Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Notch3 Promotes Prostate Cancer-Induced Bone Osteoblastic Metastasis in an MMP-3-Dependent Manner

Sourik S Ganguly, Galen Hostetter, Lin Tang, Sander Frank, Kathylynn Saboda, Rohit Mehra, Lisha Wang, Xiaohong Li, Evan T Keller, Cindy K Miranti
doi: https://doi.org/10.1101/349043
Sourik S Ganguly
Van Andel Research Institute;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Galen Hostetter
Van Andel Research Institute;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lin Tang
University of Arizona Cancer Center;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sander Frank
Van Andel Research Institute;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathylynn Saboda
University of Arizona;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rohit Mehra
University of Michigan;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisha Wang
University of Michigan;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaohong Li
Van Andel Reserach Institute
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Evan T Keller
University of Michigan;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cindy K Miranti
University of Arizona Cancer Center;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: cmiranti@email.arizona.edu
  • Abstract
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Purpose: Over ninety percent of prostate cancer metastasis is localized in the bone where it induces a unique osteoblastic response. Elevated Notch signaling is associated with advanced high-grade disease and metastasis, but how it contributes to osteoblastic bone metastasis is unknown. Experimental Design: To determine how Notch affects prostate cancer bone metastasis, Notch expression was manipulated in mouse tibia xenografts and tumor growth, lesion phenotype, and tumor microenvironment assessed. Patient bone metastases were assessed for Notch3 and MMP-3 expression. Results: Osteoblastic tumor cells expressed 5-6 times more Notch3, than osteolytic tumor cells. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogenesis. This was accompanied by a respective decrease and increase in number of active osteoclasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated in NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced block in osteolytic lesions, suppressed osteoblast proliferation, and stimulated osteoclastogenesis. Human bone metastasis samples had higher levels of Notch3 and MMP-3 compared to patient matched visceral metastases. Conclusions: We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that promotes osteoblastic lesion formation by blocking osteoclast differentiation, while stimulating osteoblastogenesis. This newly identified Notch3-MMP-3 axis could be used as a therapeutic target for inhibiting osteoblastic bone metastasis.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted June 16, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Notch3 Promotes Prostate Cancer-Induced Bone Osteoblastic Metastasis in an MMP-3-Dependent Manner
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
Share
Notch3 Promotes Prostate Cancer-Induced Bone Osteoblastic Metastasis in an MMP-3-Dependent Manner
Sourik S Ganguly, Galen Hostetter, Lin Tang, Sander Frank, Kathylynn Saboda, Rohit Mehra, Lisha Wang, Xiaohong Li, Evan T Keller, Cindy K Miranti
bioRxiv 349043; doi: https://doi.org/10.1101/349043
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Notch3 Promotes Prostate Cancer-Induced Bone Osteoblastic Metastasis in an MMP-3-Dependent Manner
Sourik S Ganguly, Galen Hostetter, Lin Tang, Sander Frank, Kathylynn Saboda, Rohit Mehra, Lisha Wang, Xiaohong Li, Evan T Keller, Cindy K Miranti
bioRxiv 349043; doi: https://doi.org/10.1101/349043

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (997)
  • Biochemistry (1485)
  • Bioengineering (941)
  • Bioinformatics (6810)
  • Biophysics (2414)
  • Cancer Biology (1783)
  • Cell Biology (2523)
  • Clinical Trials (106)
  • Developmental Biology (1688)
  • Ecology (2558)
  • Epidemiology (1491)
  • Evolutionary Biology (5007)
  • Genetics (3605)
  • Genomics (4620)
  • Immunology (1160)
  • Microbiology (4233)
  • Molecular Biology (1618)
  • Neuroscience (10764)
  • Paleontology (82)
  • Pathology (236)
  • Pharmacology and Toxicology (408)
  • Physiology (554)
  • Plant Biology (1450)
  • Scientific Communication and Education (410)
  • Synthetic Biology (542)
  • Systems Biology (1870)
  • Zoology (259)