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J Clin Invest. 2018 Feb 1;128(2):589-606. doi: 10.1172/JCI95200. Epub 2017 Dec 18.

Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
3
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
4
Department of Cancer Biology.
5
The Center for RNA Interference and Non-Coding RNAs, and.
6
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Department of Systems Medicine and Bioengineering, and.
8
NCI Center for Modeling Cancer Development, Houston Methodist Research Institute, Houston, Texas, USA.
9
Comprehensive Cancer Center, Division of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Abstract

The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.

KEYWORDS:

Cancer; Cell Biology; Oncology

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