Ovarian cancer (OvCa) is the deadliest cancer of the female reproductive system, ranking fifth in overall cancer deaths among women. Unlike the majority of cancers, OvCa metastasizes via diffusion through the peritoneal cavity, resulting in multiple metastatic sites, including the omentum and peritoneum. These metastasizing OvCa cells induce rapid mesothelial cell retraction and readily adhere to the sub-mesothelial collagen of the extracellular matrix. Epidemiologic data identifies age as a significant risk factor in OvCa, as about half of diagnoses are in women over the age of 63. Despite this, age is understudied in the OvCa field. Using a C57Bl/6 mouse model of aging, young (Y) mice ranging from 3-6 months of age, and aged (A) mice ranging from 20-23 months of age, corresponding to women aged 20-30 years (Y) and 60-67 years (A) were used to study the role aging has on metastasis. Fluorescently tagged C57Bl/6 syngeneic ID8 p53-/- mouse OvCa surface epithelial cells were injected intraperitoneally in young and aged mice and disease progression was evaluated for 5.5 weeks. Organ-specific tumor burden was quantified with ImageJ, revealing increased tumor burden in aged mice compared to their young counterparts. These results were reproduced in the FVB mouse model using syngeneic PTENshRNA/KRASG12V modified FVB OvCa oviductal epithelial cells. Second Harmonic Generation Microscopy (SHG) was used to visualize collagen of the peritoneal and omental tissues from young and aged C57Bl/6 mice. Distinct structural differences were shown in omental collagen in the Y vs A cohorts and validated with Scanning Electron Microscopy (SEM). Additionally, Nanoindentation illustrated mechanical differences between young and aged peritoneal samples. In conclusion, aging induces changes in the structure and mechanical strength of peritoneal and omental collagen, which contribute to OvCa metastasis.
Citation Format: Elizabeth Harper, Elizabeth Loughran, Annemarie Leonard, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Emma Sheedy, Zonggao Shi, Matthew Leevy, Matthew Ravosa, M. Sharon Stack. Aging promotes changes to peritoneal and omental collagen structure that contribute to increased ovarian cancer metastatic success [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5005.