With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment

Abstract

Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally injected with ovarian tumor cells. While very few papers have been published looking at the direct link between ovarian cancer metastasis and age, there is a wealth of information on how age affects metastatic microenvironments. Mesothelial cells, the peritoneal extracellular matrix (ECM), fibroblasts, adipocytes and immune cells all exhibit distinct changes with age. The aged peritoneum hosts a higher number of senescent cells than its younger counterpart, in both the mesothelium and the stroma. These senescent cells promote an inflammatory profile and overexpress Matrix Metalloproteinases (MMPs), which remodel the ECM. The aged ECM is also modified by dysregulated collagen and laminin synthesis, increases in age-related crosslinking and increasing ovarian cancer invasion into the matrix. These changes contribute to a vastly different microenvironment in young and aged models for circulating ovarian cancer cells, creating a more welcoming “soil”.

Obesity-Induced Peritoneal Dissemination of Ovarian Cancer and Dominant Recruitment of Macrophages in Ascites

“…Older women have higher rates of diagnosis and death from OC (36) and activation of estrogen receptor prevents fat accumulation (37). Because ovariectomy eliminates the protection of female mice from gaining body weight (38), we used OVX WT and OB mice on standard diets to reflect a postmenopausal status.…”

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

“…Once a colony is established at a secondary site, the cells can undergo a mesenchymal-to-epithelial transition (MET) and begin to grow rapidly [4]. For a more detailed description of metastatic processes in ovarian cancer, readers are referred to the following references [4,25,27,28].…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…The mesothelium lining of the peritoneum is a cobblestone monolayer of cells with characteristics of both epithelial and mesenchymal cells that normally act as a barrier and secrete factors to maintain peritoneal homeostasis [ 118 ]. The aged peritoneum accommodates increasing numbers of senescent mesothelial cells that secrete various factors (e.g., fibronectin, ICAM-1, beta-galactosidase, and angiogenic and inflammatory mediators) into the ovarian cancer TME that enhance cellular adhesion and tissue stiffness [ 76 , 118 ]. Senescent mesothelial cells also induce ovarian cancer cell production of angiogenic factors, and promote migration and invasion [ 119 ].…”