The Role of CSF1 in Hepatocellular Carcinoma‐Recruited Macrophages

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is clear that local tissue microenvironment plays a key role in its progression. Macrophages are suspected to effect tumor expansion and malignancy by promoting inflammatory responses and tissue remodeling. Colony stimulating factor (CSF1) has been shown to promote macrophage differentiation, survival and proliferation. Although CSF1 is highly expressed in liver, little is known about how CSF signaling impacts macrophages in HCC. We found that CSFR positive macrophages are located in hyperplastic non‐tumor and peri‐tumoral regions of a chemically induced murine HCC model. This expression mimics that seen in HCC specimens from human patients with a poor prognosis. We hypothesized that CSF1 derived from HCC cells promotes macrophage differentiation and viability. Murine bone marrow derived precursor cells were differentiated into macrophages using HCC conditioned culture media. Macrophages treated with a colony stimulating receptor small molecule inhibitor (CSFRi) exhibited altered morphology and decreased proliferation in vitro. Small molecule mediated inhibition of CSFR promoted a shift in macrophage polarization from M2 (pro‐tumor) to M1 (anti‐tumor). These findings suggest a critical role for HCC‐cell mediated CSF signaling in macrophage proliferation, viability, and polarization.