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.
Highlights
Obesity has been recognized as a major risk factor for several types of cancer by a number of epidemiological studies.[1,2] In colorectal cancer (CRC), studies have shown that for every 2.4 unit increase in body mass index (BMI), CRC risk increases by 7%.3 obesity is associated with reduced survival compared with normal weight CRC patients when treated with standard chemotherapy.[4,5] Given the prevalence of obesity, a better understanding of how adipose tissue and adipocytes support tumor growth and progression is urgently needed
Our findings reveal a novel role of adipocytes in promoting mitochondrial fatty acid oxidation (FAO) and autophagy in colon cancer cells
Our results show that colon cancer cells become more resistant to nutrient deprivation after cocultured with adipocytes and that fatty acids acquired from adipocytes can be utilized by cancer cells in an autophagydependent manner
Summary
Obesity has been recognized as a major risk factor for several types of cancer by a number of epidemiological studies.[1,2] In colorectal cancer (CRC), studies have shown that for every 2.4 unit increase in body mass index (BMI), CRC risk increases by 7%.3 obesity is associated with reduced survival compared with normal weight CRC patients when treated with standard chemotherapy.[4,5] Given the prevalence of obesity, a better understanding of how adipose tissue and adipocytes support tumor growth and progression is urgently needed. Obesity is associated with reduced survival compared with normal weight CRC patients when treated with standard chemotherapy.[4,5] Given the prevalence of obesity, a better understanding of how adipose tissue and adipocytes support tumor growth and progression is urgently needed. Previous studies using animal models have demonstrated that obesity has an important role in promoting colon cancer tumorigenesis. Studies conducted mostly in breast cancer have indicated that elevated levels of blood insulin/IGF-1 and proinflammatory cytokines associated with obesity may contribute to tumorigenesis via a systemic mechanism.[10,11,12] Recently, it has been reported that lipids produced in adipocytes can be transferred to cancer cells to promote tumor growth in ovarian cancer models, suggesting that local adipose tissues may have a direct role in supporting cancer cells.[13]. Our findings reveal a novel role of adipocytes in promoting mitochondrial fatty acid oxidation (FAO) and autophagy in colon cancer cells
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