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Tumor-stromal interactions in Type I and Type II endometrial cancer: the role of CXCL12/CXCR4 and HGF/c-Met/bFGF in a large cohort of endometrial cancer patients

Felix, Ashley Sinclair (2011) Tumor-stromal interactions in Type I and Type II endometrial cancer: the role of CXCL12/CXCR4 and HGF/c-Met/bFGF in a large cohort of endometrial cancer patients. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Endometrial cancer (EC) is the most common gynecologic malignacy in the United States. In 2010, 43,470 cases were newly diagnosed with 7,950 deaths reported. Certain subtypes of EC are responsible for a disproprtionate number of deaths each year. Specifically, high-grade Type I, papillary serous (PS), and clear cell (CC) tumors account for 60% of all deaths, despite accounting for only 20% of new cases. The molecular mechanisms related to poor survival in these subtypes are unknown. The tumor microenvironment refers to the complex milieu of supporting cells, i.e. stromal cells, which co-exist with the primary tumor. Broad classes of stromal cells including inflammatory cells, endothelial cells, and fibroblasts, support the growth and dissemination of the primary tumor through their interactions with cancer cells. The primary goal of this research was to determine the prognostic roles of two stromal-related pathways [CXCL12 and CXCR4; hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF)] in a sample of EC cases (N=216) treated at Magee-Womens Hospital. Paraffin-embedded tissue blocks were retrieved from the Pathology Department at Magee-Womens Hospital and protein expression was measured using immunohistochemistry (IHC). Chi-square tests, Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used to examine the relationship between tumor and stromal protein expression, clinicopathologic factors, overall survival (OS), and recurrence-free survival (RFS). In the first microenvironmental pathway, positive CXCL12 expression was significantly associated with better OS (hazard ratio, HR: 0.17 95% CI 0.05, 0.59) and RFS (HR: 0.10 95% CI 0.02, 0.57) in high-grade Type I cases. In the second pathway of interest, better OS was detected in HGF positive, stromal bFGF positive patients compared to HGF positive, stromal bFGF negative patients (HR: 0.14, 95% CI 0.03, 0.60). Additionally, worse RFS was observed in HGF positive, tumor bFGF positive patients compared to patients with negative expression of both markers (HR: 9.88, 95% CI 2.63, 37.16). This study provides evidence that tumor microenvironmental proteins can serve as independent prognostic biomarkers in EC. The public health implications include a better understanding of the biology of EC and potential targets for molecularly-targeted treatments in EC.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Felix, Ashley Sinclairashley.felix@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWeissfeld, Joeljwepid@pitt.eduJWEPID
Committee MemberLinkov, Fainafaina.linkov@gmail.com
Committee MemberBowser, Robertbowserrp@upmc.edu
Committee MemberEdwards, Robertredwards@mail.magee.edu
Committee MemberStone, Roslynroslyn@pitt.eduROSLYN
Date: 29 June 2011
Date Type: Completion
Defense Date: 25 March 2011
Approval Date: 29 June 2011
Submission Date: 1 April 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Epidemiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: endometrial cancer; prognosis; tumor markers; tumor microenvironment
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04012011-182630/, etd-04012011-182630
Date Deposited: 10 Nov 2011 19:33
Last Modified: 15 Nov 2016 13:38
URI: http://d-scholarship.pitt.edu/id/eprint/6695

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