Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor

Characterization of Chromosomal Instability in Murine Colitis-Associated Colorectal Cancer

Patients suffering from ulcerative colitis (UC) bear an increased risk for colorectal cancer. Due to the sparsity of colitis-associated cancer (CAC) and the long duration between UC initiation and overt carcinoma, elucidating mechanisms of inflammation-associated carcinogenesis in the gut is particularly challenging. Adequate murine models are thus highly desirable. For human CACs a high frequency of chromosomal instability (CIN) reflected by aneuploidy could be shown, exceeding that of sporadic carcinomas. The aim of this study was to analyze mouse models of CAC with regard to CIN. Additionally, protein expression of p53, beta-catenin and Ki67 was measured to further characterize murine tumor development in comparison to UC-associated carcinogenesis in men.The AOM/DSS model (n = 23) and IL-10(-/-) mice (n = 8) were applied to monitor malignancy development via endoscopy and to analyze premalignant and malignant stages of CACs. CIN was assessed using DNA-image cytometry. Protein expression of p53, beta-catenin and Ki67 was evaluated by immunohistochemistry. The degree of inflammation was analyzed by histology and paralleled to local interferon-γ release.CIN was detected in 81.25% of all murine CACs induced by AOM/DSS, while all carcinomas that arose in IL-10(-/-) mice were chromosomally stable. Beta-catenin expression was strongly membranous in IL-10(-/-) mice, while 87.50% of AOM/DSS-induced tumors showed cytoplasmatic and/or nuclear translocation of beta-catenin. p53 expression was high in both models and Ki67 staining revealed higher proliferation of IL-10(-/-)-induced CACs.AOM/DSS-colitis, but not IL-10(-/-) mice, could provide a powerful murine model to mechanistically investigate CIN in colitis-associated carcinogenesis

Variations in the management of diarrhoea induced by cancer therapy: results from an international, cross-sectional survey among European oncologists.

Chemotherapy-induced diarrhoea (CID) is a common side effect of cancer treatment. While cytotoxic agents are the main cause of CID, targeted drugs, immunotherapy and radiotherapy can also cause diarrhoea. Patients with severe CID often require hospital admission for intravenous fluid resuscitation and supportive treatment. In other patient populations, such as children with infectious diarrhoea, therapy is based on evidence from randomised-controlled clinical trials. In contrast, few trials have investigated CID management, and hence, treatment guidelines are largely based on expert opinion. We conducted an online survey on CID management and institutional routines across Europe to obtain a more detailed picture of current practice in CID treatment. We analysed the responses from a total of 156 clinicians from 83 different medical centres in 31 countries. CID (any grade) is recognised as a common clinical problem in patients undergoing antitumoral treatment and it can require hospital admission in a substantial subgroup of patients. There is a strong consensus among clinicians as to the choice of resuscitation strategies and drug treatment for severe CID; 85.9% (n=134) of all respondents prefer intravenous crystalloid fluids and 95.5% (n=149) routinely use loperamide. In sharp contrast, we have identified disparities in the use of bowel rest in CID; approximately half of all participants (57.7%; n=90) consider bowel rest in initial CID management, while the remainder (42.3%; n=66) does not. As previous studies have shown that bowel rest is associated with adverse outcomes in diarrhoea due to causes other than chemotherapy, the results from this survey suggest that further research is needed as to its role in CID