Tumor-associated macrophage-derived transforming growth factor-β promotes colorectal cancer progression through HIF1-TRIB3 signaling

Tumor-associated macrophages (TAMs), one of the most common cell components in the tumor microenvironment, have been reported as key contributors to cancer-related inflammation and enhanced metastatic progression of tumors. To explore the underlying mechanism of TAM-induced tumor progression, TAMs were isolated from colorectal Cancer patients, and the functional interaction with colorectal Cancer cells was analyzed. Our study found that coculture of TAMs contributed to a glycolytic state in colorectal Cancer, which promoted the stem-like phenotypes and invasion of tumor cells. TAMs produced the cytokine Transforming Growth Factor-β to support hypoxia-inducible factor 1α (HIF1α) expression, thereby upregulating Tribbles pseudokinase 3 (TRIB3) in tumor cells. Elevated expression of TRIB3 resulted in activation of the β-catenin/Wnt signaling pathway, which eventually enhanced the stem-like phenotypes and cell invasion in colorectal Cancer. Our findings provided evidence that TAMs promoted colorectal Cancer progression in a HIF1α/TRIB3-dependent manner, and blockade of HIF1α signals efficiently improved the outcome of chemotherapy, describing an innovative approach for colorectal Cancer treatment.