During the past decade, as the incidence of obesity has risen dramatically throughout the world, so has the appreciation that obesity can actually be a causative factor for the development of cancer. The exact agent(s) leading up to cancer in obesity settings have remained unknown.
In the present report,* the team used a mouse model to study the effect of high-fat diet in combination with an application of a mild dose of oncogenic stimuli: obese mice fed a high-fat diet (HFD) and lean mice fed a normal diet were also subjected to a treatment with the known carcinogen DMBA (7,12-dimethylbenz[a]anthracene). The cellular senescence marker p21Waf1/Cip1 was monitored in p21-p-luc mice noninvasively using luciferase-based bioluminescence imaging.
The team found an increase of the bioluminescent signal in the abdomen of the obese mice, and it originated mainly from liver cancer (see Figure 1). Interestingly, the mice in the high-fat diet group developed cancer only in the liver, while the control (lean-diet) group developed sporadic tumors in the lung but not in the liver (presumably baseline-level tumors formed as a result of the DMBA application). This finding prompted the team to search for the causative agent within the gut microbiota and after a series of liquid chromatography mass spectrometry (LC-MS) analyses of the metabolites associated with the two treatment groups, a prominent elevation in the concentration of deoxycholic acid (DCA), a secondary bile acid produced by the 7α-dehydroxylation of primary bile acids, was detected.
DCA is produced primarily by gut bacteria belonging to Clostridium cluster XI and XIVa6 (VCM-sensitive gram-positive bacteria), and the level of these bacteria was found to be elevated upon placement of mice on high-fat diet (see Figure 2); importantly, humans do not possess an efficient metabolic path toward degradation/elimination of DCA.
Earlier studies had demonstrated that DCA caused DNA damage and resulted in increased incidence of liver and colon cancer. Here, the team found that modulation of the DCA levels affected the rate of HCC development (see Fig. 3 in the article). Thus, modulation of the microbiota represented within the Clostridium cluster XI could be considered as a potential strategy to at least partially alleviate the cancer-causing effects of high-fat diet.
*Abstract from Nature 2013, Volume 499: 97–101.
Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed.
Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice.
Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumor-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice.
Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
Anton Simeonov, Ph.D., works at the NIH.
ASSAY & Drug Development Technologies, published by Mary Ann Liebert, Inc., offers a unique combination of original research and reports on the techniques and tools being used in cutting-edge drug development. The journal includes a “Literature Search and Review” column that identifies published papers of note and discusses their importance. GEN presents here one article that was analyzed in the “Literature Search and Review” column, a paper published in Nature titled “Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome”. Authors of the paper are Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, and Ohtani N.
