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Digital archive of theses discussed at the University of Pisa


Thesis etd-01132021-181132

Thesis type
Tesi di dottorato di ricerca
Thesis title
The impact of inflammatory response on cell cancer endocavitary spread in colonic and ovarian malignancies
Academic discipline
Course of study
tutor Prof. Chiarugi, Massimo
  • colon cancer
  • ovarian cancer
  • peritoneal carcinomatosis
  • peritoneal inflammation
Graduation session start date
The term “peritoneal carcinomatosis” (PC), usually indicating the shedding, implantation and dissemination of a tumor to the peritoneal coating that covers the abdominal cavity and the viscera within it, is the result of a complex sequence of molecular events by which tumor cells disseminate from their primary organ to establish independent metastatic deposits on the visceral and parietal lining of the abdominal cavity. Several studies in the last decade have shown as inflammatory mediators promote not only carcinogenesis, but also tumor progression. The systemic inflammatory response, usually made of composite ratios or cumulative scores of different circulating white blood cells or acute phase proteins, has shown some prognostic significance; the production of these mediators participates in the up-regulating of adhesion molecules on the peritoneal surface, thus enhancing the metastatic potential of tumor cells. In this view, an intriguing topic concerns the relationship between carcinosis and the ATP-sensitive P2X7 receptor (P2X7R), a powerful and multifaceted inflammatory mediator. In most tumors, P2X7R is constantly and tonically active, thus stimulating cell growth, proliferation and migration, and influencing tumor microenvironment. Fifty-two female adult patients aging 40-80 years, with clinical indication for primary surgical treatment for intraperitoneal CC or EOC in the section of General Surgery and Gynecologic Oncology of the University Hospital in Pisa, Italy, between January 2016 and June 2018 were consecutively enrolled on a volunteer basis. The final population consisted of 15 patients with histological diagnosis of EOC and 18 patients with intraperitoneal CC. Causes of patient exclusion were the mismatch between the histological inclusion criteria and the tumoral staging (parameter T) on anatomo-pathological examination, and the scarce amount of RNA extracted from tissue samples, insufficient to perform a molecular analysis. At the beginning of the surgical procedure two samples of disease-free parietal and omental peritoneum were collected in each patient. A partially differential expression pattern was observed, with a significantly higher expression of CD68, FGFR1 and IL-6 in adipocytes from CRC patients and enhanced VEGF expression in adipocytes from EOC. The expression of other generic markers of tissue inflammation, matrix deposition and cell migration, like TNFα, TGFβ or MCP-1 did not differ between the two cancers. Similarly, the inflammatory platform P2X7R-NLRP3 did not differ, with P2X7R barely expressed in both and NLRP3 showing an ample variability. P2X7R and NLRP3 were the only inflammatory factors significantly more expressed in patients carrying both types of carcinosis. The presence of extra-abdomen metastases was associated with a higher adipocyte expression of FGFR1 and TGFβ. The presence of extra-abdomen metastases was associated with a higher adipocyte expression of FGFR1 and TGFβ. We confirm here the role of TGFβ as marker of invasion and potential epithelial-mesenchimal transition in both CRC and EOC. These preliminary results suggest a putative role of the adipocyte P2X7R-NLRP3 inflammasome in modulating chemotaxis and metastatic spread in CC and EOC; further studies on larger groups of patients are required to better characterize the role of such pathway