Two sides to colon cancer: mice mimic human anatomical region disparity in colon cancer development and progression

Abstract

Aim: Strong evidence reveals important differences between cancers in the proximal vs. distal colon. Animal models of metastatic colon cancer are available but with varying degrees of reproducibility and several important limitations. We explored whether there were regional differences in the location of murine colon cancers and assessed the utility of murine models to explore the biological basis for such differences. Methods: We re-analyzed data from our previous studies to assess the regional distribution of murine colon cancer. In survival surgery experiments, we injected HT-29 human colon cancer cells into the wall of the cecum or distal colon of Nu(NCr)-Foxn1nu or NOD.Cg-PrkdcscidIl2rgTim1Wji/SzJ mice and compared the development of primary tumors and metastases. Results: Within 7–17 weeks after intramural cecal injection of HT-29 cells, eight mice failed to develop solid primary tumors or metastases. In contrast, within four weeks after cell injection into the distal colon, 13 mice developed metastases - 12 mice developed subcutaneous metastases; of these, four developed liver metastases and one developed both liver and lung metastases. One mouse developed liver metastases only. Histological examination confirmed these lesions were adenocarcinomas. Conclusion: Our findings reveal the preferential growth of murine colon neoplasia and invasive human orthotopic xenografts in the distal mouse colon. The new approach of injecting cells into the distal colon wall results in a pattern of colon cancer development that closely mimics the progression of metastatic colon cancer in humans. This novel model of colon neoplasia has great potential for exploring anatomical differences in colon cancer and testing novel therapeutics.

Exploiting unique features of the gut-brain interface to combat gastrointestinal cancer

“…These multidirectional interactions between the gut microbiome, CRC cells, and enteric neurons are likely to promote cancer progression; stronger evidence awaits better experimental models (153). Because differences in immune, epithelial, and neural cell functions and microbial diversity in one region of the colon may impact cancer development and progression at other sites, purely reductionist approaches to explore links between the microbiome, ENS, and neoplasia may be misleading (157,158).…”

“…More cynically, these models represent only a change in culture medium from in vitro solutions to live organisms; xenograft experiments almost uniformly mirror in vitro findings without offering novel mechanistic insights, providing only an incremental advance and limited validation of in vitro findings. Orthotopic xenografts may more faithfully replicate human cancer progression and metastasis, e.g., human colon cancer cells implanted in the mouse sigmoid colon (157,184). Patient-derived xenografts (PDXs) can provide real-time information to develop cancer-specific treatment (176).…”

Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer

“…M 3 R is overexpressed in colon cancer, a finding that correlates with poor prognostic features including increased tumor burden, invasion, and metastasis [ 62 , 101 , 102 ]. M 3 R signal transduction, via the EGFR/ERK and PKC/p38 MAPK pathways, results in the induction and release of selected matrix metalloproteinases (MMP1, MMP7, and MMP10), collagenases that facilitate cell invasion by breaking down the extracellular matrix [ 103 , 104 ]. Additional studies showed that ACh-induced MMP1 expression and colon cancer cell invasion can be abolished by pre-treatment with inhibitors of muscarinic receptor or MMP1 activation [ 12 , 105 ].…”

“…Suppressing M 3 R expression using RNA interference attenuated bile acid-induced expression of markers of colon cancer stem cells. It appears plausible that M 3 R activation by exposure to luminal bile acids may explain, at least in part, the increased incidence of colon cancer in individuals who consume diets high in saturated fats that are known to increase levels of secondary bile acids in the stool [ 42 , 103 , 109 , 110 ].…”