The Missing Link between Obesity and Cancer?
Obesity is a steadily increasing health burden that currently affects 30% of the western population. Recently, obesity has been recognized to not only cause predisposition to classical obesity-associated disorders, such as the development of T2DM and insulin resistance, but also increase the incidence of numerous cancer entities.
Obesity is known to result in a chronic low grade pro-inflammatory state as a consequence of immune cells infiltrating white adipose tissue and liver. Moreover, this so-called metabolic inflammation in turn results in elevated circulating concentrations of cytokines such as TNFa and IL-6. Therefore, obesity-associated metabolic inflammation provides a potential link between obesity and cancer. Our group investigates these and other links in mouse models of hepatocellular and colorectal cancer.
The function of inflammatory mediators in the tumor microenvironment of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a classical inflammation-driven cancer entity for which obesity shows the highest prevalence. According to epidemiological studies, obese men have a 5-fold increased risk of developing HCC. HCC progression critically depends on the tumor microenvironment, which is comprised of infiltrating immune cells as well as of cytokines and growth factors. The dietylnitrosamine (DEN)-induced HCC mouse model recapitulates numerous features of human HCC, and we and others have recently shown that HFD-induced obesity indeed promotes HCC development. We have also demonstrated that stabilization of the anti-apoptotic Bcl-2 family member Mcl-1 is of critical importance for HCC progression and that under lean conditions, a complex mechanism derived from IL-6Ra signaling impacts on Mcl-1 posttranslational modifications. However, in obesity, IL-6Ra signaling is dispensable for HCC progression since IL-6Ra deficient animals developed similar tumor numbers and the IL-6 effect on Mcl-1 stabilization is at least in part indirect via another IL-6 responsive cell type that promotes HCC progression. In line with this notion, we have shown that the chronic metabolic inflammation in obese mice leads to hepatic IL-6 resistance that is manifested as the inability to react to acute IL-6 or IL-6 type cytokine signaling – presumably owing to overexpression of the negative feedback regulator SOCS-3.Collectively, our lab aims at dissecting the underlying molecular and cellular mechanisms as to how obesity-induced metainflammation affects HCC development as a first step to translating our findings into clinical therapy.
The role of obesity-associated metainflammation in colorectal cancer development
Colorectal cancer (CRC) is one of the most frequent cancer entities worldwide and obese individuals show a higher prevalence to developing CRC. A well-established mouse model for colonic tumorigenesis is the azoxymethane/dextransufate two-step model of colitis-associated adenoma. Our studies have shown that HFD-induced obese C57/BL6 mice exhibit a higher tumor burden as compared to their lean littermate controls. Accompanied with increased tumorigenesis under obese conditions is an increased metainflammation in the colons. Thus, we hypothesize that meditors of metainflammation drive colon cancerogenesis. However, alterations of the microbiota in obesity have also been reported to contribute to colon cancer and also the development of obesity-induced insulin resistance might affect colon tumorigenesis. We are currently investigating numerous lines of evidence to determine how obesity promotes colorectal cancer development.
Generation of novel genetic tools to dissect obesity-associated cancer
Our lab constantly develops novel techniques and methods to further improve the current state of modern mouse genetics. For example, we generate novel sophisticated reporter mouse lines to study inflammatory signaling that can be adjusted by the investigator’s means. Furthermore, we established Dre/rox as a second recombinase system in vivo, thereby allowing for more defined approaches in mice. To this end, we modify BACs via RedET and ES cells via gene targeting. Microinjections are performed in collaboration with the MPI AGE and the CECAD injection facilities. Taken together, our lab is committed to improving current mouse models to help better investigate age- and obesity-related diseases.