TGFβ1 in fibroblasts-derived exosomes promotes epithelial-mesenchymal transition of ovarian cancer cells.

Wenqian Li,Ding Ma,Jiahong Tan,Canhui Cao,Ji Wang,Qinglei Gao,Mengchen Li,Xiaoxue Zhang

doi:10.18632/oncotarget.21635

Wenqian Li, Ding Ma + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.21635

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Abstract

Cancer-associated fibroblasts (CAF), a major component of the tumor microenvironment, play an important role in interacting with neoplastic cells to promote ovarian cancer progression. Exosomes are nano-sized vesicles that mediate the cross-talk between different cell types. An increasing number of studies have focused on the fact that tumor cell-derived exosomes influence stromal cells. However, the mechanism by which CAF-derived exosomes modulate cancer cells in ovarian cancer remains obscure. To investigate the role of CAF exosomes in ovarian cancer, we examined the exosomal content of paired primary, metastatic and normal fibroblasts from seven stage IIIC ovarian cancer patients by ELISA. We found that in ovarian CAF-derived exosomes, TGFβ1 was upregulated compared to normal omentum fibroblasts (NOF). Exosomes derived from CAF were taken up by ovarian SKOV-3 and CAOV-3 cell lines during co-culture and induced malignant behaviors in cancer cells, including an enhanced migration and invasion ability and the promotion of epithelial-mesenchymal transition (EMT) by activating the SMAD signaling pathway. Our results indicate that the role of TGFβ1 in CAF exosomes triggers ovarian cancer cells into a more aggressive phenotype, suggesting that targeting CAF exosomes could be a potential treatment in ovarian cancer.

Highlights

Epithelial ovarian cancer, one of the leading causes of death in women, is generally characterized by widespread peritoneal metastasis and a poor 5-year survival rate [1, 2]
Our results indicate that the role of TGFβ1 in Cancer-associated fibroblasts (CAF) exosomes triggers ovarian cancer cells into a more aggressive phenotype, suggesting that targeting CAF exosomes could be a potential treatment in ovarian cancer
We investigated whether the release of CAF exosomes and their contained proteins is involved in inducing an epithelialmesenchymal transition (EMT) phenotype in cancer cells and promoting peritoneal metastasis in ovarian cancer

Summary

Introduction

Epithelial ovarian cancer, one of the leading causes of death in women, is generally characterized by widespread peritoneal metastasis and a poor 5-year survival rate [1, 2]. The tissue-specific metastasis or premetastatic niches, usually referred to as “seed and soil”, represent a specialized microenvironment that is favorable for tumor cells to survive and grow [4, 5]. Previous studies suggest that CAF play a pivotal role in establishing a metastatic niche and promoting tumor cell proliferation, invasion and metastasis by secreting chemokines and cytokines in this environment [8,9,10]. It is still unclear how fibroblasts reprogram tumor cells and how they contribute to omentum metastasis at early ovarian cancer progression

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