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Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance
Open accessAbstract
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.
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“Since excessive fibrosis also acts as the obstacle of obtaining anticancer effects from drug treatments,[ 37 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [37]
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Metadata
- Authors
- Leung, C. S., Yeung, T.-L., Yip, K.-P., Wong, K.-K., Ho, S. Y., Mangala, L. S., Sood, A. K., Lopez-Berestein, G., Sheng, J., Wong, S. T. C., Birrer, M. J., & Mok, S. C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of South Florida (US)
- Houston Methodist Research Institute (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Birrer, Michael J.
- Mok, Samuel C.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2017-12-18
- Volume
- 128
- Issue
- 2
- Pages
- 589-606
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5785271
- OpenAlex
- W2774854449
- Cited by
- 132
- References
- 44
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 14 · 2023: 16 · 2022: 16 · 2021: 23 · 2020: 17 · 2019: 18 · 2018: 12
- FWCI
- 14.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA133057, R01CA142832, RC4CA156551, U54CA151668, P50CA083639, P50CA098258)
- Cancer Prevention and Research Institute of Texas (RP100094, RP110595)
- U.S. Department of Defense (W81XWH-17-1-0126, W81XWH-16-2-0038)
- Topics
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- cancer-associated fibroblasts, ovarian cancer, chemoresistance, LPP, endothelial cells, tumor vasculature, endothelial cell motility, focal adhesions, calcium signaling, MFAP5, focal adhesion kinase, ERK, paclitaxel delivery, siRNA therapeutics
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Cell Movement, Cytoskeletal Proteins, Female, Fibrosis, Humans, Microcirculation, Neovascularization, Pathologic, Ovarian Neoplasms, Permeability, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Treatment Outcome, Disease Progression, Drug Resistance, Neoplasm, Gene Silencing, Gene Expression Profiling, Focal Adhesions, RNA, Small Interfering, Endothelial Cells, Cell Line, Tumor, Mice, LIM Domain Proteins
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