Macrophages and tumor progression: on the way to macrophage-specific therapy

According to the current paradigm proposed by Piter Novell [1], carcinogenesis is a process of clonal evolution in which consequent cycles of clonal selection in the adaptive tissue microenvironment give rise to tumors with a variety of genetic and other molecular changes determining the biological behavior of each individual tumor. Selection of clones with different properties provides heterogeneity of cancer cells within one tumor and thus results in a low effectiveness of chemotherapy.

On the average, only 40–60% of cancer patients respond to chemotherapy, and even in the case of complete regression, there is a high probability of tumor recurrence [2, 3]. Increasing the effectiveness of solid tumor therapy and reducing the possibility of recurrence requires not only the use of optimal individual schemes of therapy for each patient, but also the development of combined approaches aimed at both the destruction of tumor cells and antitumor programming of the microenvironment, where immune cells plays a prominent regulatory role. The key cells of the immune system that determine the relationship between tumor cells and the microenvironment, from early stages of tumor growth, including the regulation of neoangiogenesis, and to terminal stage of dissemination of malignant process, are tumor-associated macrophages (TAM) [4– 6]. Identification of the pathways responsible for the tumor-supporting function of macrophages makes it possible to develop therapeutic approaches combining chemotherapy with the macrophage blocking strategy. Inhibition of macrophage infiltration into tumor, their removal with anti-macrophagal agents, and switching off the function of the macrophage colony-stimulating factor can be the macrophage blocking tools. Approaches of simultaneous alteration of cancer stem cells and TAM to abolish chemoresistance and inhibit tumor progression are promising. Strategies for reprogramming of macrophages to switch off towards the antitumor phenotype are developing.

Thus, an extremely wide range of regulatory and effector activity and high functional plasticity of macrophages promise the development of macrophage-targeted therapeutic agents to modulate relationships between tumor and microenvironment to prevent the tumor progression. 

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