Colorectal cancer remains one of the most common and lethal malignancies worldwide despite the use of various therapeutic strategies. A better understanding of the mechanisms responsible for tumor initiation and progression is essential for the development of novel, more powerful therapies. The traditional, so-called "stochastic model" of tumor development, which assumes that each cancer cell is tumorigenic, has been deeply challenged during the past decade by the identification of cancer stem cells (CSCs), a biologically distinct subset of cells within the bulk of tumor mass. This discovery led to the development of the hierarchical model of tumorigenesis which assumes that only CSCs have the ability to initiate tumor growth, both at primary and metastatic sites. This model implies that the elimination of all CSCs is fundamental to eradicate tumors and that failure to do so might be responsible for the occurrence of relapses and/or metastases frequently observed in the clinical management of colorectal cancer patients. Identification and isolation of CSCs is essential for a better understanding of their role in the tumorigenetic process and for the development of CSC-specific therapies. Several methods have been used for this purpose and many efforts have been focused on the identification of specific CSC-surface markers. This review provides an overview of the proposed roles of CSC in human colorectal tumorigenesis focusing on the most important molecules identified as CSC-specific markers in colorectal cancer and on the potential strategies for the development of CSC-targeted therapy.

Exosomes are involved in intercellular communication. We previously reported that sodium butyrate-induced differentiation of HT29 colon cancer cells is associated with a reduced CD133 expression. Herein, we analyzed the role of exosomes in the differentiation of HT29 cells. Exosomes were prepared using ultracentrifugation. Gene expression levels were evaluated by real-time PCR. The cell proliferation rate was assessed by MTT assay and with the electric cell-substrate impedance sensing system, whereas cell motility was assessed using the scratch test and confocal microscopy. Sodium butyrate-induced differentiation of HT29 and Caco-2 cells increased the levels of released exosomes and their expression of CD133. Cell differentiation and the decrease of cellular CD133 expression levels were prevented by blocking multivesicular body maturation. Exosomes released by HT29 differentiating cells carried increased levels of miRNAs, induced an increased proliferation and motility of both colon cancer cells and normal fibroblasts, increased the colony-forming efficiency of cancer cells, and reduced the sodium butyrate-induced differentiation of HT29 cells. Such effects were associated with an increased phosphorylation level of both Src and extracellular signal regulated kinase proteins and with an increased expression of epithelial-to-mesenchymal transition-related genes. Release of exosomes is affected by differentiation of colon cancer cells; exosomes might be used by differentiating cells to get rid of components that are no longer necessary but might continue to exert their effects on recipient cells.

Background We evaluated whether integration of novel diets for donors and patients in addition to fecal transplantation (FT) could increase FT remission rate in refractory ulcerative colitis (UC). Methods This was a blinded randomized controlled trial in adults with active UC, defined by a simple clinical colitis activity index (SCCAI) of ≥5 and ≤ 11 and endoscopic Mayo score 2-3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on day 1and rectal enemas on days 2 and 14 without dietary conditioning of the donor. Group 2: FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet (UCED) for the patients. Group 3 received the UCED alone. The primary endpoint was week 8 clinical steroid free remission, defined as SCCAI <3. Results Sixty two of 96 planned patients were enrolled. Remission week 8 Group 1 was 2/17 (11.8%), Group 2 4/19 (21.1%), Group 3 6/15 (40%) (NS). Endoscopic remission was Group 1 2/17 (12%), Group 2 3/19 (16%), Group 3 4/15 (27%) (Group 1 vs.3 p=0.38). Mucosal healing (Mayo 0) was achieved only in Group 3 (3/15, 20%) vs. 0/36 FT patients (p=0.022). Exacerbation of disease occurred in 3/17 (17.6%) Group 1, 4/19 (21.1%) Group 2, and 1/15 (6.7%) Group 3 (Group 2 vs.3, p=0.35). Conclusions UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.

(2015) Laparoscopic surgery for colorectal cancer is not associated with an increase in the circulating levels of several inflammation-related factors, Cancer Biology & Therapy, 16:5,[671][672][673][674][675][676][677]

Our study supports the role of TNF-alpha polymorphisms in predicting the response to anti-TNF-alpha agents. In particular, we found that the presence of -238G>A and -308G>A polymorphisms is associated with poor response to a 3-month therapy with etanercept. However, our data have yet to be validated in larger cohorts.