Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

Gaofeng Xiong, Jie Chen, Guoying Zhang, Shike Wang, Kunito Kawasaki, Jieqing Zhu, Yan Zhang, Kazuhiro Nagata, Zhenyu Li, Binhua P. Zhou, Ren Xu

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.

Original languageEnglish
Pages (from-to)3748-3758
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number7
DOIs
StatePublished - Feb 18 2020

Bibliographical note

Funding Information:
Facility at the Markey Cancer Center (P30CA177558). This study was supported by National Cancer Institute Grants 1R01 CA207772, 1R01 CA215095, and 1R21 CA209045 (to R.X.).

Funding Information:
We appreciate the technical support provided by the University of Kentucky Flow Cytometry and Cell Sorting Core Facility; and the Biospecimen Procurement and Translational Pathology Shared Resource Facility at the Markey Cancer Center (P30CA177558). This study was supported by National Cancer Institute Grants 1R01 CA207772, 1R01 CA215095, and 1R21 CA209045 (to R.X.).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Breast cancer
  • Cancer metastasis
  • Circulating tumor cell
  • Epithelial-mesenchymal
  • Extracellular matrix
  • Transition

ASJC Scopus subject areas

  • General

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