Current understanding of the interactions between tumor stromal cells such as tumor-associated fibroblasts (TAFs) and tumor-associated macrophages (TAMs) is incomplete, but fundamentally important for understanding tumor growth. Delineating the mechanisms by which such interactions promote tumor growth may reveal new and effective therapeutic approaches for treating cancer. TAFs specifically express proteins such as Fibroblast Activation Protein-? (FAP), a protease that is typically only expressed during development and repair. Ablation of FAP-expressing TAFs inhibits the growth of cancer cells in mice by increasing the immune response to the tumors. Moreover, increased FAP-expression in the tumor microenvironment enhances tumor growth. Together these results demonstrate the importance of TAFs in modulating tumor growth, likely by FAP-mediated modulation of the microenvironment. Similarly, increased TAM infiltration in cancer is associated with enhanced tumor progression and poor prognosis. In tumors, TAMs polarize toward a tumor-promoting M2 phenotype characterized by secretion of immunosuppressive cytokines (e.g., IL-10) and fibroblast activators (e.g., TGF?). Identifying tumor-specific factors that indue an M2 macrophage phenotype is therefore very important, and our recently published data indicate that class A scavenger receptors (SR-A) adhere macrophages to modified collagen and promote M2 polarization via a mechanism involving cyclooxygenase (COX)-dependent prostaglandin production. Our preliminary data further demonstrate that FAP-modified collagen is a substrate for SR-A-mediated macrophage adhesion. Based on these data, we hypothesize that TAF-mediated modification of the extracellular matrix induces SR-A-mediated macrophage adhesion and polarization of macrophages to an immunosuppressive M2 phenotype, which in turn promotes fibroblast activation and tumor growth. We will test this hypothesis in two specific aims.
The first aim i s to determine if a positive feedback cycle exists in which TAFs modify extracellular matrix and elaborate factors that induce macrophages to polarize toward an M2 phenotype and release fibroblast activators.
The second aim i s to demonstrate that TAF-expressed FAP activity and TAM-expressed SR-A synergize to promote tumor growth. The proposed experiments use both cell culture and animal models, and take advantage of the combined expertise of the investigators in fibroblast and macrophage biology. Successful completion of these studies will provide the foundation for additional research on the use of inhibitors to disrupt the TAF-TAM interaction as a new strategy for converting the tumor microenvironment into one that is unfavorable for tumor growth.
A critical component of cancer growth is the interaction between the cells present in the tumor microenvironment. The interactions between host stromal cells such as tumor-associated fibroblasts and tumor-associated macrophages are understudied, but are important for tumor growth. Delineating the mechanisms by which host stromal cells interact to promote tumor growth may reveal new and effective therapeutic approaches for treating cancer.
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|Mazur, Anna; Holthoff, Emily; Vadali, Shanthi et al. (2016) Cleavage of Type I Collagen by Fibroblast Activation Protein-? Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion. PLoS One 11:e0150287|