Hemidesmosome integrity protects the colon against colitis and colorectal cancer.

OBJECTIVE: Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the α6ß4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM. DESIGN: We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6ΔIEC) or in adults (α6ΔIEC-TAM). RESULTS: Strikingly, all α6ΔIEC mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of α6 integrin induced in adult mice (α6ΔIEC-TAM) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1ß secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation. CONCLUSIONS: We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.

Combined NADPH oxidase 1 and interleukin 10 deficiency induces chronic endoplasmic reticulum stress and causes ulcerative colitis-like disease in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1dKO mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2α phosphorylation preceding inflammation. In IL10/Nox1dKO mice, salubrinal preserved eIF2α phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2α pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2α pathway could lead to the molecular remission needed to treat UC.

The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells.

MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression.

Operatively induced chronic reflux in rats: a suitable model for studying esophageal carcinogenesis?

BACKGROUND: The mechanisms of esophageal reflux leading to esophageal adenocarcinoma (EA) remain poorly understood. This study appraises critically an operatively induced chronic reflux rat model. METHODS: We randomized 108 Sprague-Dawley rats into 2 experimental groups; one was performing esophagoduodenal (ED) anastomosis with or without gastrectomy to induce duodeno-esophageal reflux (DER group; n = 63), and the other involved duodeno-gastro-esophageal reflux (DGER group; n = 45). Control groups included (i) Roux-en-Y esophagojejunal anastomosis, (ii) laparotomy alone, (iii) subtotal gastrectomy to induce duodenogastric reflux (DGR group), and (iv) the same procedure as in the DGER group plus proton pump inhibition (PPI group). The esophagus underwent histologic and molecular analyses. RESULTS: The prevalence of Barrett's esophagus (BE), dysplasia, and EA in the experimental groups was 41%, 7%, and 11%, respectively. Histologic and molecular analyses in groups DER, DGER, and DGR suggested that BE occurred through de novo intestinal metaplasia and proximal migration of duodenal cells. No distant metastases were identified. The molecular characteristics of both BE and EA were similar to humans. BE was more common, and dysplasia and EA less frequent in the DER group when compared with the DGER group (44% vs 24% [P = .038] and 7% vs 25% [P = .012], respectively). Compared with the DGER group, carcinogenic sequence occurred less frequently in the PPI-treated group (P = .019). CONCLUSION: Despite pathophysiologic differences with humans, the rat model of esophagoduodenostomy reproduces accurately histologic and molecular lesions in the carcinogenetic sequence of BE and allowed us to identify novel, tumor-associated proteins that may be potential biomarkers and new therapeutic targets in EA.

Use of biological mesh versus standard wound care in infected incisional ventral hernias, the SIMBIOSE study: a study protocol for a randomized multicenter controlled trial.

BACKGROUND: In infected incisional ventral hernias (IVHs), the use of a synthetic non-absorbable mesh is not recommended and biological meshes hold promise. However, the level of evidence for their safety and efficacy remains low. METHODS: The SIMBIOSE trial is a multicenter, phase III, randomized, controlled trial comparing the use of a biological mesh versus traditional wound care in patients with an IVH. The primary end point is 6-month infectious and/or wound morbidity. Secondary end points are wound infection and recurrent hernia rates, post-operative pain, quality of life, time to heal, reoperation need, impact of the cross-linked mesh structure, and a medico-economic evaluation. One hundred patients need to be included. RESULTS: The main results expected with biological mesh use are a significant decrease of post-operative morbidity, hernia recurrence, time to heal, and costs with an improved quality of life. CONCLUSIONS: For the first time, the impact of biological meshes in the treatment of IVHs will be evaluated in an academic, randomized, phase III trial to provide scientific evidence (NCT01594450). TRIAL REGISTRATION: ClinicalTrial.gov, NCT01594450.

Palliative resection for advanced gastric and junctional adenocarcinoma: which patients will benefit from surgery?

BACKGROUND: Whereas palliative chemotherapy offers a median survival of approximately 10 months in advanced gastric and junctional adenocarcinoma (AGJA), the survival impact of primary tumor resection is controversial. Our purpose was to identify which AGJA patients benefit from palliative resection. METHODS: In 3,202 AGJA patients scheduled for surgery in 21 French centers between 1997 and 2010, prognostic factors were identified in palliative group and the impact of each combination of these factors on survival was studied. RESULTS: Surgery was defined as palliative due to solid organ metastasis (5.6 %), localized (4.6 %) or diffuse (2.3 %) peritoneal carcinomatosis (PC), or incomplete tumoral resection (12.8 %). Median survival of AGJA patients resected with a palliative intent (n = 677) was longer than in nonresected patients (n = 532; 11.9 vs. 8.5 months, P < 0.001). Multivariable analyses identified ASA score III-IV (P < 0.001) as a predictor of postoperative mortality and solid organ metastasis (P = 0.009), localized PC (P = 0.004), diffuse PC (P = 0.046), and signet ring cell histology (SRC; P = 0.02) as predictors of survival. Only ASA I-II patients with incomplete resection without metastasis or PC, one site solid organ metastasis without PC, or localized PC without SRC had a survival benefit after palliative surgery with median survivals from 12.0 to 18.3 months. Nonresected ASA I-II patients with same risk factors had median survivals from 3.5 to 8.8 months (P < 0.05 for each). CONCLUSIONS: In AGJA, patient and tumor-related factors should be used to select candidates for palliative surgery in association with chemotherapy.

The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein.

MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.