| 摘要、提要註: |
Breast cancer mortality results from frequent metastasis to specific vital organs (organotropism), a process facilitated by the collaborative effort put forth between neoplastic epithelial and stromal cells within the tumor microenvironment at the primary and metastatic sites. Organotropism requires the degradation of surrounding collagen(s), which is accomplished predominantly by the matrix metalloproteinases (MMPs), and chemotactic abilities, which materializes from chemokine/receptor interactions. Collagenase, MMP-1, and chemokine receptor, CXCR4, represent two of four genes predicative of breast cancer metastasis to bone. Three main studies are described herein. First, we asked whether MMP-1 is necessary for breast cancer metastasis. Second, we investigated the effects of breast cancer-derived MMP-1 on osteolysis. For these studies, MDA-MB-231 breast cancer cells stably expressing shRNAs against MMP-1 or a control sequence were injected intravenously, or into the hind limb, respectively, of immunocompromised mice. While breast cancer-derived MMP-1 was not necessary for metastasis, it mediated invasion through soft tissues and bone via mechanisms involving matrix degradation, angiogenesis, and osteoclast activation. Third, we examined the effects breast cancer cells have on mammary fibroblasts, which are termed carcinoma-associated fibroblasts (CAFs) and have been strongly implicated in cancer development. As tumors have been compared to "wounds that never heal," CAFs have been equated to activated fibroblasts, which are present in inflammatory environments, where they aid in tissue remodeling and repair. MMP-1 and CXCR4, are elevated in activated fibroblasts, where they facilitate angiogenesis and matrix degradation, processes that are also vital to breast cancer metastasis. Thus, we investigated MMP-1 and CXCR4 expression in normal human mammary fibroblasts (HMFs) exposed to breast cancer factors. Interestingly, breast cancer factors stimulated MMP-1 and CXCR4 expression in HMFs, affording them an invasive and migratory phenotype. CAFs obtained from primary breast cancer specimens also displayed elevated MMP-1 and CXCR4 levels compared to counterpart fibroblasts, and were more invasive and migratory, confirming the clinical importance of our findings. Taken together, these data suggest that breast cancer factors initiate the transdifferentiation of HMFs to tumor-promoting CAFs. Collectively, the studies presented herein demonstrate several ways in which breast cancer cells exploit surrounding normal cells to further their own growth. |