Tumor-associated fibrosis: a unique mechanism promoting ovarian cancer metastasis and peritoneal dissemination

Abstract

Epithelial ovarian cancer (EOC) is often diagnosed in advanced stage with peritoneal dissemination. Recent studies indicate that aberrant accumulation of collagen fibers in tumor stroma has a variety of effects on tumor progression. We refer to remodeled fibrous stroma with altered expression of collagen molecules, increased stiffness, and highly oriented collagen fibers as tumor-associated fibrosis (TAF). TAF contributes to EOC cell invasion and metastasis in the intraperitoneal cavity. However, an understanding of molecular events involved is only just beginning to emerge. Further development in this field will lead to new strategies to treat EOC. In this review, we focus on the recent findings on how the TAF contributes to EOC malignancy. Furthermore, we will review the recent initiatives and future therapeutic strategies for targeting TAF in EOC.

Keywords: Extracellular matrix; Fibrosis; Mesothelial; Metastasis; Ovarian cancer.

Fig. 1

Example of Masson-trichrome staining in an omental metastasis from a patient with high-grade serous ovarian cancer (unpublished data). It shows complex structures of cancer cells with substantial fibrous stroma around the tumor

Fig. 2

Schematic diagram of tumor-associated fibrosis. Left: pre-fibrosis. Right: post-fibrosis. Accumulation of collagen fibers alters tumor microenvironment by biochemical cross-talking with CAFs, which affects the nature of the tumors, such as tumor growth, angiogenesis, and immune cell infiltration. Abbreviation: ECM, extracellular matrix

Fig. 3

Tumor stiffness stimulates EOC cells by activating integrin/FAK and its subsequent signaling pathways: Rho/ROCK pathway, and Hippo pathway. MEK/MAPK pathway is also stimulated by stiff external stimuli, and it might be activated by integrin/FAK. These signal pathways responding to tumor stiffness facilitates tumor progression. Stiffness may also augment collagen production via Hippo pathway in OCAMs or CAFs. These reactions against tumor stiffness also promote tumor progression and more collagen production, augmenting tumor stiffness. Abbreviations: EOC, epithelial ovarian cancer; OCAM, ovarian-cancer associated mesothelial cell; CAF, cancer-associated fibroblast

Fig. 4

EOC metastasis and recurrence cycle of tumor stroma. 1 (top right): Chemokines and cytokines, such as TGF-β, and exosomes alter the stroma in future-metastatic sites. 2 (bottom right): After tumor cells attach to mesothelial cells, they establish the “soil” by remodeling the collagen-rich stroma. Expression patterns of various types of collagens, stiffness, and alignment of collagen are altered to create a tumor-favorable environment. 3 (bottom left): Tumor-associated fibrosis affects various tumor cell functions. 4 (top left): Chemotherapy induces further fibrosis, which may lead tumor cells into dormancy and enable them to persist in the harsh environment. After chemotherapy, tumor cells can sprout leading to recurrence. Abbreviations: EOC, epithelial ovarian cancer; EMT, epithelial mesenchymal transition; MMT, mesothelial-mesenchymal transition; CAF, cancer-associated fibroblast