Role of Age-Related Changes in the Tumor Microenvironment on Ovarian Cancer Progression

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Project Summary/Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecologic disease that is most commonly diagnosed in women postmenopausal, aged 55-64 years (median, 63). Although survival of patients with EOC has shown some improvement over the past three decades for younger women, the same is not true for older patients. Two major factors that impact prognosis and survival are metastasis and recurrence, and these are known to be positively related to aging. The mechanisms that underlie the influence of age on ovarian cancer development, progression and recurrence are poorly defined. We will use a xenograft rat model of EOC to help fill these gaps in knowledge and define how aging impacts EOC development and progression. Based on limited prior studies, we hypothesize that the gene regulation pathways and metabolic modification of aged versus younger tumor microenvironment (TME) – with a focus on the ECM – contribute to a more aggressive ovarian cancer phenotype. Our specific aims are: 1) to determine gene expression and cellular metabolic profiles of abdominal fat tissues from young and aged (estropause) rats; and 2) to determine gene expression and cellular metabolic profiles of ovarian cancer stroma tissues. The longitudinal study design will permit analysis throughout the course of cancer development and progression with three targeted timepoints, including analysis prior to cancer initiation, during cancer progression and at recurrence. Given the strong propensity for ovarian cancer cells to embed and grow in omental fat, we will specifically focus attention on changes in this fat tissue TME during aging (and estropause in rat) and over the course of disease. We will determine how metabolic and RNAseq gene expression profiles differ between young and aged rats without malignancy and then examine how age-specific differences vary in the context of cancer progression. Bioinformatic analyses will determine if there is enrichment of particular gene ontology terms and pathways among the differentially expressed genes. We expect findings from this study will provide data to support a larger study by revealing new targets to aid prevention of metastasis and/or recurrence which can be further evaluated in preclinical models with the objective of translation to clinical trials for older and postmenopausal EOC patients.