Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer

YA Tang, Y Chen, Y Bao, S Mahara… - Proceedings of the …, 2018 - National Acad Sciences
YA Tang, Y Chen, Y Bao, S Mahara, SMJM Yatim, G Oguz, PL Lee, M Feng, Y Cai, EY Tan…
Proceedings of the National Academy of Sciences, 2018National Acad Sciences
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or
progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are
known to contribute to chemoresistance, it remains not fully understood how CSCs in the
hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-
inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2
converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting …
Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2−mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.
National Acad Sciences