Abstract
Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review some of these indisputable experimental and clinical evidences of cancer related smouldering inflammation. The most common myeloid infiltrate in solid tumors is composed of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells promote tumor growth by several mechanisms, including their inherent immunosuppressive activity, promotion of neoangiogenesis, mediation of epithelial-mesenchymal transition and alteration of cellular metabolism. The pro-tumoral functions of TAMs and MDSCs are further enhanced by their cross-talk offering a myriad of potential anti-cancer therapeutic targets. We highlight these main pro-tumoral mechanisms of myeloid cells and give a general overview of their phenotypical and functional diversity, offering examples of possible therapeutic targets. Pharmacological targeting of inflammatory cells and molecular mediators may result in therapies improving patient condition and prognosis. Here, we review experimental and clinical findings on cancer-related inflammation with a major focus on creating an inventory of current small molecule-based therapeutic interventions targeting cancer-related inflammatory cells: TAMs and MDSCs.
Highlights
In the first part of our review we summarize the current knowledge of the role of tumor-infiltrating immune cells in tumor pathogenesis
Accumulating evidence supports that tumor or tumor stroma-derived free or microvesicle wrapped soluble mediators (IL-10, indolamine-2,3-deoxigenase, ROS, ArgI, PGE2) and even cell junction proximity with myeloid cells endow tumor-associated macrophages (TAMs) and MDSCSs with immunosuppressive phenotype dampening both innate and adaptive tumor cell clearance [44,62,63]
In an ovarian carcinoma model myeloid-derived suppressor cells (MDSCs) triggered miR-101 expression in cancer cells, subsequently miR-101 silenced corepressor gene C-terminal binding protein-2 (CtBP2) which resulted in increased cancer stemness and dissemination [86]
Summary
In the first part of our review we summarize the current knowledge of the role of tumor-infiltrating immune cells in tumor pathogenesis. While immune surveillance may eliminate malignant cells, preventing tumor formation in the early stage, in late stage cancers, several components of the immune system may promote, rather than suppress tumor growth. In the second part of the review we point out that, intentionally or unintentionally, many anti-tumor drugs target tumor-promoting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We provide an extensive, not exhaustive, list of these small molecule—based therapeutic agents and their targets. Synthesizing these data, rational strategies can be proposed for identifying new tumor therapies that target, eliminate or re-educate, tumor promoting myeloid and lymphoid cells
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