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1 Laboratoire UPRES EA 27-10, Institut Gustave Roussy/Institut de Radioprotection et de Surete Nucleaire, Villejuif, France; Laboratoire d'etude des pathologies radio-induites, SRBE/DRPH, Institut de Radioprotection et de Surete Nucleaire, Fontenay aux roses, France
2 Laboratoire d'etude des pathologies radio-induites, SRBE/DRPH, Institut de Radioprotection et de Surete Nucleaire, Fontenay aux roses, France
3 Laboratoire UPRES EA 27-10, Institut Gustave Roussy/Institut de Radioprotection et de Surete Nucleaire, Villejuif, France
4 Laboratoire UPRES EA 27-10, Institut Gustave Roussy/Institut de Radioprotection et de Surete Nucleaire, Villejuif, France; Radiation Oncology Department, Institut Gustave Roussy, Villejuif, France
* To whom correspondence should be addressed. E-mail: vozenin{at}igr.fr.
Radiation enteritis, a common complication of radiation therapy for abdominal and pelvic cancers, is characterized by severe transmural fibrosis associated with mesenchymal cell activation, tissue disorganization, and deposition of fibrillar collagen. In order to investigate the mechanisms involved in this pathological accumulation of extracellular matrix, we studied gene expression of matrix components along with that of genes involved in matrix remodeling, MMPs, and TIMPs. Hybrid selection on high-density cDNA array, real time RT-PCR, gelatin zymography and imunohistochemistry were used to characterize the mRNA expression profile, activity and tissue location of extracellular matrix-related genes in radiation enteritis as compared to healthy ileum. cDNA array analysis revealed a strong induction of genes coding for collagen I, III, IV, VI, VIII, SPARC and tenascin-C, extracellular-matrix degrading enzymes (MMP-1, -2, -3, -14, -18+19), and metalloproteinase inhibitors (TIMP-1, -2, and PAI-1) in radiation enteritis. This increase was correlated with the degree of infiltration of the mucosa by inflammatory cells, and the presence of differentiated mesenchymal cells in the submucosa and muscularis propria. Despite the fact that expression of collagens, MMPs, and TIMPs simultaneously increase, quantification of net collagen deposition shows an overall accumulation of collagen. Our results indicate that late radiation enteritis tissues are subjected to active process of fibrogenesis as well as fibrolysis, with a balance towards fibrogenesis. This demonstrates that established fibrotic tissue is not scarred fixed tissue, but is subjected to a dynamic remodeling process.
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