Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance
Cecilia S. Leung, … , Michael J. Birrer, Samuel C. Mok
Cecilia S. Leung, … , Michael J. Birrer, Samuel C. Mok
Published December 18, 2017
Citation Information: J Clin Invest. 2018;128(2):589-606. https://doi.org/10.1172/JCI95200.
View: Text | PDF
Research Article Cell biology Oncology Article has an altmetric score of 1

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

  • Text
  • PDF
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.

Authors

Cecilia S. Leung, Tsz-Lun Yeung, Kay-Pong Yip, Kwong-Kwok Wong, Samuel Y. Ho, Lingegowda S. Mangala, Anil K. Sood, Gabriel Lopez-Berestein, Jianting Sheng, Stephen T.C. Wong, Michael J. Birrer, Samuel C. Mok

×

Figure 3

CAF-derived MFAP5 modulates endothelial LPP expression and tumor vasculature.

Options: View larger image (or click on image) Download as PowerPoint
CAF-derived MFAP5 modulates endothelial LPP expression and tumor vascula...
(A) Plot shows a significant correlation between LPP expression in endothelial cells and MFAP5 expression in CAFs (n = 96; R = 0.652, P < 0.001, by Spearman rank correlation). Hematoxylin-counterstained images of immunolocalization of MFAP5 and LPP in 2 HGSC tissue samples showing that high levels of endothelial LPP expression were associated with high levels of stromal MFAP5 (Case 815) and that low levels of endothelial LPP expression were associated with low levels of stromal MFAP5 (Case 1265). Scale bars: 50 μm. (B) qRT-PCR analyses show that TIME and hMEC-1 MECs treated with recMFAP5 had significantly higher levels of LPP mRNA than did PBS-treated MECs (mean ± SEM of 3 independent experiments; P values were determined by 2-tailed Student’s t test). (C) Western blots show that TIME and hMEC-1 MECs treated with recMFAP5 had markedly increased LPP protein expression levels compared with PBS-treated MECs. (D) Murine fibroblasts transfected with 3 different Mfap5-specific siRNAs had significantly lower levels of Mfap5 mRNA expression than did those transfected with the scrambled siRNA or the vehicle (mean ± SEM of 3 independent experiments; †P < 0.001, by 2-tailed Student’s t test). (E) Bioluminescence images showing markedly decreased luciferase signals in A224 ovarian tumor–bearing mice treated with chitosan nanoparticles incorporated with Mfap5-targeting siRNAs compared with mice injected with chitosan nanoparticles incorporated with the scrambled siRNA. Tumor growth was monitored using the IVIS 200 Bioluminescence and Fluorescence Imaging System. (F) Box and whisker plot showing significantly lower luminescence signal intensities in mice treated with chitosan nanoparticles incorporated with Mfap5-targeting siRNA 68 and Mfap5-targeting siRNA 69 than signals in mice injected with chitosan nanoparticles incorporated with the scrambled siRNA. Boxes represent the interquartile range of the records, and the lines across the boxes indicate the median. Whiskers indicate the highest and lowest values that were no greater than 1.5 times the interquartile range (n = 10 per group; *P < 0.01, by Mann-Whitney U test). (G) Box and whisker plot showing that the tumor weights in mice treated with Mfap5-targeting siRNA were significantly lower than tumor weightsin mice treated with scrambled siRNA at the experimental endpoint (n = 10/group; *P < 0.01, by Mann-Whitney U test). (H) Hematoxylin-counterstained images of immunolocalization of murine Mfap5 and CD34 show that tumors from Mfap5-targeting siRNA– treated mice had markedly lower stromal Mfap5 expression and lower CD34-positive microvessel densities than did tumors from control mice (n = 5 per group; mean ± SD; *P < 0.01, by Mann-Whitney U test). Tumor cells were injected i.p. Scale bars: 50 μm. (I) Hematoxylin-counterstained images of immunolocalization of murine Mfap5 and CD34 show that tumors from Mfap5-targeting siRNA– treated mice had markedly lower stromal Mfap5 expression and lower CD34-positive microvessel densities than did tumors from control mice (n = 5 per group; mean ± SD; *P < 0.01, by Mann-Whitney U test). Tumor cells were delivered by intraovarian injection. Scale bars: 50 μm. S, Stroma; T, Tumor. (J) Hematoxylin-counterstained images of immunolocalization of Lpp show that tumors from mice treated with Mfap5-targeting siRNAs had significantly lower endothelial Lpp expression levels than did those treated with scrambled siRNA. Arrowheads indicate microvessels in the tumor tissue. Scale bars: 50 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 1 X users
89 readers on Mendeley
See more details