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Tumor fibroblast – derived epiregulin promotes growth of colitis-associated neoplasms through ERK

Startseite Dienstag, 16. Juli 2013

© Published in Volume 123, Issue 4 (April 1, 2013). Der Artikel auf der Webseite der "The Journal of Clinical Investigation" beschäftigt sich mit Tumor Fibroblasten.


Introduction

Lesen Sie hier den vollständigen Bericht des Journal of Clinical Investigation.

Inflammatory bowel disease (IBD) is a present health problem believed to have a complex genetic and environmental etiology that can severely compromise the life quality of affected individuals of all ages. IBD involves an overactive immune response in genetically predisposed individuals driven by the bacterial flora. Aside from the symptomatic disease burden caused by relapsing intestinal inflammation, IBD patients are threatened by long-term complications including increased susceptibility to colorectal cancer (CRC) development. The elevated risk for colitis-associated cancer (CAC) is well documented for ulcerative colitis (UC) , and more recent studies provided evidence of an increased intestinal cancer development in individuals with Crohn’s disease (CD) (5). Notably, the risk for CAC in IBD patients appears to be influenced by the inflammatory activity as well as the extent of colitis and duration of the disease. In fact, the severity of inflammation is a key risk factor for progression to colorectal neoplasia in UC. Even though the molecular mechanisms that explain how chronic inflammatory states contribute to the development of CAC are not fully understood, experimental models of colitis-associated tumorigenesis have suggested that chronic inflammation can facilitate tumor initiation and progression. In particular, it has been suggested that increased levels of reactive oxygen or nitrogen species may elevate the risk for mutations in intestinal epithelial cells (IEC) of the colon.

In humans, CACs share several characteristics with sporadic CRCs, which represent the most frequent group within the heterogeneous variety of CRCs. CAC and sporadic CRC also differ strikingly in numerous features. In sporadic CRC, healthy epithelium can typically turn into CRC in the adenoma-carcinoma sequence spanning several years. In contrast, CAC precursor lesions are often flat and multifocal, and such lesions may grow more rapidly.

Experimental data on molecular mechanisms that can modulate growth of CAC and sporadic CRC are increasing. Numerous variables seem to be involved in influencing the development of intestinal neoplasms including the bacterial flora. In addition, there are striking differences along the GI tract itself with respect to the cellular composition and the structure of the intestinal wall. Different regional susceptibilities for intestinal tumors are well known, but not sufficiently understood.

To improve translational relevance, our study focused on a direct comparison between experimental CAC and experimental sporadic CRC originating from the same rectosigmoid region of the lower GI tract that is the most frequent location for CAC and sporadic CRC in humans.

The molecular basis for characteristics specific to CAC as compared with sporadic CRC has not previously been clarified, although mechanisms such as different order of mutations in the multistep process of colon carcinogenesis have been hypothesized in humans. For the differential molecular analysis of CAC and sporadic CRC, we performed comparative whole-genome expression profiling between CAC and sporadic CRC in experimental mouse models and evaluated the potential role of differentially expressed candidate genes. Strikingly, functional studies including experiments with gene-deficient mice identified epiregulin (EREG) as a predominant regulatory factor for growth of CAC.

Lesen Sie hier den vollständigen Bericht des Journal of Clinical Investigation.