Abstract
Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells.
Document Type
Article
Publication Date
2-2-2017
Digital Object Identifier (DOI)
https://doi.org/10.1038/cddis.2017.21
Funding Information
This work was supported by R01CA133429 (TG) and the National Center for Advancing Translational Sciences (NIH) through grant UL1TR000117.
Related Content
Supplementary Information accompanies this paper on Cell Death and Disease website (http://www.nature.com/cddis)
Repository Citation
Wen, Yang-An; Xing, Xiaopeng; Harris, Jennifer W.; Zaytseva, Yekaterina Y.; Mitov, Mihail I.; Napier, Dana L.; Weiss, Heidi L.; Evers, B. Mark; and Gao, Tianyan, "Adipocytes Activate Mitochondrial Fatty Acid Oxidation and Autophagy to Promote Tumor Growth in Colon Cancer" (2017). Markey Cancer Center Faculty Publications. 88.
https://uknowledge.uky.edu/markey_facpub/88
Supplementary Figures
Notes/Citation Information
Published in Cell Death & Disease, v. 8, e2593, p. 1-12.
© The Author(s) 2017
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.