Targeting the tumor stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm.

The lack of targeted therapy for women with triple negative breast cancer demands a "think-outside-the-box" approach in search of novel treatment strategies. Although cancer drug development traditionally focused on targeting the tumor cell cycle, emphasis has recently shifted toward the tumor microenvironment for novel therapeutic and prevention strategies. The tumor microenvironment is a dynamic composite of cells broadly categorized as immune cells and nonimmune cells within a scaffold of extracellular matrix, where tumor cells thrive. Among the various nonimmune cell types, cancer stromal cells have emerged as critical players in promoting tumor proliferation, neovascularization, invasion, and metastasis as well as interacting with immune cells to tilt the equilibrium toward a tolerogenic environment that favors the tumor cells. In view of recent work that demonstrated that the depletion of fibroblast activation protein (FAP) expressing tumor stromal cells resulted in stunted tumor growth and improved response to tumor vaccination, the tumor microenvironment is, therefore, fertile ground for development of novel therapy with the potential of augmenting existing treatment and prevention options. In this review, we will focus on current evidence supporting the role of cancer associated fibroblasts (CAFs), with a special focus on FAP(+) stromal cells, in promoting tumor growth. The role of CAFs in promoting an immunosuppressive environment, which may accelerate tumor progression, will be discussed with the hope that therapeutics developed to target the "generic" tumor microenvironment may be effective for malignancies such as triple negative breast cancer, for which targeted therapy is not available to date, in the future.