ABSTRACT
Authors have only now noticed that in the Figure 3a, the immunohistochemical analysis of IL-4Rα on paraffin-embedded sections from breast is incorrect: IL-4 from breast was duplicated and used for the IL-4Rα staining. The correct Figure 3a has been included in the amendment to this paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.
Subject(s)
Carcinogenesis/metabolism , Cell Transformation, Neoplastic/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Wnt Signaling Pathway , Acyltransferases/antagonists & inhibitors , Adenoma/etiology , Adenoma/metabolism , Adenoma/pathology , Adenomatous Polyposis Coli Protein/deficiency , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Animals , Carcinogenesis/drug effects , Cell Transformation, Neoplastic/drug effects , Colorectal Neoplasms/etiology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Enzyme Inhibitors/pharmacology , Intestinal Mucosa/drug effects , Ligands , Membrane Proteins/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pyrazines/pharmacology , Pyridines/pharmacology , Stem Cells/drug effects , Wnt Signaling Pathway/drug effectsABSTRACT
We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.
Subject(s)
Apoptosis , Autocrine Communication , Breast Neoplasms/metabolism , Carcinoma/metabolism , Colonic Neoplasms/metabolism , Drug Resistance, Neoplasm , Interleukin-4/metabolism , Lung Neoplasms/metabolism , Adult , Aged , Antibodies, Monoclonal , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis Regulatory Proteins , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism , Carcinoma/drug therapy , Carcinoma/pathology , Cell Death , Cell Proliferation , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Humans , Interleukin-4/immunology , Interleukin-4 Receptor alpha Subunit/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Middle Aged , Phosphoproteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , TNF-Related Apoptosis-Inducing Ligand/metabolism , Time Factors , Tumor Cells, Cultured , Up-Regulation , bcl-X Protein/metabolismABSTRACT
PURPOSE: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01), histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. CONCLUSIONS: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.
