (TGF-β).

• #29 The pathogenesis of bone metastasis in solid tumors: a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8275949/

  Tumor cell dormancy refers to the G0/G1 phase of the cell cycle. This quiescent state triggers the development of metastatic disease many years after the primary tumor development. […] Tumor cells exploit the communication pathways between osteoblasts and osteoclasts, which serve as qualitative, quantitative, and temporal regulators of bone remodeling. Bone resorption promoted by tumor cells establishes a positive feedback mechanism (vicious cycle) that results in the spread of bone metastatic disease. […] In breast cancer, bone metastases have been associated with the presence of miR-10a and miR-10b (microRNAs), although their target mRNAs have not been accurately identified. […] An important factor in the development of bone metastases is DKK1, an inhibitor of the Wnt/-catenin signaling pathway. This protein plays a double role in tumor metastasis at different sites: it inhibits breast cancer lung metastasis by modulating the noncanonical Wnt signaling pathways formation and stimulates bone metastasis formation by modulating the canonical Wnt signaling pathways.

• #30

  https://link.springer.com/article/10.1007/s10585-007-9112-8

  Advanced cancers are prone to metastasize. […] Several molecular mechanisms bring about cancer cells to metastasize to bone, and osteotropic cancer cells are believed to acquire bone cell-like properties which improve homing, adhesion, proliferation and survival in the bone microenvironment. […] The acquisition of a bone cell pseudo-phenotype, denominated osteomimicry, is likely to rely on expression of osteoblastic and osteoclastic genes, thus requiring a multigenic programme. […] Several microenvironmental factors improve the ability of cancer cells to develop at skeletal sites, and a reciprocal deleterious stimulation generates a vicious cycle between the tumour cells and the cells residing in the bone environment. […] The impact of the stem cell niche in the development of bone metastases and in the phenomenon of tumour dormancy, that allows tumour cells to remain quiescent for decades before establishing overt lesions, is at present only speculative. […] However, the osteoblast niche, known to maintain the haematopoietic stem cell population in a quiescent status, is likely to be involved in the development of bone metastases and this promising research field is rapidly expanding.

• #31 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  After bone metastasis of prostate cancer, dormant cancer cells congregate around osteoblasts and expresses high levels of tyrosine kinase receptors, which were involved in regulating the expression of transforming growth factor (TGF-) and its receptors. […] RANKL secreted by bone cells could be correlated with the Receptor activator of nuclear factor-B, which is highly expressed in prostate cancer. […] The Wnt / catenin signaling pathway is related to the dormancy of prostate cancer. […] The activated tumor cells can enter the proliferative stage under the stimulation of various factors in the bone microenvironment. […] Bone metastasis in prostate cancer changes the balance between osteoclast absorption and osteoblast formation, and reconstructs the original bone structure and function, which is mainly manifested as osteoblastosis, accelerates the original bone injury at the end of metastasis, and forms the woven bone with random arrangement of collagen fibers.

• #32 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Bone metastasis of prostate cancer is completed in four steps, including colonization, dormancy, reactivation, and reconstruction. […] Studies have shown that a variety of cytokines are involved in the process of bone metastasis in prostate cancer. […] The relative balance between osteoblasts and osteoclasts in the bone microenvironment maintains the integrity of bone structure. […] The cytokines synthesized during bone matrix release and bone turnover promote the colonization of prostate cancer cells in the bone. […] Studies have demonstrated that chemokine and receptor interactions play an important role in bone metastasis of prostate cancer. […] The increase of chemokine ligand 12 (C-X-C motif chemokine ligand 12, CXCL12) in bone tissue is associated with tumor metastasis. […] Dormant diffuse tumor cells can often develop into secondary tumors of bone, and dormant cells are often resistant to conventional chemotherapeutic drugs, preventing drug clearance from tumor cells.

• #33 The pathogenesis of bone metastasis in solid tumors: a review

  https://hrcak.srce.hr/278137

  Owing to its frequent occurrence and severe clinical picture, bone metastasis is an important problem in the clinical course of tumor diseases. Bone metastasis develops when the physiological remodeling process is disrupted by tumor cells via the same molecular mechanisms used by native bone cells. […] The process includes molecular crosstalk between osteocytes and osteoblasts and osteoclasts. Osteolytic bone metastasis, most often seen in breast cancer, is characterized by promoted differentiation and function of osteoclasts and reduced osteoblast function. Tumor cells take advantage of factors released by bone tissue resorption, thus establishing a vicious cycle that promotes the metastatic process. […] In osteoblastic metastasis, most often seen in prostate cancer, osteoblast function and differentiation are promoted, while osteoclast activity is reduced, resulting in net gain of bone tissue. Mechanisms involved in the early stages of bone metastasis and cancer cell dormancy have been understudied, and their exploration may pave the way for potential therapeutic strategies.

• #34 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  The type of metastasis is a reflection of the local interaction between tumor cells and the bone remodeling system. […] As a result of the dynamic nature of bone remodeling and the potential heterogeneity of metastatic lesions, patients can have both osteolytic and osteosclerotic lesions or mixed lesions containing both elements. […] Osteolytic metastasis occurs in solid tumors including breast cancer, prostate cancer, thyroid cancer, lung cancer, and renal cancer. […] Most in vivo studies indicate that osteolysis is caused by osteoclast stimulation, not by the direct effects of cancer cells on bone. […] Osteolytic metastases are associated with increased osteoclast activity and reduced osteoblast activity that is uncoupled from bone resorption. […] It is becoming evident that osteolytic bone metastases are derived from a complex cycle of progressive interactions between tumor cells and the bone microenvironment, which has been called a viscous cycle.

• #35 Progress in the research on the mechanism of bone metastasis in lung cancer (Review)

  https://www.spandidos-publications.com/10.3892/mco.2016.917

  Lung cancer exhibits a strong predilection to develop to bone metastasis, which would bring not only physical torment, including pain, broken bones and spinal compression, but also the mental affliction to the patients, which greatly reduce the quality of life and overall survival of the patients. […] Despite the fact that the medical management of bone metastases in lung cancer has made great progress, the effective curative clinical therapy is limited. Additionally, the mechanism regarding bone metastasis remains poorly understood in the pathogenesis of lung cancer. […] The present review aimed to introduce the functions of various molecules involved in different processes of bone metastasis in lung cancer. […] The osteolytic lesion is predominant in the bone metastasis of lung cancer.

• #36 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  New therapeutics are needed, and a greater understanding of bone tropic tumor cells, especially those properties that lead to their successful growth within the bone microenvironment is one path to devise innovative approaches. […] Osteotropic cancers are a specific example of the more general observation that primary tumors show organ-specific patterns of metastasis. […] The ability of cells to survive, clonally expand, and recruit a blood supply is expected to determine successful metastasis. […] The expression of RANK ligand (RANKL) on the surface of osteoblasts engages the receptor, RANK, on osteoclast precursors, leading to their maturation. […] Bone metastases are generally characterized as osteolytic, leading to bone destruction, or osteosclerotic (osteoblastic), leading to new bone formation.

• #37 Progress in the research on the mechanism of bone metastasis in lung cancer (Review)

  https://www.spandidos-publications.com/10.3892/mco.2016.917

  In the pathophysiology of bone metastasis, multiple evidence has demonstrated that it is the osteoclast that destroys the bone, rather than the tumor cells. […] In this osteolytic lesion, the tumor cells promote osteoclast formation by continuously secreting pro-osteoclastogenic factors, including parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-B (RANK)L and macrophage colony-stimulating factor. […] Therefore, this tumor-osteoclast cooperation forms a vicious cycle in the bone microenvironment, accelerating the bone injury, as well as the pain. […] The most important and critical pathway is the RANK/RANKL axis. […] It has been previously reported that the soluble RANKL and OPG in the serum are elevated in lung cancer patients with bone metastases, indicating that the axis serves a role in the bone metastasis of lung cancer.

• #38 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  One prerequisite for the occurrence of osteolytic bone metastases is osteoclast activation. […] The differentiation of osteoclast precursors is initiated after exposure to the two main regulatory factors, macrophage colony-stimulating factor and RANKL. […] RANKL, produced by osteoblasts, binds to its receptor RANK on the osteoclast precursor surface, which stimulates downstream signaling molecules, including mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K)/Akt, and promotes the maturation of osteoclast precursors into functional osteoclasts. […] RANK is a surface receptor of the tumor necrosis factor (TNF) family. […] This receptor is crucial for the formation, activation, and function of osteoclasts and also regulates calcium metabolism. […] RANKL has been found on both T and B lymphocytes.

• #39 Current progress and mechanisms of bone metastasis in lung cancer: a narrative review – Wu – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/47783/html

  Evidences showed that lung cancer cells cannot directly cause osteolytic by the secretion of proteolytic enzymes to local tissues. […] Instead, the microenvironment between lung cancer cells and bone tissue played an important role by activating osteoclasts. […] As a result, osteoclasts destroy the bone and lead to osteolytic lesion. […] Tumor cells can lead to the imbalance of osteoblasts and osteoclasts, thus interrupting bone reconstruction. […] The RANKL/RANK pathway may be an important link in mediating osteolytic bone destruction in bone metastasis of lung cancer. […] Parathyroid hormone-related protein (PTHrP) is considered to be one of the main regulatory factors in the process of osteolytic bone metastasis in lung cancer. […] The PTHrP secreted by lung cancer cells binds to the PTH/ PTHrP receptor on the surface of osteoblasts, enhancing the expression of RANKL gene on the surface of osteoblasts and decreasing the synthesis of osteoprotegerin.

• #40 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The modulation of immune responses plays a pivotal role in the progression and control of metastatic cancer. […] The activation of myeloid-derived suppressor cells (MDSCs) plays a significant role in the progression of bone metastases. […] The proliferation of tumor cells in the bone microenvironment disrupts the delicate balance of bone remodeling by releasing substances such as interleukins (ILs) and parathyroid hormone-related protein (PTHrP), which prompt osteoblasts to increase the synthesis of receptor activator of NF-κB ligand (RANKL). […] The process of osteoclast precursors developing into active, bone-resorbing osteoclasts is initiated by the binding of RANKL to the receptor RANK on osteoclasts. […] Enhanced osteoclast formation and heightened bone resorption lead to the release of substances from the deteriorating bone matrix that support tumor development, such as transforming growth factor-β (TGF-β).

• #41 Current progress and mechanisms of bone metastasis in lung cancer: a narrative review – Wu – Translational Lung Cancer Research

  https://tlcr.amegroups.org/article/view/47783/html

  Evidences showed that lung cancer cells cannot directly cause osteolytic by the secretion of proteolytic enzymes to local tissues. […] Instead, the microenvironment between lung cancer cells and bone tissue played an important role by activating osteoclasts. […] As a result, osteoclasts destroy the bone and lead to osteolytic lesion. […] Tumor cells can lead to the imbalance of osteoblasts and osteoclasts, thus interrupting bone reconstruction. […] The RANKL/RANK pathway may be an important link in mediating osteolytic bone destruction in bone metastasis of lung cancer. […] Parathyroid hormone-related protein (PTHrP) is considered to be one of the main regulatory factors in the process of osteolytic bone metastasis in lung cancer. […] The PTHrP secreted by lung cancer cells binds to the PTH/ PTHrP receptor on the surface of osteoblasts, enhancing the expression of RANKL gene on the surface of osteoblasts and decreasing the synthesis of osteoprotegerin.

• #42 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  Tumor cells produce chemokine receptors, cell adhesion molecules, and cell surface receptors that enable them to attach to the bone matrix and establish growth in bone. […] A specific type of osteolytic metastasis is cortical metastasis, which is most commonly seen in lung and renal cancer patients and may be particularly relevant for the later stage of disseminated disease. […] Tumor cells produce factors that stimulate osteoclastic bone resorption directly or indirectly. […] PTHrP is one of the major mediators of breast cancer related osteolytic bone metastasis. […] TGF released from the bone microenvironment activates and stimulates cancer cells to produce more PTHrP, which in turn further activates osteoclastic bone resorption. […] Thus, tumor cells, tumor-produced PTHrP, osteoclasts and bone derived TGF form a vicious cycle to promote the development and progression of bone metastasis.

• #43 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The growth of tumor cells within the bone and the process of bone remodeling are considered to be closely related. […] It is not uncommon to see those metastatic cells in the bone result in an imbalance between bone formation and bone resorption. […] On the one hand, tumor cells release various factors that promote osteoclast activity and bone resorption, including the parathyroid hormone-related protein (PTHrP), lysophosphatidic acid (LPA), macrophage-stimulating protein (MSP), prostaglandin E2 (PGE2), interleukin-8 (IL-8), interleukin-11 (IL-11), matrix metalloproteinase-1 (MMP-1), CCN3, platelet-derived lysophosphatidic acid (LPA), and granulocyte–macrophage colony-stimulating factor. […] Activin A, the BMP inhibitor noggin, dickkopf-1 (DKK-1), and sclerostin (SOST-1) are mainly responsible for osteoblast suppression.

• #44 Effect of colony‑stimulating factor in the mechanism of bone metastasis development (Review)

  https://www.spandidos-publications.com/10.3892/or.2024.8824

  Bone metastasis (BM) is a common complication of cancer and contributes to a higher mortality rate in patients with cancer. […] The mechanisms by which osteoclast and osteoblast-mediated BM occur are comprehensively described. […] The occurrence of BM is associated with osteoblasts and osteoclasts (OCs) in the bone microenvironment. BM can be categorized into osteolytic and osteogenic subtypes. […] Tumor cells in osteolytic BM can stimulate OCs and promote their differentiation by secreting cytokines such as TNF, RANKL, prostaglandins, leukemia inhibitory factor and IL-6, 8, 11, 15 and 17. […] OCs-mediated bone matrix degradation releases various cytokines and growth factors that promote tumor cell growth. […] Colony-stimulating factors (CSF) are a group of cytokines responsible for hemopoiesis, blood cell function regulation and maintaining homeostasis and overall immunity.

• #45 Effect of colony‑stimulating factor in the mechanism of bone metastasis development (Review)

  https://www.spandidos-publications.com/10.3892/or.2024.8824

  CSF promotes the bone metastatic potential of tumor cells. CSF increases the metastatic potential of cancer cells by promoting neoangiogenesis and enhancing their invasiveness. […] In addition, tumor cells induce metastasis by forming pre-metastatic niches in the bone, comprising clusters of bone marrow-derived cells, creating a favorable environment for the subsequent invasion and growth of tumor cells. […] M-CSF is essential for OC generation and increased OC activity promotes osteolytic BM. […] M-CSF affects osteoclastogenesis and influences other members of the CSF family on OCs.

• #46 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The growth of tumor cells within the bone and the process of bone remodeling are considered to be closely related. […] It is not uncommon to see those metastatic cells in the bone result in an imbalance between bone formation and bone resorption. […] On the one hand, tumor cells release various factors that promote osteoclast activity and bone resorption, including the parathyroid hormone-related protein (PTHrP), lysophosphatidic acid (LPA), macrophage-stimulating protein (MSP), prostaglandin E2 (PGE2), interleukin-8 (IL-8), interleukin-11 (IL-11), matrix metalloproteinase-1 (MMP-1), CCN3, platelet-derived lysophosphatidic acid (LPA), and granulocyte–macrophage colony-stimulating factor. […] Activin A, the BMP inhibitor noggin, dickkopf-1 (DKK-1), and sclerostin (SOST-1) are mainly responsible for osteoblast suppression.

• #47 The pathogenesis of bone metastasis in solid tumors: a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8275949/

  Tumor cell dormancy refers to the G0/G1 phase of the cell cycle. This quiescent state triggers the development of metastatic disease many years after the primary tumor development. […] Tumor cells exploit the communication pathways between osteoblasts and osteoclasts, which serve as qualitative, quantitative, and temporal regulators of bone remodeling. Bone resorption promoted by tumor cells establishes a positive feedback mechanism (vicious cycle) that results in the spread of bone metastatic disease. […] In breast cancer, bone metastases have been associated with the presence of miR-10a and miR-10b (microRNAs), although their target mRNAs have not been accurately identified. […] An important factor in the development of bone metastases is DKK1, an inhibitor of the Wnt/-catenin signaling pathway. This protein plays a double role in tumor metastasis at different sites: it inhibits breast cancer lung metastasis by modulating the noncanonical Wnt signaling pathways formation and stimulates bone metastasis formation by modulating the canonical Wnt signaling pathways.

• #48 Mechanisms of Bone Metastasis – G D Roodman – Discovery Medicine

  https://www.discoverymedicine.com/G-D-Roodman/2009/06/18/mechanisms-of-bone-metastasis/

  Thus, there is a vicious cycle where bone destruction results in increased tumor growth, which in turn increases bone destruction. […] The mechanisms responsible for the increased bone formation in osteoblastic metastases are only beginning to be uncovered. […] These results suggest that there may also be a vicious cycle occurring with osteoblastic metastasis in which tumors increase osteoblast numbers and bone formation and that process results in the release of growth factors that increase the amount of tumor cells in the bone. […] The underlying mechanisms responsible for both bone destruction and bone forming metastases are just beginning to be identified.

• #49 Molecular mechanism of bone metastasis in breast cancer -ORCA

  https://orca.cardiff.ac.uk/id/eprint/173419/

  Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. […] However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. […] Specifically, we elaborated how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. […] We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.

• #50 Molecular Mechanisms of Bone Metastasis | Cancer Genomics & Proteomics

  https://cgp.iiarjournals.org/content/13/1/1

  Osteolysis is based on a self-perpetuating signaling system (vicious cycle) that is maintained by mitogenic factors for tumor cells such as transforming growth factor- (TGF-), insulin-like growth factor-1 (IGF-1), fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs) and Ca-ions released from demineralized bone as well as parathyroid hormone-related peptide (PTHrP) derived from tumor cells. […] A bone metastasis suppressive pathway was identified using a breast cancer in vivo system. […] Additionally, lung cancer-derived bone metastases are predominantly osteolytic. […] Osteoblastic bone metastases are preferentially associated with prostate cancer. […] Pre-metastatic niches in the bone marrow can be newly-induced as a result of tumor-secreted factors or they can be adapted from pre-existing physiological niches such as stem cell niches.

• #51 The Molecule Mechanisms of Bone Metastasis in Breast Cancer | OMICS International

  https://www.omicsonline.org/open-access/the-molecule-mechanisms-of-bone-metastasis-in-breast-cancer-joo-1000102.php?aid=64956

  The interaction of BSP and the integrin alpha-v-beta3 promotes cell attachment and plays a fundamental role in allowing BSP to engage with endothelial cells, osteoclasts and tumor cells. […] The reciprocal interaction between breast-cancer cells and the bone microenvironment results in a vicious circle that increases both bone destruction and the tumor burden. […] PTHrP acts through a shared receptor with parathyroid hormone (PTH), the PTH/PTHrP receptor. […] In patients with metastatic breast cancer, PTHRP expression levels are increased in bone metastases compared with the primary tumour. […] The osteolytic lesions produced by MDA-MB-231 cells in mouse models is reduced by inhibiting PTHrP with neutralizing antibodies. […] The TGF- in bone could also modulate many other pro-metastatic and osteolytic factors.

• #52 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  Some neoplasia produce bone metastases which are predominantly osteoblastic, most notably prostate cancer and approximately 15-20% breast cancers. […] During osteoblastic bone metastases, the balance between bone resorption and bone formation is tipped in favor of the latter. […] There is an accumulating body of evidence implicating Endothelin-1 (ET-1) as a central mediator of osteoblastic metastasis. […] ET-1 mediates its effects on bone formation through the Endothelin A (ETA) receptor. […] In a xenograft breast cancer model of osteoblastic bone metastasis, treatment with endothelin-1A-receptor antagonist reduced both osteoblastic bone metastases and tumor burden. […] Proteases such as urokinase-type plasminogen receptor (uPA) and Prostate Specific Antigen (PSA) are also implicated in osteoblastic bone metastasis.

• #53 Sclerotic bone metastases | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/sclerotic-bone-metastases?lang=us

  Sclerotic or osteoblastic bone metastases are distant tumor deposits of a primary tumor within bone characterized by new bone deposition or new bone formation. […] Osteoblastic bone metastases are characterized by increased bone formation. However, the exact mechanism that leads to osteoblastic formation is not entirely elucidated. Several tumor-derived growth factors are assumed to increase osteoblast activity while osteoclast activity is restricted.

• #54 Effect of colony‑stimulating factor in the mechanism of bone metastasis development (Review)

  https://www.spandidos-publications.com/10.3892/or.2024.8824

  The present article reviews the CSF family, its relationship to BM, the underlying mechanisms involved and the preclinical applications of CSF. […] The mechanism of osteolytic bone metastasis is that cancer cells can promote the secretion of RANKL and inhibit the secretion of OPG through the secretion of IL-8, IL-6 and PTHrP, among others, so that the activity of osteoclasts is enhanced. […] The mechanism of osteoblastic bone metastasis is as follows: Bone morphogenetic protein (BMP)-2, BMP-6 and PDGF, produced by tumor cells, can promote the secretion of OPG and inhibit the secretion of RANKL while enhancing the activity of osteoblasts. […] CSFs play complex and diverse roles in developing and progressing BM in various types of cancer. […] They affect not only the hematopoietic system but also the skeletal microenvironment and the behavior of tumor cells through various mechanisms.

• #55 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Prostate cancer cells secrete bone morphogenetic protein-4 to promote the transformation of bone marrow endothelial cells into osteoblasts. […] Integrin is regulated by a variety of cytokines and plays a role in modifying the cytoskeleton and increasing the metastatic ability of prostate cancer. […] The exploration of bone-targeting drugs with strong specificity and high targeting based on effective biomarkers in related mechanisms provides a new idea for the treatment of bone metastasis of prostate cancer.

• #56

  https://www.orthobullets.com/pathology/8045/metastatic-disease-of-extremity

  induction of angiogenesis […] via vascular endothelial growth factor (VEGF) expression […] lytic lesions […] osteolytic bone lesions create a „vicious circle” […] tumor cells secrete PTHrP which stimulates the release of RANKL from osteoblasts […] RANKL then binds to the RANK receptor on osteoclast precursor cells […] differentiation to active osteoclasts occurs, which causes bony destruction […] TGF-B, ILGF-1, and calcium are released from resorbed bone, which stimulates tumor cells to release more PTHrP […] the tumor continues to grow through the release of growth factors, proinflammatory cytokines (IL-6 and IL-8), and VEGF […] osteoblastic lesions […] prostate and breast cancer mets […] due to tumor-secreted endothelin-1(ET-1) […] binds to endothelin A receptor (ETAR) on osteoblasts and stimulates osteoblasts […] ET-1 decreases WNT suppressor DKK-1 […] activates WNT pathway, increasing osteoblast activity.

• #57

• #58 Pathogenesis of bone metastasis – Journal of Oncological Sciences

  https://journalofoncology.org/articles/pathogenesis-of-bone-metastasis/doi/j.jons.2015.11.004

  Bone metastases are more frequently seen as a complication of cancer than primary bone tumors. […] For example, it can be seen in as many as 70% of advanced stage breast and prostate cancer cases. […] Metastatic bone disease is generally categorized as osteoblastic, and osteolytic disease. […] However most of the cancer types demonstrate a wide spectrum between these two extremes. […] Paracrine interaction between parathyroid hormoneerelated protein (PTHrP) which increases the rate of bone osteolysis, and transforming growth factor-b (TGF-b) plays a role in osteolytic metastasis. […] Increased local bone PTHrP concentration increases expression of receptor activator of nuclear factor kappa-B ligand (RANKL) with resultant activation of osteoclastogenesis. […] Endothelin e 1 (ET-1), and dickkopf homolog -1 (DKK-1) produced by tumor involve in osteoblastic metastasis. […] DKK-1 is the central regulator of osteoblastic activity, and osteoblastic bone metastasis. […] For the elaboration of treatment strategies against frequently seen complication, that is, bone metastases, targets involving in pathogenesis of these complications should be taken into consideration.

• #59

  https://link.springer.com/article/10.1007/s10585-007-9112-8

  Advanced cancers are prone to metastasize. […] Several molecular mechanisms bring about cancer cells to metastasize to bone, and osteotropic cancer cells are believed to acquire bone cell-like properties which improve homing, adhesion, proliferation and survival in the bone microenvironment. […] The acquisition of a bone cell pseudo-phenotype, denominated osteomimicry, is likely to rely on expression of osteoblastic and osteoclastic genes, thus requiring a multigenic programme. […] Several microenvironmental factors improve the ability of cancer cells to develop at skeletal sites, and a reciprocal deleterious stimulation generates a vicious cycle between the tumour cells and the cells residing in the bone environment. […] The impact of the stem cell niche in the development of bone metastases and in the phenomenon of tumour dormancy, that allows tumour cells to remain quiescent for decades before establishing overt lesions, is at present only speculative. […] However, the osteoblast niche, known to maintain the haematopoietic stem cell population in a quiescent status, is likely to be involved in the development of bone metastases and this promising research field is rapidly expanding.

• #60

  https://journals.lww.com/oncology-times/fulltext/2007/02250/new_targets_in_the_mechanism_of_bone_metastasis.29.aspx

  Osteomimicry may be the reason prostate cancer cells can move to the bone, survive there, and then overcome the dormancy, he said. […] We really know very little about the role of the stem cell in bone metastasis, but we’re beginning to learn. It’s something that’s evolving, and it should be a very interesting mechanism to target with therapy if that pans out.

• #61 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  There is evidence that osteoblastic metastasis also involves considerable osteolysis. […] One theory as to why osteoclastogenesis is important for osteoblastic bone metastasis is that bone resorption by osteoclasts releases a variety of growth factors, which are stored as inactive forms in the bone matrix. […] The unique environment in the bone and the variety of interactions that mediate cancer metastatic growth are just now being identified. […] A more detailed understanding of potential therapeutic targets are expected to be derived from the continued improvement of animal models and in vitro organ cultures, as well as the application of genomic technologies such as microarrays and proteomics to clinical bone metastatic samples.

• #62 Mechanisms of cancer metastasis to the bone | Cell Research

  https://www.nature.com/articles/7290266

  There is evidence that osteoblastic metastasis also involves considerable osteolysis. […] One theory as to why osteoclastogenesis is important for osteoblastic bone metastasis is that bone resorption by osteoclasts releases a variety of growth factors, which are stored as inactive forms in the bone matrix. […] The unique environment in the bone and the variety of interactions that mediate cancer metastatic growth are just now being identified. […] A more detailed understanding of potential therapeutic targets are expected to be derived from the continued improvement of animal models and in vitro organ cultures, as well as the application of genomic technologies such as microarrays and proteomics to clinical bone metastatic samples.

• #63 Mechanisms of Bone Metastasis – G D Roodman – Discovery Medicine

  https://www.discoverymedicine.com/G-D-Roodman/2009/06/18/mechanisms-of-bone-metastasis/

  Thus, there is a vicious cycle where bone destruction results in increased tumor growth, which in turn increases bone destruction. […] The mechanisms responsible for the increased bone formation in osteoblastic metastases are only beginning to be uncovered. […] These results suggest that there may also be a vicious cycle occurring with osteoblastic metastasis in which tumors increase osteoblast numbers and bone formation and that process results in the release of growth factors that increase the amount of tumor cells in the bone. […] The underlying mechanisms responsible for both bone destruction and bone forming metastases are just beginning to be identified.

• #64 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The hypoxic bone microenvironment could promote cancer cell metastasis and growth. […] A key mediator of hypoxic signaling is hypoxia-inducible factor-1 (HIF-1), which initiates the transcription of hypoxia-response-related genes. […] Tumor cells that can survive in the hypoxic bone microenvironment then colonize and thrive in bones, leading to a vicious cycle of bone metastases. […] The expression of these molecules on cancer cells can further enhance cancer cell proliferation and metastasis. […] Metastatic tumor cells in localized bone regions produce lactic acid, resulting in acidosis of the bone microenvironment. […] Tumor acidosis, in turn, increases the secretion of proteins that degrade the ECM and thus facilitate metastases, such as cathepsin B and matrix metallopeptidases (MMPs).

• #65 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The hypoxic bone microenvironment could promote cancer cell metastasis and growth. […] A key mediator of hypoxic signaling is hypoxia-inducible factor-1 (HIF-1), which initiates the transcription of hypoxia-response-related genes. […] Tumor cells that can survive in the hypoxic bone microenvironment then colonize and thrive in bones, leading to a vicious cycle of bone metastases. […] The expression of these molecules on cancer cells can further enhance cancer cell proliferation and metastasis. […] Metastatic tumor cells in localized bone regions produce lactic acid, resulting in acidosis of the bone microenvironment. […] Tumor acidosis, in turn, increases the secretion of proteins that degrade the ECM and thus facilitate metastases, such as cathepsin B and matrix metallopeptidases (MMPs).

• #66 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  The hypoxic bone microenvironment could promote cancer cell metastasis and growth. […] A key mediator of hypoxic signaling is hypoxia-inducible factor-1 (HIF-1), which initiates the transcription of hypoxia-response-related genes. […] Tumor cells that can survive in the hypoxic bone microenvironment then colonize and thrive in bones, leading to a vicious cycle of bone metastases. […] The expression of these molecules on cancer cells can further enhance cancer cell proliferation and metastasis. […] Metastatic tumor cells in localized bone regions produce lactic acid, resulting in acidosis of the bone microenvironment. […] Tumor acidosis, in turn, increases the secretion of proteins that degrade the ECM and thus facilitate metastases, such as cathepsin B and matrix metallopeptidases (MMPs).

• #67 Molecular mechanisms and clinical management of cancer bone metastasis | Bone Research

  https://www.nature.com/articles/s41413-020-00105-1

  Several osteotropic factors, including parathyroid hormone (PTH), vitamin D3, TNF-, Wnt Family Member 5A, and IL-6, can stimulate RANKL expression, thus promoting osteoclastogenesis. […] RANKL also induces the phosphorylation of another transcription factor, microphthalmia transcription factor (MITF), and activates downstream MAPK. […] In a breast cancer model, RANKL exerts its promigratory effect on cancer cells and thus promotes their metastasis to bone. […] The balance between RANKL and OPG activities primarily determines the level of osteoclastogenesis, with a relatively higher OPG level leading to decreased bone resorption. […] The extracellular calcium of cancer cells is recognized through the CaSR or the P2X receptor, which manipulates calcium influx and efflux through ion channels or transporters.

• #68 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The modulation of immune responses plays a pivotal role in the progression and control of metastatic cancer. […] The activation of myeloid-derived suppressor cells (MDSCs) plays a significant role in the progression of bone metastases. […] The proliferation of tumor cells in the bone microenvironment disrupts the delicate balance of bone remodeling by releasing substances such as interleukins (ILs) and parathyroid hormone-related protein (PTHrP), which prompt osteoblasts to increase the synthesis of receptor activator of NF-κB ligand (RANKL). […] The process of osteoclast precursors developing into active, bone-resorbing osteoclasts is initiated by the binding of RANKL to the receptor RANK on osteoclasts. […] Enhanced osteoclast formation and heightened bone resorption lead to the release of substances from the deteriorating bone matrix that support tumor development, such as transforming growth factor-β (TGF-β).

• #69 Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

  https://www.mdpi.com/2227-9059/12/5/1075

  The modulation of immune responses plays a pivotal role in the progression and control of metastatic cancer. […] The activation of myeloid-derived suppressor cells (MDSCs) plays a significant role in the progression of bone metastases. […] The proliferation of tumor cells in the bone microenvironment disrupts the delicate balance of bone remodeling by releasing substances such as interleukins (ILs) and parathyroid hormone-related protein (PTHrP), which prompt osteoblasts to increase the synthesis of receptor activator of NF-κB ligand (RANKL). […] The process of osteoclast precursors developing into active, bone-resorbing osteoclasts is initiated by the binding of RANKL to the receptor RANK on osteoclasts. […] Enhanced osteoclast formation and heightened bone resorption lead to the release of substances from the deteriorating bone matrix that support tumor development, such as transforming growth factor-β (TGF-β).

• #70 Multidimensional analysis to elucidate the possible mechanism of bone metastasis in breast cancer | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11588-6

  Breast cancer (BC) patients tend to suffer from distant metastasis, especially bone metastasis. […] In our study, we identified the molecules involved in BC bone metastasis based on the data from multiple BC cohorts. Then, we comprehensively investigated the effect pattern and underlying biological role of these molecules. We found that in the identified molecules, the EMP1, ACKR3, ITGA10, MMP13, COL11A1, and THY1 were significantly correlated with patient prognosis and mainly expressed in CAFs. […] Results showed that CAFs could activate multiple carcinogenic pathways and most of these pathways play an important role in cancer metastasis. […] Moreover, we found that CAFs could induce the remodeling of the BC microenvironment and promote the malignant behavior of BC cells. […] The result showed that MMP13 could enhance the malignant phenotype of BC cells.

• #71 Multidimensional analysis to elucidate the possible mechanism of bone metastasis in breast cancer | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11588-6

  Our research aims to meticulously unravel these molecular dynamics, providing crucial insights into the biological processes that promote tumor cell resilience and expansion within the bone marrow niche. […] MMP13 is a member of matrix metalloprotease. It is reported that MMP is an interesting gene associated with cancer progression, angiogenesis promotion, metastasis and immune surveillance avoidance. […] MMP13s capability to degrade collagens and other ECM components enables cancer cells to navigate through the physical barriers and intravasate into the circulatory system, propelling metastatic spread. […] Our results indicated that the CAFs might contribute to the bone metastasis process of BC, making it a potential target for clinical applications.

• #72 Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

  https://elifesciences.org/reviewed-preprints/89613

  Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. […] Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells. […] It was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor microRNAs, such as miR-99b-3p. […] Mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. […] Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects.

• #73 Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

  https://elifesciences.org/reviewed-preprints/89613

  This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression. […] We hypothesized that bone tissues release some substance that inhibits tumor growth and sustains tumor dormancy in bone metastasis. […] We demonstrated that osteocytes inhibit NSCLC cell proliferation by releasing sEVs containing tumor suppressor miRNAs, such as miR-99b-3p. […] Both in vitro and in vivo experiments demonstrated that mechanical loading stimulated osteocytes to release more sEVs and miR-99b-3p to delay the progression of bone metastasis of NSCLC. […] Our findings identified MDM2 as a direct target of miR-99b-3p, emphasizing the crucial role of miRNA in bone metastases. […] Taken together, our work elucidated a mechanism for the clinical observation that bone metastasis was inhibited by moderate exercise.

• #74 Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

  https://elifesciences.org/reviewed-preprints/89613

  This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression. […] We hypothesized that bone tissues release some substance that inhibits tumor growth and sustains tumor dormancy in bone metastasis. […] We demonstrated that osteocytes inhibit NSCLC cell proliferation by releasing sEVs containing tumor suppressor miRNAs, such as miR-99b-3p. […] Both in vitro and in vivo experiments demonstrated that mechanical loading stimulated osteocytes to release more sEVs and miR-99b-3p to delay the progression of bone metastasis of NSCLC. […] Our findings identified MDM2 as a direct target of miR-99b-3p, emphasizing the crucial role of miRNA in bone metastases. […] Taken together, our work elucidated a mechanism for the clinical observation that bone metastasis was inhibited by moderate exercise.

• #75 Molecular mechanism of bone metastasis in breast cancer -ORCA

  https://orca.cardiff.ac.uk/id/eprint/173419/

  Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. […] However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. […] Specifically, we elaborated how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. […] We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.

• #76 Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors – UpToDate

  https://www.uptodate.com/contents/osteoclast-inhibitors-for-patients-with-bone-metastases-from-breast-prostate-and-other-solid-tumors

  Osteoclast inhibitors (also referred to as antiresorptive agents, bone modifying agents, or bone targeting agents), such as bisphosphonates and denosumab, significantly reduce the frequency of and delay the time to onset of skeletal-related events (SREs) in patients with bone metastases from a wide variety of cancer types. […] Osteoclast inhibition has become an important component of managing patients with bone metastases to reduce the frequency and delay the onset of SREs and SSEs.

• #77 Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors – UpToDate

  https://www.uptodate.com/contents/osteoclast-inhibitors-for-patients-with-bone-metastases-from-breast-prostate-and-other-solid-tumors

  Osteoclast inhibitors (also referred to as antiresorptive agents, bone modifying agents, or bone targeting agents), such as bisphosphonates and denosumab, significantly reduce the frequency of and delay the time to onset of skeletal-related events (SREs) in patients with bone metastases from a wide variety of cancer types. […] Osteoclast inhibition has become an important component of managing patients with bone metastases to reduce the frequency and delay the onset of SREs and SSEs.

• #78 Bone-modifying agents for bone metastasis in patients with breast cancer

  https://www.kosinmedj.org/journal/view.php?number=1286

  Bone-modifying agents, bisphosphonates and denosumab, significantly reduce the risk of and delay SREs in patients with bone metastases from various cancer types, including breast cancer. […] Bone-modifying agents, bisphosphonate and denosumab, are effective in reducing SREs in breast cancer patients with bone metastasis; however, survival benefit are controversial.

• #79

  https://journals.lww.com/oncology-times/fulltext/2007/02250/new_targets_in_the_mechanism_of_bone_metastasis.29.aspx

  Bone tissue provides a high concentration of specific growth factors embedded in the bone matrix, giving metastatic lesions there an environment unique to bone. […] Traditional therapy hasn’t really cured bone metastasis. […] Therapies targeting these new metastatic tumor factors will not replace traditional therapy as single agents, but will be used in combination with standard anticancer therapies, she predicted in an interview. […] You can target many factors and not get the end result, so to understand what is regulating all of those factors is really the key to identifying what would be a good target. […] RANK ligand may be one of the common regulatory targets because it’s a central regulator of osteoplast formation, but it could also have a role in tumor growth as well, Dr. Guise said.

• #80

  https://journals.lww.com/oncology-times/fulltext/2007/02250/new_targets_in_the_mechanism_of_bone_metastasis.29.aspx

  Another central regulatory mechanism might be transforming growth factor (TGF)-beta, which controls much of the tumor production of osteolytic and osteoblastic factors. […] And hypoxia may also be a central regulatory mechanism because hypoxia occurs in bone metastasis, and that stimulates a host of factors that are similar to those regulated by TGF-beta, Dr. Guise added. […] Although it is not a master switch, some researchers believe its overexpression may be a mechanism by which the primary tumor mediates bone metastases, Dr. Guise said. […] We believe beta 2-microglobulin is a major growth factor whose abnormal function and signaling could lead to prostate cancer metastases and their survival in the bone, Dr. Chung said in an interview after his presentation. […] Cancer cells mimic the bone probably by changing the methylational status of the promoter, which allows them to express a certain gene at a certain time, he explained.

• #81

  https://journals.lww.com/oncology-times/fulltext/2007/02250/new_targets_in_the_mechanism_of_bone_metastasis.29.aspx

  Osteomimicry may be the reason prostate cancer cells can move to the bone, survive there, and then overcome the dormancy, he said. […] We really know very little about the role of the stem cell in bone metastasis, but we’re beginning to learn. It’s something that’s evolving, and it should be a very interesting mechanism to target with therapy if that pans out.

Zobacz więcej