Abstract
Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial–mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide
The objectives of this study were (1) to investigate the correlation between tumor-associated macrophages (TAMs) subtype and colon cancer cell progression; (2) to determine the mechanism involved in their interaction; (3) to explore the mechanisms underlying TAM-related cancer progression with respect to PI3Kγ regulation; and (4) to determine the prognostic value of TAM subtype in the CRC microenvironment
Similar results were observed when the expression level of epithelial–mesenchymal transition (EMT) markers was measured in a mouse xenograft model transplanted with HCT116 cells that were cocultured with different macrophage subtypes (Fig. 3f). These results demonstrate that M2 macrophages induce the EMT phenotype in colon cancer cells
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide. To improve the survival rates of patients with CRC, many researchers have studied the underlying mechanisms of carcinogenesis related to both the tumor cell itself and the tumor microenvironment. Like most other solid carcinomas, CRC has a microenvironment that is infiltrated by a variety of immune cells, including tumor-associated macrophages (TAMs), monocytes, dendritic cells, natural killer cells, CD4+ T cells, and CD8+ T cells[1,2,3]. Among these immune cells, TAMs are usually the most abundant immune cells in the tumor microenvironment[4,5,6]. PI3Kγ is a class IB isoform of PI3K that is abundantly expressed in myeloid cells, including macrophages.
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