Targeting IL-34/MCSF-1R Axis in Colon Cancer

Abstract

Colorectal carcinoma (CRC) is one of the most common neoplasias in the Western world and it is still one of the most deadly cancers worldwide mainly due to the fact that metastatic CRC is not responsive to current pharmacologic treatment. Identification of pathways that sustain CRC cell behaviour could help develop effective therapeutic compounds. A large body of evidence indicates that colon carcinogenesis is a dynamic process in which multiple cell types present in the tumor microenvironment either stimulate or suppress CRC cell growth, survival, and diffusion mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine initially known for its ability to regulate monocyte/macrophage survival and function, is highly produced in human CRC by both cancer cells and non-tumoral cells. IL-34 function is mainly mediated by interaction with the macrophage colony-stimulating factor-1 receptor (MCSF-1R), which is also over-expressed by CRC cells as well as by tumour-associated macrophages (TAMs) and cancer-associated fibroblasts. IL-34-driven MCSF-1R activation triggers several pro-tumoral functions in the colon. In this article, we review the current understanding of the involvement of IL-34 and its receptor in CRC, with particular attention to the available evidence about the IL-34/MCSF-1R axis-mediated regulation of TAMs and the role of IL-34 and MCSF-1R in promoting cancer resistance to chemotherapy and immunotherapy.

Manuscript contribution to the field: In this review, we highlight the multiple effects of IL-34 and its receptor, macrophage colony-stimulating factor-1 receptor, on the activity of colorectal cancer (CRC) cells and non-tumoral cells, with particular attention to the available data supporting the role of IL-34/MCSF-1R axis in the control of tumor-associated macrophages. The findings summarized in this manuscript could help understand whether targeting IL-34/MCSF-1R can be exploited for therapeutic intervention in CRC.

Keywords: MCSF-1; cancer-associated fibroblasts; colorectal carcinoma; tumor microenvironment; tumor-associated macrophages.

Figure 1

Blood-derived monocytes are recruited to the tumor sites, where cytokines promote their polarization towards M1 or M2 macrophages. M1 macrophages are differentiated in response to the simulation with interferon-γ (IFN−γ), Toll−like receptor ligands, such as lipopolysaccharide (LPS), or granulocyte−macrophage colony−stimulating factor. These cells produce interleukin (IL)-12, which in turn stimulates Th1 cell differentiation and activation of CD8+ T cells. Altogether these cell types limit cancer growth and diffusion. In contrast, together with regulatory T cells and myeloid-derived suppressor cells, M2 macrophages, which are differentiated in response to stimulation with IL−4, IL−10, and IL-34/MCSF-1, contribute to generate a microenvironment that sustains cancer cell behaviour.

Figure 2

Schematic view of the cell targets and biological effects of interleukin-34 (IL-34) in human colorectal cancer.