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MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer

Anirban K. Mitra, Marion Zillhardt, Youjia Hua, Payal Tiwari, Andrea E. Murmann, Marcus E. Peter and Ernst Lengyel
Anirban K. Mitra
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Marion Zillhardt
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Youjia Hua
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Payal Tiwari
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Andrea E. Murmann
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Marcus E. Peter
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Ernst Lengyel
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago; and 2Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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DOI: 10.1158/2159-8290.CD-12-0206 Published December 2012
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Abstract

Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit.

Significance: The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. Cancer Discov; 2(12); 1100–8. ©2012 AACR.

Read the Commentary on this article by Chou and Werb, p. 1078

This article is highlighted in the In This Issue feature, p. 1065

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • M.E. Peter and E. Lengyel share last authorship.

  • Received May 8, 2012.
  • Revision received August 8, 2012.
  • Accepted September 7, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Discovery: 2 (12)
December 2012
Volume 2, Issue 12
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MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Anirban K. Mitra, Marion Zillhardt, Youjia Hua, Payal Tiwari, Andrea E. Murmann, Marcus E. Peter and Ernst Lengyel
Cancer Discov December 1 2012 (2) (12) 1100-1108; DOI: 10.1158/2159-8290.CD-12-0206

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MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Anirban K. Mitra, Marion Zillhardt, Youjia Hua, Payal Tiwari, Andrea E. Murmann, Marcus E. Peter and Ernst Lengyel
Cancer Discov December 1 2012 (2) (12) 1100-1108; DOI: 10.1158/2159-8290.CD-12-0206
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