Reprogramming of Tumor Microenvironment in Therapy

The tumor microenvironment is a pathological niche in which progression of cancer occurs. The microenvironment is created, among others, by cancer-specific fibroblasts (CAFs), endothelial cells of tumor blood vessels, and immune cells that inhibit the antitumor immune response. The network of blood vessels that arises in tumor is defective and functionally impaired. It leads to the formation of hypoxia regions. Hypoxia induces an inflammatory reaction similar to the one present in damaged tissue. Cancer cells secrete a number of cytokines and chemokines that affect the tumor microenvironment. Inflammatory response signals recruit immune cells, including monocytes. Recruited cells, under the influence of factors secreted by cancer cells, undergo a specific reprogramming. Monocytes differentiate into tumor-associated macrophages (TAMs). TAMs are involved in tumor progression: angiogenesis, immunosuppression, matrix remodeling, invasiveness, and metastasis. TAM phenotype is similar to M2 macrophage phenotype. Repolarization of TAMs from pro-tumor M2 toward antitumor M1 phenotype is one of the aims of the new therapeutic strategies. A combination of antiangiogenic and immunostimulating agents reverts the TAM phenotype. An example is the combination of endoglin (ENG)-based DNA vaccine and interleukin 12 (IL-12). The combination of these factors induces the repolarization of TAM phenotype from M2 (promoting tumor growth) to M1 (inhibiting tumor growth). It stimulates the antitumor immune response; affects the structure of tumor blood vessels, which become more regular (normalization); and, consequently, increases the effectiveness of chemotherapy and inhibits the growth of tumors. New therapeutic strategies, apart from targeting cancer cells, transform the microenvironment, leading to the inhibition of tumor growth.