Cell proliferation downregulated by TGF-β2-triggered G1/S checkpoint in clinical CAFs

ABSTRACT

The metabolic reprogramming is indispensible for the fast growth of tumor cells. The metabolism of CAFs is reprogrammed to aerobic glycolysis too. However, it is not clear whether this metabolic reprogramming promotes the growth of CAFs themselves. In this study, we found that the proliferation rate of CAFs was slower than NAFs, which was determined by cell counting, BrdU assay and flow cytometry analysis. Moreover, we found TGF-β signaling regulated cell growth of CAF through RNA-sequencing analysis and Western blot, which was further supported by the observation that TGF-β2 was highly expressed in colon cancer tissues. In the end, we demonstrated that CAFs were critical to tumor cell proliferation, which was supported by the evidence of their close localization in clinical tumor tissue and tumor promoting effect in mice. In brief, our data have manifested that the proliferation rate is decreased in CAFs, which enable CAFs generate more intermediate metabolites to support tumor cells growth, suggesting CAFs is an ideal target for tumor therapy.

KEYWORDS:

• Cancer-associated fibroblasts (CAF)
• cell cycle checkpoint
• Non-activated fibroblasts (NAF)
• proliferation

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This study was supported by grants from the Shanghai Committee of Science and Technology (11DZ2260200), the National Science Foundation of China (81372194) (81572300) to Dr. Mi; Shanghai Municipal Science and Technology Commission of Science and Technology Innovation Action Plan Key Project (10411953400) and Shanghai Baoshan District Science and Technology Commission Project (14-E-4) to Jiangmin Zhao; and Precision Medicine Research Academy of Sciences (KJZD-EW-L14), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020343), and National Basic Research Program of China (973 program, 2012CB518302 and 2013CB911001) to Dr. Sun.

Author contributions

J.W, and R.F. performed most of the experiments; Y.X. performed some of the experiments; J.Z. provided reagents and revised the paper; J. M. designed the project and wrote the article; all authors reviewed the manuscript.