The extracellular matrix of ovarian cortical inclusion cysts modulates invasion of fallopian tube epithelial cells

Abstract

A growing body of research supports the idea that the fallopian tube epithelium (FTE) is the precursor for most high-grade serous ovarian cancers (HGSOCs) but that the ovary plays a critical role in tumor metastasis. Cortical inclusion cysts (CICs) in the ovarian cortex have been hypothesized to create a niche environment that plays a role in HGSOC progression. Through histological analysis of pathology samples from human ovaries, we determined that collagen I and III were elevated near CICs and that the collagen fibers in this dense region were oriented parallel to the cyst boundary. Using this information from human samples as design parameters, we engineered an in vitro model that recreates the size, shape, and extracellular matrix properties of CICs. We found that FTE cells within our model underwent robust invasion that was responsive to stimulation with follicular fluid, while ovarian surface epithelial cells, the native cells of the ovary, were not invasive. We provide experimental evidence to support a role of the extracellular matrix in modulating FTE cell invasion, as a decrease in collagen I concentration or the addition of collagen III to the matrix surrounding FTE cells increased FTE cell invasion. Taken together, we show that an in vitro model of CICs obtained from the analysis of human tissue can act as an important tool for understanding FTE cell interactions with their environment.

Esophageal extracellular matrix hydrogel mitigates metaplastic change in a dog model of Barrett’s esophagus

“…Specific components of the tumor microenvironment such as COL11A1, fibroblast activation protein (-FAP), and COX-2 have been suggested as both diagnostic/prognostic markers for the presence or progression of neoplasia (11) and as potential therapeutic targets (12). Among the tissues and organs investigated with respect to the relationship between ECM microenvironment and development and progression of neoplasia are the ovary (13), breast (14), and esophagus (15)(16)(17).…”

Engineering the Extracellular Matrix to Model the Evolving Tumor Microenvironment

“…In this model, a lumen with a diameter of approximately 300 mm is lined with normal mammary epithelial cells and then left empty in the center (normal) or filled with breast cancer cells (DCIS) (Ayuso et al, 2018). This lumen-generating method has been modified to generate models of ovarian cortical inclusion cysts, demonstrating that, of the two proposed cells of origin for ovarian cancer, only fallopian tube epithelial cells are able to invade into the surrounding matrix (Fleszar et al, 2018). As cortical inclusion cysts range in size and are believed to resolve over time, a recent paper modeled the range of curvatures observed in human cysts and determined that as curvature increased (i.e., the cyst diameter decreased) the fallopian tube epithelial monolayer transitioned from stable to invasive (Fleszar et al, 2019).…”

Bioengineering models of female reproduction

“…Theory shows that cortical inclusion cysts (CICs) in the ovary play a role in HGSC progression. Other studies use human samples to engineer an in vitro model that mimics the size, shape, and extracellular matrix properties of CICs [88,89]. Taken together, these engineered platforms can provide new knowledge on basic gynecologic cancer biology and pathology and for potential drug screening and development.…”