Ovarian cancer (OvCa) is the most fatal gynecologic cancer with a low (<27%) 5-year survival rate. Survival of women with OvCa has not changed appreciably in over 30 years and most women diagnosed will die of painful complications that arise as a result of widely disseminated intraperitoneal (IP) metastasis. Epidemiologic data indicate that age is a significant risk factor for OvCa incidence; however disease progression in the aged host has not been examined experimentally. In the previous funding period we developed a suite of new in vitro, ex vivo, and in vivo model systems and imaging modalities with which to examine the mechanistic link between host age and ovarian cancer metastatic success. Using these models, our preliminary data show age-related alterations in peritoneal mesothelial cells (MC) and sub-mesothelial collagen together with enhanced tumor burden in aged relative to young mice and suggest that Wnt5a can function as a mediator of tumor:host cross-talk in the peritoneal cavity. Experiments in the current project will address the hypothesis that host ageing induces changes in peritoneal structure and function that influence tumor cell adhesion, matrix anchoring, and subsequent metastatic success. To address this hypothesis, Aim 1 will examine age-induced changes in peritoneal MCs, the response of aged MCs to compression and strain, and the resulting impact on MC receptivity to metastatic implantation.
Aim2 will focus on ageing of the sub-MC collagen matrix, evaluate age-induced matrix crosslinking and biophysical properties, and the ultimate effect on metastatic anchoring.
Aim3 will investigate Wnt5a as a mediator of tumor:host cross-talk in the ageing peritoneal cavity. Successful completion of these aims will provide unparalleled insight into ageing and IP metastasis. As the high mortality of OvCa is directly attributable to IP metastasis, innovative approaches that integrate data from both tumor and host will identify critical determinants of metastatic success for future targeted intervention.

Public Health Relevance

Age is a significant risk factor for ovarian cancer (OvCa), as the majority of women are diagnosed over age 63. At the time of diagnosis, most women already have metastatic disease spread throughout the abdomen; however the impact of ageing peritoneal tissues on metastatic success has not been evaluated. This project integrates mechanistic biochemistry with tissue explants and mouse tumor models to understand the role of host ageing in OvCa metastasis. The goal is to identify specific molecules, structures and events that may be new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA109545-10A1
Application #
9440893
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2006-07-01
Project End
2023-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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