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”.

Keywords: adipocytes; age; extracellular matrix; fibroblast; immune; mesothelial cells; ovarian cancer; peritoneum; tumor microenvironment.

Figure 1

Changes in the Aged Microenvironment. Young: In the young metastatic microenvironment, collagens I and III form a directionally random meshwork that supports the tissue. In addition, there are low rates of senescence in mesothelial cells, fibroblasts and adipocytes, all of which secrete factors into the extracellular environment, forming the young secretome. The young secretome is characterized by decreased Matrix Metalloproteinase (MMP) expression, increased cytokine expression by immune cells, decreased cytokine expression by fibroblasts and decreased adipocyte-associated inflammatory factors. Milky spot immune cell aggregates exist in both young and aged metastatic environments, providing the tumor with abundant vascularization. Aged: In the aged metastatic microenvironment, there are lower levels of collagens I and III, which are remodeled to form more aligned, linear structures. In addition, higher levels of senescence alter the secretome, increasing inflammation and other factors that can promote ovarian cancer (OvCa) metastasis.

Figure 2

Age-related changes in omental collagen structure. Second harmonic generation imaging of omental tissue isolated from young and aged mice shows a distinct difference in structure. Aged collagen forms crosslinks that result in the loss of meshwork, formation of tendon-like structures and increased anisotropy. This causes a disruption of tissue structure that can affect how metastasizing OvCa cells interact with the tumor microenvironment.

Figure 3

Stromal-Epithelial Crosstalk. Active crosstalk occurs between senescent and activated fibroblasts and OvCa cells. This induces activated fibroblasts, while concurrently inducing proliferation and malignancy of the invading tumor.

Figure 4

The effects of aging on the peritoneal microenvironment. (a) Tumor-Inducing Effects: Aging of the host stimulates a vast and interconnected network of alterations to the peritoneal microenvironment. These changes are often correlated with increased tumor burden due to heightened angiogenesis of the region and OvCa cell adhesion, invasion, proliferation and survival. As depicted, the multifactorial causes and results of aging present significant challenges for analysis; (b) Tumor-Suppressing Effects: While our review generally concludes that aging alters the microenvironment in a way conducive to tumor growth, in contrast certain aspects of aging seem to impair tumorigenesis. Aged and senescent mesothelial cells secrete less hyaluronic acid, which is hypothesized to decrease OvCa adhesion to the extracellular matrix (ECM). Inactivated aged macrophages are less capable of cytokine secretion, which thereby decreases angiogenesis potential and cell invasion. The aged BM thickens due to less collagen IV turnover, which we speculate could in theory decrease OvCa invasion (however, to our knowledge no conclusions have been drawn regarding this). The aged basement membrane (BM) also has a decreased laminin content, which may decrease cell adhesion. * While not shown to be a causative link, in aged adipose tissue there is an increase in reactive oxygen species (ROS) that is correlated with adipocytes presenting a senescent phenotype, suggesting that ROS plays the same role in adipocytes that it does in other cell types [145]. p53 has been shown to have numerous effects on adipose tissue and is likely also contributing to the senescent phenotype [145]. ** Aged macrophages paradigm: aged macrophages have been shown to both induce tumorigenesis and inhibit it., we depict both pathways. Note: Color gradients intended to help viewer differentiate between different effects of each component of the aging microenvironment.