CSF-1R in Cancer: More than a Myeloid Cell Receptor

Abstract

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumors characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported in the cell membrane of the cancer cells of different solid tumors, capturing the interest of various research groups interested in investigating the role of this receptor in non-myeloid cells. This review summarizes the current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R⁺ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in an autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small-molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cells.

Keywords: CSF-1R; cancer cell signaling; cell migration; cell proliferation; chemoresistance; stemness.

Figure 1

CSF1R mRNA expression (log2-transformed, using a pseudo-count of 1) in cell line models from the Dependency Map (DepMap) Public 23Q4 (https://depmap.org/portal/ (accessed on 28 December 2023)). Cell lines are grouped by cancer types defined as Oncotree Subtype. Cancer subtypes with more than 10 cell line models are shown.

Figure 2

CSF-1R signaling in cancer cells. The image is a schematic representation of the available data regarding CSF-1R signaling and function in different cancer cell types. In mammary epithelial cells, Src signaling correlated with CSF-1R activation [52]. ERK 1/2 pathway activation following CSF-1R induction was reported in lung, breast and glioma cancer cells, associated with cell proliferation [11,41,48]. In breast cancer, CSF-1R signaling induced the transcription of the proliferative genes CCND1, c-JUN and c-MYC [29], even though MCF-7 cells overexpressing CSF-1R increased the expression levels of p21 [44]. In different tumor types, CSF-1R promoted proliferation and chemoresistance via the activation of PI3K/AKT signaling [12,49,53]. In colorectal cancer, the CSF-1R/STAT3/mir-34a axis was involved in the development of a chemoresistant and invasive phenotype [54]. Moreover, mir-34a negatively regulated the expression of the stem-like gene Lrg5 and the acquisition of stem-like traits [55]. In mesothelioma, CSF-1R expression correlated with stemness marker expression, such as SOX2, NANOG, OCT4 and c-MYC, and drug-resistance markers including ABCG2 transcription [12]. In colorectal cancer, glioma and mesothelioma CSF-1R induced the expression of EMT-related genes, like SNAIL and SLUG, Vimentin (VIM) and matrix metalloproteinase-9 (MMP-9) and CD44 [12,48,54]. Moreover, in osteosarcoma cells, CSF-1R expression was associated with Twist and N-cadherin expression [56]. According to Giricz et al. [13], in a subset of chemoresistant melanoma cells, the main regulator of CSF-1R expression might be RUNX1, which is associated with the CSF-1R promoter region [13]. In both cervical and breast cancer, the expression levels of CSF-1R linked with TGF-β receptor activity [28,46]. Accumulation of nuclear beta-catenin was also regulated via CSF-1R in intestinal tumor cells [55]. Created in Biorender.com (accessed on December 22, 2023).