Dynamic Changes in the Extracellular Matrix in Primary, Metastatic, and Recurrent Ovarian Cancers

Abstract

Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1+ CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8+ T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8+ T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment.

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

“…The ECM is significantly gaining attention as a key contributor to OC tumor progression and recurrence 73,74 . To better study the ECM, the matrisome was established as an ensemble of over 1000 ECM-related genes that encode for two groups of ECM proteins, either matrisome-associated or core matrisome.…”

Heterogeneity of primary and metastatic CAFs: From differential treatment outcomes to treatment opportunities (Review)

“…In addition, the deposition of ECM traps immune cells in the tumor stroma and increases their resistance to infiltration into the tumor parenchyma (14). Gertych et al (15) observed that there was a difference in the proportion of CAFs in primary tumors and metastases and the differences in the matreotypes between the two were determined by COL11A1+ CAFs, although there is high CD8+ T cell infiltration in metastases, they are excluded by the proliferating ECM, resulting in a lower survival rate.…”

“…Compared with pCAFs, mCAFs generally have a stronger ability to shape the ECM, and in immunosuppression and angiogenesis (12)(13)(14)(15)(16). The results of preclinical studies suggest that targeting mCAFs can alleviate the progression of metastatic cancer and mitigate therapeutic resistance, indicating that mCAFs are a promising target for metastatic cancer (17).…”

The β-arrestin1/endothelin axis bolsters ovarian fibroblast-dependent invadosome activity and cancer cell metastatic potential

“…In addition, several signaling pathways, ligands, and receptors are involved in the communication between CAFs and cancer cells with prognostic and therapeutic relevance [ 7 – 12 ]. An abundance of CAFs is associated with advanced stage and metastasis to the omentum and lymph nodes, contributing to the formation of the premetastatic niche and the failure of drug treatments by exchanging signals with tumor cells [ 7 , 13 ]. CAFs can form the core of spheroids and serve as a scaffolding to aggregate in heterotypic spheroids with cancer cells, via the activation of cadherins and integrins, representing metastatic units with high malignant potential.…”