ABSTRACT
Colorectal cancer lethality usually results from post-treatment relapse in the majority of stage II-IV patients, due to the enhanced resistance of Cancer Stem Cells (CSCs). Here, we show that the nuclear receptor Pregnane X Receptor (PXR, NR1I2), behaves as a key driver of CSC-mediated tumor recurrence. First, PXR is specifically expressed in CSCs, where it drives the expression of genes involved in self-renewal and chemoresistance. Clinically, high levels of PXR correlate with poor recurrence-free survival in a cohort of >200 stage II/III colorectal cancer patients treated with chemotherapy, for whom finding biomarkers of treatment outcome is an urgent clinical need. shRNA silencing of PXR increased the chemo-sensitivity of human colon CSCs, reduced their self-renewal and tumor-initiating potential, and drastically delayed tumor recurrence in mice following chemotherapy. This study uncovers PXR as a key factor for CSC self-renewal and chemoresistance and targeting PXR thus represents a promising strategy to minimize colorectal cancer relapse by selectively sensitizing CSCs to chemotherapy.
Subject(s)
Colonic Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Neoplastic Stem Cells/cytology , Receptors, Steroid/metabolism , Aged , Aldehyde Dehydrogenase/metabolism , Aldehyde Dehydrogenase 1 Family , Animals , Antineoplastic Agents/pharmacology , Biomarkers, Tumor , Cohort Studies , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Pregnane X Receptor , Prognosis , Retinal Dehydrogenase , Spheroids, Cellular/metabolismABSTRACT
BACKGROUND: Peristomal hernia (PH) is a common complication of colostomy. It often leads to a decrease in the patient's quality of life. Surgical procedures for PH are difficult and present high failure and morbidity rates. This randomized, double blind, multicentre trial was conducted to determine the benefits and risks of mesh reinforcement vs conventional stoma formation in preventing PH. METHODS: 200 patients undergoing a permanent end colostomy are randomized into two groups. In the mesh group an end-colostomy is created inserting a lightweight (<50g/m(2)) monofilament mesh in a sublay location, and compared to a group with traditional stoma creation. The presence or absence of a PH is determined by another practitioner by clinical exam and by a CT scan or MRI after 24 months of follow-up. 19 university hospitals participate during a 3-year inclusion period. The primary endpoint is the comparison of the PH incidence. To find a difference of 20% with a power of 80% a total number of 174 patients must be included. CONCLUSION: This GRECCAR study is a multicentre, double blind, and randomized trial conducted to determine whether a preventive insertion of a prosthetic mesh decreases the incidence of a PH with an acceptable morbidity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01380860.
