Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts

Abstract

The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non-steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation.

Consumption of Low-Dose of Ethanol Suppresses Colon Tumorigenesis in 1,2-Dimethylhydrazine-Treated Rats

“…Expression of other genes related to inflammation and cancer examined were not affected. IL-6 has been suggested to play an important role in the development of cancer and inflammatory bowel disease but may exert antitumor activity under certain conditions (34)(35)(36). Accumulating evidence suggests that IL-6 signaling is condition-dependent, with dual aspects in the tumor microenvironment activity, tumor cell proliferation, survival, metastasis, and angiogenesis as well as immune suppression (36).…”

Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model

“…OCT has previously been shown to identify distinct layers of tissue in the colon (mucosa, submucosa, and muscularis propria) and distinguish between normal tissue, lymphoid aggregates, and adenoma in mouse models of colorectal cancer (23, 25). This type of imaging technique has also previously been utilized to observe disease progression over time by detecting changes in the colonic tissue of these mouse models (23).…”

The role of diosgenin in crohn’s disease

“…The expression of SOCS3 have been found in IBD rat mode, thus suggesting a possible role in the pathogenesis of Crohn's and Colitis [165,166].The role of IL6/STAT3/SOCS3 in the regulation of homeostasis have been well explained, as such the inflammation observed in Crohn's disease is as a result of the striking imbalance between SOCS3 expression and IL6/STAT3 signaling [167,168]. It is worthy to note, IL6/STAT3 signaling, including constitutive activation of STAT3, was found to generally mediate development and progression of colorectal adenoma and carcinoma without inflammation in background [168,169], in which IL6/STAT3 may be activated by microbial translocation through impaired mucosal barrier and function in physiological modulation of mucosal immunity (Fig. 3).…”