Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells

Figure 2

TGF-β-MMPs system and tumor stroma-infiltrating myeloid cells interplay during tumor progression. MMPs produced by resident tumor stroma cells, such as cancer associated fibroblast (CAFs) or pericytes, may activate latent TGF-β, and both can enhance the recruitment of immune cells, leukocytes, and myeloid cells to the tumor stroma. TGF-β, in turn, may regulate myeloid cells phenotype, to promote the protumorigenic M2 phenotype of tumor-associated macrophages (M2-TAMs) and the N2 phenotype of the tumor associated neutrophils (N2-TANs). At the same time, TGF-β regulates mast cells degranulation and stimulates the expression of IL-6. In addition, mast cells produce TGF-β, incrementing the level of the factor in tumor stroma. Meanwhile, TGF-β maintains dendritic cells (DC) in an immature stage, which in turn, can activate regulatory T cells (Tregs) to enhance immunosuppression. Stimulated Tregs in concert with mast cell produce IL-6 and induce the differentiation of Th17 cells which in turn may collaborate in the proinflammatory tumor response. Tumor stroma-infiltrating myeloid cells also produce large amounts of MMPs which can intensify TGF-β activation, and the TGF-β-MMPs-myeloid cells interplay to induce a tumor growth permissive stroma supporting tumor progression, thus strengthening the cancer cells invasion and metastasis.