Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy

Abstract

Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

“…Another major component of the tumor microenvironment are tumor-associated macrophages, which play a pivotal role HCC [ 119 , 120 ]. Macrophages are heterogeneous by nature, as they actively engage in both induction and resolution of inflammation.…”

IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma

“…TAMs have been shown to be involved in the modulation of HCC cell growth and metastasis (20). Co-culture of HepG2 and Huh7 cells with TAMs increased cell viability (P<0.05; Figure 5A), however, si-IRAK1 transfection reversed the TAM-induced increase in cell viability (P<0.05 or P<0.01 compared to NC + TAMs group).…”

Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances

“…It has been shown, in Hepa1-6 HCC tumors, that, in the early phase of tumor development, infiltrated macrophages displayed a tumor-suppressing phenotype, while, at advanced stages, the TAM population increases and is associated with tumor progression [95]. Thus, it is becoming apparent that macrophage polarization plays a crucial role in the initiation of liver diseases, and its role in HCC needs to be further clarified, particularly since it may affect immunotherapy efficacy [96]. At the same time, tumor cells have been found to release Wnt ligands that promoted M2 polarization of macrophages and, in turn, promoted tumor growth, invasion, and immunosuppression in HCC [97].…”