Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer

Huimin Lu, Nicholas Bowler, Larry A. Harshyne, D. Craig Hooper, Shiv Ram Krishn, Senem Kurtoglu, Carmine Fedele, Qin Liu, Hsin Yao Tang, Andrew V. Kossenkov, William K. Kelly, Kerith Wang, Rhonda B. Kean, Paul H. Weinreb, Lei Yu, Anindita Dutta, Paolo Fortina, Adam Ertel, Maria Stanczak, Flemming ForsbergDmitry I. Gabrilovich, David W. Speicher, Dario C. Altieri, Lucia R. Languino

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvβ6 is transferred from cancer cells to monocytes, including β6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvβ6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvβ6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvβ6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc−/− prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvβ6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvβ6 from cancer cells to monocytes through exosomes.

Original languageEnglish
Pages (from-to)20-35
Number of pages16
JournalMatrix Biology
Volume70
DOIs
StatePublished - Sep 2018
Externally publishedYes

Keywords

  • Exosomes
  • M2 polarization
  • Monocytes
  • Prostate Cancer
  • STAT1
  • αvβ6 integrin

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