BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation (original) (raw)
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Isolation and characterization of a new cell line from a renal carcinoma bone metastasis
Anticancer research
The use of cell lines isolated from metastases should enable the assessment of peculiar aspects of bone resorbing cytokine expression, as well as angiogenetic activity of renal carcinoma bone metastases. A cell line (CRBM-1990) was isolated from a renal cell carcinoma bone metastasis and compared with the ACHN and Caki-1 established lines. The expression of osteolytic cytokine and angiogenetic growth factors mRNAs, as well as the effect on migration and proliferation of a bovine bone cell line (BBE) were determined. There were no significant differences between the three lines in IL-6, TGF-beta, VEGF-A, VEGF-B, VEGF-C and FGF-2 mRNAs expression. VEGF-D, PIGF, or RANK-L-specific mRNA were not expressed. CRBM-1990-, Caki-1- and ACHN-conditioned media significantly stimulated the migration and proliferation of BBE. CRBM-1990 expressed IL-6-specific mRNA, but not RANK-L, expressed angiogenetic growth factors and induced migration and proliferation of bone endothelial cells at a non-sign...
Anticancer …, 2006
Background: The contribution of angiogenesis to renal carcinoma bone metastases is virtually unknown. Materials and Methods: The effect of a cell line from a renal carcinoma bone metastasis (CRBM) was compared in vitro with the primitive renal adenocarcinoma line ACHN, by evaluating the influence on the ability of bone endothelial cells to activate osteoclasts. Results: The ACHN-conditioned medium produced a significant expression of macrophage-colony-stimulating factor mRNA. The conditioned medium from ACHN, CRBM, or from endothelial cells previously stimulated with the neoplastic cellconditioned media, had no direct effect on osteoclast differentiation from blood precursors (PBMC), such as CRBM and ACHN co-cultured with PBMC. However, PBMC cocultured with endothelial cells previously stimulated with the CRBM-conditioned medium showed significantly higher levels of tartrate-resistant acid phosphatase. Conclusion: It is possible that the bone metastatic line CRBM releases factors that induce endothelial cells to favor osteoclast differentiation. Renal cell carcinoma (RCC) bone metastases are osteolytic and rich in vessels. The process of new capillary formation from pre-existing vessels is essential for tumor growth and metastasis. Endothelial cells, after stimulation with interleukin-1 or tumor necrosis factor • (TNF•), produce bone-resorbing cytokines that may also play a role in bone metastasis. The expression of osteoprotegerin and the receptor activator of nuclear factor κB ligand (RANK-L) mRNAs was demonstrated in human microvascular 3065
The Role of TGF-β in Bone Metastases
Biomolecules, 2021
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabli...
TGF-β in cancer and bone: Implications for treatment of bone metastases
Bone, 2011
Bone metastases are common in patients with advanced breast, prostate and lung cancer. Tumor cells co-opt bone cells to drive a feed-forward cycle which disrupts normal bone remodeling to result in abnormal bone destruction or formation and tumor growth in bone. Transforming growth factor-beta (TGF-β) is a major bone-derived factor, which contributes to this vicious cycle of bone metastasis. TGF-β released from bone matrix during osteoclastic resorption stimulates tumor cells to produce osteolytic factors further increasing bone resorption adjacent to the tumor cells. TGF-β also regulates 1) key components of the metastatic cascade such as epithelial-mesenchymal transition, tumor cell invasion, angiogenesis and immunosuppression as well as 2) normal bone remodeling and coupling of bone resorption and formation. Preclinical models demonstrate that blockade of TGF-β signaling is effective to treat and prevent bone metastases as well as to increase bone mass.
Cancer Science, 2008
Metastatic prostate tumors in the bone microenvironment stimulate bone resorption, resulting in release of growth factors from the bone matrix that play important roles in tumor growth and osteoclast induction. Transforming growth factor β β β β (TGFβ β β β) is one of the most abundantly stored cytokines in bone matrix, regulating diverse biological activities. Here we evaluate its involvement in prostate tumor growth in the bone microenvironment, comparing with tumor growth in the subcutaneous microenvironment as a control. Rat prostate tumors were transplanted onto the cranial bone and into the subcutis of F344 male rats. Tumor cell proliferation, apoptosis, and TGFβ β β β signal transduction were compared between the tumor-bone interface and the tumorsubcutaneous interface. Effects of TGFβ β β β on osteoclast differentiation were also evaluated in vitro. Inhibitory effects of TGFβ β β β receptor 1 antisense oligonucleotide on TGFβ β β β signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo. Osteolytic changes were extensively observed at the tumor-bone interface, where the TGFβ β β β level, TGFβ β β β signal transduction, and tumor cell proliferation were higher than at the tumor-subcutaneous interface. In vitro treatment with receptor activator of nuclear factor-κ κ κ κB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFβ β β β exerted promotive effects on osteoclast induction. Intratumoral injection of TGFβ β β β receptor 1 antisense oligonucleotide significantly reduced TGFβ β β β signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFβ β β β derived from bone matrix promotes cell proliferation of rat prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment. (Cancer Sci 2008; 99: 316-323)
PLoS ONE, 2012
Background: Breast to bone metastases frequently induce a ''vicious cycle'' in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. Given the role of MMP-2 in extracellular matrix degradation and growth factor/cytokine processing, we tested whether osteoblast derived MMP-2 contributed to the vicious cycle of tumor progression in the bone microenvironment. Methodology/Principal Findings: To test our hypothesis, we utilized murine models of the osteolytic tumor-bone microenvironment in immunocompetent wild type and MMP-2 null mice. In longitudinal studies, we found that host MMP-2 significantly contributed to tumor progression in bone by protecting against apoptosis and promoting cancer cell survival (caspase-3; immunohistochemistry). Our data also indicate that host MMP-2 contributes to tumor induced osteolysis (mCT, histomorphometry). Further ex vivo/in vitro experiments with wild type and MMP-2 null osteoclast and osteoblast cultures identified that 1) the absence of MMP-2 did not have a deleterious effect on osteoclast function (cd11B isolation, osteoclast differentiation, transwell migration and dentin resorption assay); and 2) that osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFb, a factor critical for cell-cell communication in the bone (ELISA, immunoblot assay, clonal and soft agar assays). Conclusion/Significance: Collectively, these studies identify a novel ''mini-vicious cycle'' between the osteoblast and metastatic cancer cells that is key for initial tumor survival in the bone microenvironment. In conclusion, the findings of our study suggest that the targeted inhibition of MMP-2 and/or TGFb would be beneficial for the treatment of bone metastases.
Cancer letters, 2018
TGF-β plays a central role in prostate cancer (PCa) bone metastasis, and it is crucial to understand the bone cell-specific role of TGF-β signaling in this process. Thus, we used knockout (KO) mouse models having deletion of the Tgfbr2 gene specifically in osteoblasts (Tgfbr2 KO) or in osteoclasts (Tgfbr2 KO). We found that PCa-induced bone lesion development was promoted in the Tgfbr2 KO mice, but was inhibited in the Tgfbr2 KO mice, relative to their respective control Tgfbr2 littermates. Since metastatic PCa cells attach to osteoblasts when colonized in the bone microenvironment, we focused on the mechanistic studies using the Tgfbr2 KO mouse model. We found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2 KO mice and correlated with increased tumor cell proliferation, angiogenesis, amounts of cancer-associated fibroblasts and osteoclasts. In vitro studies showed that osteoblastogenesis was inhibited, osteoclastogenesis was stimulated, but PC3 viability...
Bone Metastasis from Renal Cell Carcinoma
International Journal of Molecular Sciences, 2016
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The "vicious cycle" hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden.
Molecular Cancer Therapeutics, 2020
Renal cell carcinoma bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFBI), secreted by 786-O renal cell carcinoma, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed threedimensional (3D) hydrogels to coculture bone-derived 786-O (Bo-786) renal cell carcinoma cells with MC3T3-E1 pre-OSBs. Culturing pre-OSBs in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-OSBs were cocultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Furthermore, treatment with bone morphogenetic protein 4, which stimulates OSB differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the coculture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 renal cell carcinoma cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D coculture system is an effective tool for screening osteoanabolic agents for further in vivo studies.
Bone Structural Components Regulating Sites of Tumor Metastasis
Current Osteoporosis Reports, 2011
Tumors such as breast, lung, and prostate frequently metastasize to bone, where they can cause intractable pain and increase the risk of fracture in patients. When tumor cells metastasize to bone, they interact with the microenvironment to promote bone destruction primarily through the secretion of osteolytic factors by the tumor cells and the subsequent release of growth factors from the bone. Our recent data suggest that the differential rigidity of the mineralized bone microenvironment relative to that of soft tissue regulates the expression of osteolytic factors by the tumor cells. The concept that matrix rigidity regulates tumor growth is well established in solid breast tumors, where increased rigidity stimulates tumor cell invasion and metastasis. Our studies have indicated that a transforming growth factor-β (TGF-β) and Rho-associated kinase (ROCK)-dependent mechanism is involved in the response of metastatic tumor cells to the rigid mineralized bone matrix. In this review, we will discuss the interactions between ROCK and TGF-β signaling, as well as potential new therapies that target these pathways.