The Fate of the Tumor in the Hands of Microenvironment: Role of TAMs and mTOR Pathway

Abstract

Since 2000, written with elegance and accuracy, Hanahan and Weinberg have proposed six major hallmarks of cancer and, together, they provide great advances to the understanding of tumoral biology. Our knowledge about tumor behavior has improved and the investigators have now recognized that inflammatory microenvironment may be a new feature for the tumor entities. Macrophages are considered as an important component of tumoral microenvironment. Biologically, two forms of activated macrophages can be observed: classically activated macrophages (M1) and alternative activated macrophages (M2). Despite the canonical pathways that control this puzzle of macrophages polarization, recently, mTOR signaling pathway has been implicated as an important piece in determining the metabolic and functional differentiation of M1 and M2 profiles. Currently, it is believed that macrophages related to tumoral microenvironment present an “M2-like” feature promoting an immunosuppressive microenvironment enhancing tumoral angiogenesis, growth, and metastasis. In the present review we discuss the role of macrophages in the tumor microenvironment and the role of mTOR pathway in M1 and M2 differentiation. We also discuss the recent findings in M1 and M2 polarization as a possible target in the cancer therapy.

γδ T Cells and Tumor Microenvironment: From Immunosurveillance to Tumor Evasion

“…The majority of macrophages that are recruited at the tumor site, called TAMs, acquire features closely similar to the M2 phenotype due to different stimuli present in the TME, such as IL-4 and TGF-β, accompanied by reduced antitumoral activity ( 40 ). TAMs play an important role for lymphangiogenesis through the release of VEGF-C and VEGF-D via VEGFR3, and neo angiogenesis by VEGF, TNF-α, CXCL8, PDGF-β, MMP2, MMP7, and MMP9, both of mechanism are critical steps for tumor growth, invasion, and metastasis ( 41 ).…”

Gene Electrotransfer of Plasmid-Encoding IL-12 Recruits the M1 Macrophages and Antigen-Presenting Cells Inducing the Eradication of Aggressive B16F10 Murine Melanoma

“…They express MHCII and produce IL-12 and IL-23, reactive oxygen species (ROS), inflammatory cytokines (IL-1 β , TNF, and IL-6), and antitumoral chemokines (CXCL-9 and CXCL-10) attracting Th1 cells to eliminate tumor cells. On the contrary, M2 macrophages are induced by IL-4, IL-13, IL-21, and IL-33, and they release IL-10 and CCL-17 and CCL-22 and CCL-24 chemokines that recruit Tregs and Th2 cells to promote tumor growth: they are weak antigen presenters, inhibiting inflammation and stimulating angiogenesis and tissue remodeling [ 5 , 6 ]. Due to the central role of the immune system and macrophages in tumor promotion and progression, current studies are focused on immunotherapy strategies with the aim of testing translational preclinical protocols to propose to human patients.…”

Ganoderma lucidum Spore Polysaccharide Inhibits the Growth of Hepatocellular Carcinoma Cells by Altering Macrophage Polarity and Induction of Apoptosis

“…However, if this stimulus is not suppressed in a short time, TAMs will be polarized into M2 type under the action of various cytokines secreted by tumor cells, which is why most TAMs in tumor tissues are M2 type [ 38 ]. In contrast to the M1 type, M2 TAMs can secrete growth factors, angiogenesis factors, and proteases, thereby stimulating tumor cell proliferation, promoting angiogenesis and tumor cell invasion and migration, and escaping the surveillance of antitumor immunity [ 43 ]. Therefore, the induction of secondary polarization of TAMs in tumor tissues and the transformation of M2 TAMs to M1 have become an essential target for tumor therapy in recent years [ 44 ].…”