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Title: Role of SPARC in inflammation and cancer
Author: Passafaro, Alfonso Luca
ISNI:       0000 0004 2740 8903
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2011
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An increasing body of evidence highlights inflammation as playing a relevant contribution in the establishment and progression of several diseases including cancer. Indeed environmental factors can determine in different organs a chronic inflammatory status, which in turn may be responsible for increased incidence of cancer. A clear relationship between smoking habits, consequent pro-inflammatory cytokines production, and lung cancer has been extensively demonstrated; a strikingly correlation between western diet consumption leading to obesity-dependent inflammation and colon cancer is becoming evident. Typical inflammation-related diseases of the gastrointestinal (GI) tract are inflammatory bowel diseases (IBOs), comprising Chron's Disease (CD) and Ulcerative Colitis (UC). Even though IBOs affect millions of people all over the world, their etiology is poorly understood yet. Furthermore particular effort is needed to treat and care for IBOs patients as they show an increased risk of developing tumours after 40 years from 10.8% (Ekbom, Helmick et al. 1990) to 25%-40% (Rutter, Saunders et al. 2006) compared to the unaffected population. Secreted protein acidic and rich in cysteine (SPARC) is involved in tissue remodelling, repair and organogenesis; it has been shown to have roles in regulating extracellular matrix composition (Lane and Sage 1994; Van and Sage 1999), tissue permeability, endothelial cell shape and barrier function (Goldblum, Ding et al. 1994) and enterocytes migration (Sansom, Mansergh et al. 2007), thus suggesting it could also play a role in maintaining or regenerating intestinal mucosa under pathogenic conditions, an aspect not investigated yet. The colonic mucosa of SPARC KO mice has a less robust stroma component, thick basement membranes and collagen network; although in physiological conditions these structural features do not cause any intestinal abnormalities they could instead contribute to a major predisposition to crypt damage in in vivo models of UC. By applying the Dextran Sodium Sulfate (DSS)-induced model of experimental colitis in SPARC KO and WT mice, the aim of my work is to reveal a potential role in IBDs (namely UCs) for extracellular matrix proteins and characterize the molecular mechanisms behind the observed phenotype. Colonic inflammation has been triggered in SPARC KO and WT mice by the administration in drinking water of the irritant DSS at two different concentrations (i.e. 2.5% and 3.5%) for 2 weeks. Samples have been collected either immediately (acute phase) or 10 days after treatment suspension (restitution phase) and characterized by mean of immunohistochemistry, RT-PCR, flow cytometry and western blotting analysis. Reciprocal bone marrow (BM) chimeras have been generated (i.e. WT BM > SPARC KO recipients and SPARC KO BM > WT recipients) and both groups treated for 1 week at 3.5% DSS. Mice have been analyzed either immediately or 14 days after treatment withdrawall, while clinical parameters were monitored along all the experimentation. DSS induced a more severe colitis-associated phenotype in SPARC KO mice compared to WT ones both at acute and restitution time points. Interestingly although under the milder experimental condition used (2.5% DSS), in both SPARC KO and WT mice the same level of tissue damage has been observed, still the former showed delayed recovery after treatment withdrawal. RT-PCR analysis revealed a different modulation of the TGF-I3/SMAD pathway in SPARC KO mice that, consequently, affected T regulatory cell (Tregs) levels. BM chimera experiments on the other hand pointed out the importance of stromal cells produced SPARC compared to that produced by epithelial cells (ECs) in determining signs of colitis. These findings highlight a new emerging role of extracellular matrix proteins like SPARC in integrating signals from wounded colonic epithelial tissues to gut immune cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available