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Cancer progression is reliant on the co-evolution of supporting stroma to sustain tumor growth and facilitate metastasis. Among stromal cells, cancer-associated fibroblasts (CAFs) have emerged as critical players in solid tumors, owing to their abundance and their pleiotropic roles in the tumor microenvironment. One of the most substantial features of CAFs is the deposition of a dense collagenous matrix that serves not only as the tumor's structural foundation but provides critical mechanical and biomechanical cues determining cancer cell fate and behavior, as well as response to therapy. Remarkably, intratumoral fibrosis is associated with poor prognosis in many human tumors and as such, represents an emerging therapeutic opportunity for cancer disease. In this chapter, we discuss the current understanding of fibrosis development in cancer; present the evidence supporting a role for fibroblasts and extracellular matrix in cancer initiation and progression; and highlight some of the available preclinical and clinical data around the therapeutic concept of targeting intratumoral fibrosis for cancer.

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