Abstract
BackgroundMost patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- β. We asked whether hypoxia (via HIF-1α) and TGF-β signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model.Methodology/Principal FindingsWe analyzed interactions between HIF-1α and TGF-β pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-β and hypoxia, with effects on the proximal promoters. We inhibited HIF-1α and TGF-β pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells.Conclusions/SignificanceHypoxia and TGF-β signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1α and TGF-β may improve treatment of bone metastases and increase survival.
Highlights
Breast cancers frequently metastasize to bone, where they disrupt normal bone remodeling to cause bone destruction, pain, pathologic fracture, hypercalcemia, and nerve compression [1]
The bone microenvironment by its unique composition of growth factors housed in the mineralized bone matrix, bone resorbing and bone forming cells, promotes a feed-forward cycle of site-specific metastasis through high concentrations of growth factors, such as transforming growth factor (TGF)-b [2], and local hypoxia [46]
Hypoxia activates signaling through hypoxia-inducible factor (HIF)-1a which, like TGF-b, increases many of the factors that promote the feed-forward metastatic cycle
Summary
Breast cancers frequently metastasize to bone, where they disrupt normal bone remodeling to cause bone destruction, pain, pathologic fracture, hypercalcemia, and nerve compression [1]. Bone is a unique microenvironment in which breast cancer thrives Growth factors, such as transforming growth factorb (TGF- b) are stored in the mineralized bone matrix. Breast cancers that metastasize to bone secrete factors, such as parathyroid hormone-related protein (PTHrP) and interleukin-11 (IL-11), that stimulate osteoclastic bone destruction and the release and activation of growth factors immobilized in the bone matrix. These factors in turn act on tumor cells to promote a feed-forward cycle of tumor growth and bone destruction which contributes to the incurability of bone metastases [2]. We asked whether hypoxia (via HIF-1a) and TGF-b signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model
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