Microenvironmental Regulation of Tumor Growth & Metastasis

Microenvironmental Regulation of Tumor Growth & Metastasis
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Cells of the innate and adaptive immune systems typically act to eliminate transformed and malignant cells. Rare tumor cells evade immune surveillance mechanisms and establish a micro­environment that stimulates tumor growth. This is primarily mediated by tumor- and stromal cell-derived chemokines, cytokines, and growth factors that suppress the immune system while promoting tumor cell proliferation, angiogenesis, and metastasis. Under these conditions, factors secreted by immune effector cells recruited to the tumor site may contribute to tumor progression.

The Immune System is a Key Determinant in the Regulation of Tumor Rejection & Escape

At the earliest stages of tumorigenesis, natural killer (NK) cells and natural killer T (NKT) cells inhibit tumor cell proliferation and angiogenesis. NK cells promote Perforin/Granzyme-mediated cell death, and along with NKT cells, secrete IFN-gamma, which induces the activation of M1 macrophages. M1 macrophages produce substances such as nitric oxide (NO) and Type I cytokines that are cytotoxic to tumor cells. Polarization of naïve CD4+ T cells toward a Th1 phenotype further promotes tumor rejection as Th1 cells assist in the activation of tumor-specific CD8+ cytotoxic T cells. Over time, tumor cells frequently escape this process of elimination leading to tumor growth. This, in part, may occur as a result of immunosuppression stimulated by tumor or stromal cell-derived cytokines and growth factors. Tumors have been described as "wounds that never heal" due to the continuous recruitment of immune effector cells to the tumor site. Growing evidence suggests that these immune cells may also aid in promoting tumor escape and subsequent proliferation. Tumor progression is associated with polarization toward a Th2 phenotype, blocking the Th1/CD8+ cytotoxic response. It involves the activation of angiogenesis-promoting M2 macrophages, impairment of immature dendritic cell (iDC) function leading to iDC accumulation, and the recruitment of myeloid-derived suppressor cells (MDSCs). MDSCs inhibit cytotoxic NK cells and CD8+ T cells and induce the development of immunosuppressive regulatory T cells (Treg). Mast cells, neutrophils, and eosinophils are also recruited to the tumor site where they secrete proliferative and pro-angiogenic factors. Together these cells create a microenvironment that is favorable for tumor growth, angiogenesis, invasion, and metastasis.

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