Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer.
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.
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Yang-An
YA
Wen
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Xiaopeng
X
Xing
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
Jennifer W
JW
Harris
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Yekaterina Y
YY
Zaytseva
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Mihail I
0000-0001-9101-5053
MI
Mitov
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Dana L
DL
Napier
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Heidi L
HL
Weiss
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
B
B
Mark Evers
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
Tianyan
T
Gao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D059016:Tumor Microenvironment / Q000235:genetics
D005227:Fatty Acids; D055372:AMP-Activated Protein Kinases