Excess Cholesterol Biosynthesis by Up-Regulated HMGCS1 in Colorectal Cancer Cells Induced M2-Like Tumor-Associated Macrophage Polarization Via Extracellular Vesicles.

Abstract

Purpose: The aetiology of colorectal cancer (CRC) is attributed to the intrinsic malignant cell transformation and the extrinsic tumor microenvironment (TME). Within the TME, M2-like tumor-associated macrophages (TAMs) play a pivotal role in promoting CRC malignancy. Although the interaction between tumor cells and TAMs has been studied, the mechanism underlying the polarization of M2-like TAMs directed by CRC cells remains unclear.

Materials and methods: Macrophage polarization was analyzed by flow cytometry. Cytokine production was quantified by qPCR. EVs were identified by transmission electron microscopy and western blotting. CRC cell apoptosis and viability were measured by flow cytometry and CCK8 assay, respectively.

Results: The results showed that CRC cells have high expression of HMGCS1, the enzyme responsible for catalyzing the synthesis of HMG-CoA during cholesterol biosynthesis. The increased expression of HMGCS1 resulted in an excess of cholesterol in CRC patients. The excess cholesterol derived from CRC cells was released via extracellular vesicles (EVs) and taken up by surrounding macrophages via the CD36 receptor. Macrophages that took up CRC cell-derived cholesterol showed a preferential polarization towards M2-like TAMs, which produced large amounts of pro-tumor cytokines. The production of these cytokines further accelerated the progression of the surrounding CRC.

Conclusion: Our findings revealed a mutual stimulatory effect between CRC cells and M2-like TAMs. CRC cells with hyper-expressed HMGCS1 facilitated M2-like TAM polarization by releasing cholesterol-rich EVs, and M2-like TAMs in turn promoted CRC malignancy. These findings suggest that inhibiting excessive cholesterol production may be a promising strategy for the treatment of advanced CRC.