Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells.

Snider Desir,Emil Lou,Phillip Wong,Subbaya Subramanian,Rachel I Vogel,Deanna Teoh,Venugopal Thayanithy,Elizabeth L Dickson,Melissa A Geller,Clifford J Steer

doi:10.18632/oncotarget.9504

Abstract

In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200). We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers.

Highlights

Ovarian cancer is the most fatal gynecologic cancer in the United States [1]
We demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200).We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy
TNT formation was detected in cocultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment

Summary

Introduction

Platinum-based chemotherapy is the primary treatment for ovarian cancer; resistance to chemotherapy continues to be a major clinical problem [2]. The molecular mechanisms of chemotherapy resistance remain unclear. It is widely accepted that chemoresistance emerges as a result of mutations in key regulatory genes with cells passing these genetic mutations via vertical transmission to daughter cells through mitotic division and clonal expansion. Horizontal (cellto-cell) transmission of regulatory factors via channels of cellular communication could be responsible for the development of chemotherapy resistance. This concept was, proposed as a model of chemoresistance in ovarian cancer over 20 years ago [3]

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