Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer.
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ABSTRACT:
SUBMITTER: Zhu M
PROVIDER: S-EPMC5595999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-β1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .
| S-EPMC6538320 | biostudies-literature
Project description:Rationale: Bone is the most frequent site for breast cancer metastasis, which accounts for the leading cause of death in advanced breast cancer patients. Serious skeletal-related events (SREs) caused by bone metastasis have a decisive impact on the life expectancy of breast cancer patients, making breast cancer almost incurable. Metastatic breast cancer cell induced pathological osteoclastogenesis is a key driver of bone metastasis and osteolytic bone lesions. We previously reported that gold clusters can prevent inflammation induced osteoclastogenesis and osteolysis in vivo. In this study, we investigated the effects of a BSA-coated gold cluster on metastatic breast cancer-induced osteoclastogenesis in vitro and tumor-induced osteolysis in vivo, and elucidated its possible mechanism. Methods: Breast cancer cell line MDA-MB-231 was used to evaluate the regulatory effects of gold clusters on breast cancer metastasis and tumor induced osteoclastogenesis in vitro. Cell counting kit-8, transwell, wound-healing and colony formation assays were performed to evaluate the effect of gold clusters on proliferation and metastasis of MDA-MB-231 cells. Tartrate-resistant acid phosphatase (TRAP) staining and filamentous-actin rings analysis were used to detect the regulatory effects of gold clusters on MDA-MB-231 cell-conditioned medium (MDA-MB-231 CM) triggered and receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived mononuclear cells (BMMs). A mouse model of breast cancer bone metastasis was used to evaluate the in vivo activity of the gold cluster on the tumor induced osteolysis. Results: The gold clusters suppressed the migration, invasion and colony formation of MDA-MB-231 cells in a dose-dependent manner in vitro. The gold clusters strongly inhibited both MDA-MB-231 CM triggered and RANKL-induced osteoclast formation from BMMs in vitro. Cell studies indicated that the gold clusters suppressed the expression of osteolysis-related factors in MDA-MB-231 cells and inhibited the subsequent activation of NF-?B pathway in BMMs. Treatment with the clusters at a dose of 10 mg Au/kg.bw significantly reduces the breast cancer cell induced osteolysis in vivo. Conclusion: Therefore, the gold clusters may offer new therapeutic agents for preventing breast cancer bone metastasis and secondary osteolysis to improve patient outcomes.
| S-EPMC7086366 | biostudies-literature
Project description:IntroductionAdrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease.MethodsThe role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR.ResultsOverexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity.ConclusionsThe results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo.
| S-EPMC4303191 | biostudies-literature
Project description:Advanced breast cancer has a high incidence of bone metastases. In bone, breast cancer cells induce osteolytic or mixed bone lesions by inducing an imbalance in bone formation and resorption. Activated fibroblast growth factor receptors (FGFRs) are important in regulation of tumor growth and bone remodeling. In this study we used FGFR1 and FGFR2 gene amplifications containing human MFM223 breast cancer cells in an experimental xenograft model of breast cancer bone growth using intratibial inoculation technique. This model mimics bone metastases in breast cancer patients. The effects of an FGFR inhibitor, dovitinib dilactic acid (TKI258) on tumor growth and tumor-induced bone changes were evaluated. Cancer-induced bone lesions were smaller in dovitinib-treated mice as evaluated by X-ray imaging. Peripheral quantitative computed tomography imaging showed higher total and cortical bone mineral content and cortical bone mineral density in dovitinib-treated mice, suggesting better preserved bone mass. CatWalk gait analysis indicated that dovitinib-treated mice experienced less cancer-induced bone pain in the tumor-bearing leg. A trend towards decreased tumor growth and metabolic activity was observed in dovitinib-treated mice quantified by positron emission tomography imaging with 2-[18F]fluoro-2-deoxy-D-glucose at the endpoint. We conclude that dovitinib treatment decreased tumor burden, cancer-induced changes in bone, and bone pain. The results suggest that targeting FGFRs could be beneficial in breast cancer patients with bone metastases.
| S-EPMC6434100 | biostudies-literature
Project description:Hypoxia is a common feature in tumors, driving pathways that promote epithelial-to-mesenchymal transition, invasion, and metastasis. Clinically, high levels of hypoxia-inducible factor (HIF) expression and stabilization at the primary site in many cancer types is associated with poor patient outcomes. Experimental evidence suggests that HIF signaling in the primary tumor promotes their dissemination to the bone, as well as the release of factors such as LOX that act distantly on the bone to stimulate osteolysis and form a pre-metastatic niche. Additionally, the bone itself is a generally hypoxic organ, fueling the activation of HIF signaling in bone resident cells, promoting tumor cell homing to the bone as well as osteoclastogenesis. The hypoxic microenvironment of the bone also stimulates the vicious cycle of tumor-induced bone destruction, further fueling tumor cell growth and osteolysis. Furthermore, hypoxia appears to regulate key tumor dormancy factors. Thus, hypoxia acts both on the tumor cells as well as the metastatic site to promote tumor cell metastasis.
| S-EPMC7429356 | biostudies-literature
Project description:A variety of osteolytic factors have been identified from breast cancer cells leading to osteolysis, but less is known about which factor plays an essential role in the initiation process prior to the overt vicious osteolytic cycle. Here, we present in vitro and in vivo evidences to clarify the role of interleukin-11 (IL-11) as an essential contributor to breast cancer bone metastasis mediated osteolysis. Animal studies showed that bone specific metastatic BoM-1833 cells induce earlier onset of osteolysis and faster tumor growth compared with MCF7 and parental MDA-MB-231 cells in BALB/c-nu/nu nude mice. IL-11 was further screened and identified as the indispensable factor secreted by BoM-1833 cells inducing osteoclastogenesis independently of receptor activator of nuclear factor κB ligand (RANKL). Mechanistic investigation revealed that the JAK1/STAT3 signaling pathway as a downstream effector of IL-11, STAT3 activation further induces the expression of c-Myc, a necessary factor required for osteoclastogenesis. By inhibiting STAT3 phosphorylation, AG-490 was shown effective in reducing osteolysis and tumor growth in the metastatic niche. Overall, our results revealed the essential role and the underlying molecular mechanism of IL-11 in breast cancer bone metastasis mediated osteolysis. STAT3 targeting through AG-490 is a potential therapeutic strategy for mitigating osteolysis and tumor growth of bone metastatic breast cancer.
| S-EPMC6491651 | biostudies-literature
Project description:RAGE is a multifunctional receptor implicated in diverse processes including inflammation and cancer. In this study, we report that RAGE expression is upregulated widely in aggressive triple-negative breast cancer (TNBC) cells, both in primary tumors and in lymph node metastases. In evaluating the functional contributions of RAGE in breast cancer, we found that RAGE-deficient mice displayed a reduced propensity for breast tumor growth. In an established model of lung metastasis, systemic blockade by injection of a RAGE neutralizing antibody inhibited metastasis development. Mechanistic investigations revealed that RAGE bound to the proinflammatory ligand S100A7 and mediated its ability to activate ERK, NF-κB, and cell migration. In an S100A7 transgenic mouse model of breast cancer (mS100a7a15 mice), administration of either RAGE neutralizing antibody or soluble RAGE was sufficient to inhibit tumor progression and metastasis. In this model, we found that RAGE/S100A7 conditioned the tumor microenvironment by driving the recruitment of MMP9-positive tumor-associated macrophages. Overall, our results highlight RAGE as a candidate biomarker for TNBCs, and they reveal a functional role for RAGE/S100A7 signaling in linking inflammation to aggressive breast cancer development.
| S-EPMC4359968 | biostudies-literature
Project description:Although the skeleton is one of the predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells, and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel-blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130-136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy.
| S-EPMC5050050 | biostudies-literature
Project description:Elevated levels of plasmacytoid dendritic cells (pDC) have been reported in breast cancer patients, but the significance remains undefined. Using three immunocompetent mouse models of breast cancer bone metastasis, we identified a key role for pDC in facilitating tumor growth through immunosuppression and aggressive osteolysis. Following infiltration of macrophages upon breast cancer dissemination, there was a steady increase in pDC within the bone, which resulted in a sustained Th2 response along with elevated levels of regulatory T cells and myeloid-derived suppressor cells. Subsequently, pDC and CD4(+) T cells, producing osteolytic cytokines, increased with tumor burden, causing severe bone damage. Microcomputed tomography and histology analyses of bone showed destruction of femur and tibia. The therapeutic significance of this finding was confirmed by depletion of pDC, which resulted in decreased tumor burden and bone loss by activating tumor-specific cytolytic CD8(+) T cells and decreasing suppressor cell populations. Thus, pDC depletion may offer a novel adjuvant strategy to therapeutically influence breast cancer bone metastasis.
| S-EPMC3531993 | biostudies-other
Project description:Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.
| S-EPMC3805834 | biostudies-other