Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewTumor-associated macrophages as an emerging target against tumors: Creating a new path from bench to bedside
Section snippets
Overview: phenotypic and functional characteristics of tumor-associated macrophages
Emerging evidence has revealed that tumor-infiltrating macrophages play a critical role in regulating tumor growth, progression and anticancer drug responses [1], [2]. Although macrophages serve as a first-line of defense against pathogens and environmental insults through release of anti-microbe mediators such as proinflammatory cytokines, they also play an important role in fine-tuning inflammatory responses that are associated with tissue repair and remodeling processes [3]. The complexity
Mechanisms regulating pro-tumor properties of macrophages: new insights from the bench
Tumor microenvironments generate distinct sets of soluble factors that contribute to the recruitment of macrophage precursors and differentiation of pro-tumor and immunosuppressive macrophages. The interaction of angiotensin-II and S1P1, which occurs preferentially in tumors, amplifies the expansion of hematopoietic stem cells, which serve as the source of macrophage precursors infiltrating tumor tissues [21]. CCL2 serves as a major chemokine in promoting the infiltration of CCR2+Ly6Chigh
Clinical evidence of TAM-mediated tumor progression
Emerging evidence has revealed the importance of TAM derived from patient materials in predicting poor prognosis in many hematologic and solid tumors [46]. In solid tumors, TAM are detected mainly as a stromal component within the invasive front along with cancer-associated fibroblasts. In hematologic tumors, including gliomas and lymphomas, TAM serve as the main component of the tumor microenvironment and the tumor infiltration of CD68+ macrophages is a sign of poor prognosis in patients with
Anticancer strategies influencing the tumorigenic activities of macrophages
Although tumor cells are the major targets for most anticancer therapeutics, compelling evidence exists that tumor microenvironments play a critical role in regulating responses to anticancer therapies. In particular, TAM serve as the main players for impeding the therapeutic efficacy of various anticancer agents, including cytotoxic chemotherapy, radiotherapy and molecular targeting therapies [55], [56].
Certain anticancer treatments elicit therapeutic responses by manipulating the infiltration
Clinical development of antitumor therapies targeting TAM
Emerging evidence has validated the concept that inhibition of key signaling pathways critical for the survival and functioning of TAM could elicit potent antitumor activities in preclinical tumor models and cancer patients. In particular, c-Fms kinase serves as an indispensable node controlling the survival and differentiation of TAM [4]. The bcr-abl and c-kit kinase inhibitors (imatinib, dasatinib, etc.) and the multi-kinase inhibitor sunitinib represent clinically approved anticancer agents
Future perspectives: creating a path for the development of TAM-specific drugs
The recent clinical success of CSF1 receptor inhibitors for human malignancies should stimulate the development of TAM-targeting strategies in the future. However, inhibition of the CSF1 receptor may cause severe adverse events, such as opportunistic infections and delayed tissue repair, since CSF1 and IL-34 are indispensable for macrophages in maintaining normal homeostasis and defending against pathogens [86], [87]. In this regard, it is necessary to focus the development of drugs on the
Grant support
This work was supported by a Grant-in-Aid for Scientific Research and Scientific Research for Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Ministry of Health, Labor and Welfare.
Conflict of interest
The authors declare that there is no conflict of interest.
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