![]() ![]() It has been shown that ECM proteins act as an anchor and promote cellular adhesion, whereas the fibers of the ECM may serve as migration tracks for cancer cells ( 13). Specifically, the ECM at the tumor site provides the structural foundation for the tumor tissue, allowing growth, survival, motility, and differentiation ( 8, 12). ![]() Cancer and stromal cells in the tumor microenvironment (TME) secrete interstitial matrix that support cell proliferation and tumor growth. It stores growth factors and bioactive molecules such as matrix metalloproteinases (MMP), heparan sulfate, fibroblast growth factor, and urokinase plasminogen activator (uPA refs. The ECM is composed of core structural macromolecules such as collagens, elastin, fibronectin, and laminin. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. Consistently, adoptive transfer of CD8 + T cells, but not CD4 + T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8 + T cells expressing LOX. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Metastasis is the main cause of cancer-related mortality.
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