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Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function

Begum, Asma, PhD*; McMillan, Ross H., MD, PhD*; Chang, Yu-Tai, PhD*; Penchev, Vesselin R., PhD*; Rajeshkumar, N.V., PhD*; Maitra, Anirban, MBBS; Goggins, Michael G., MD; Eshelman, James R., MD, PhD; Wolfgang, Christopher L., MD, PhD§; Rasheed, Zeshaan A., MD, PhD*; Matsui, William, MD*

doi: 10.1097/MPA.0000000000001249
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Objective Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs).

Methods Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin–focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor.

Results Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth.

Conclusion Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.

From the *Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD;

Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX; and

Departments of Pathology and

§Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.

Received for publication May 29, 2018; accepted December 20, 2018.

Address correspondence to: William Matsui, MD, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Health Discovery Building, Suite 6.310, 1701 Trinity St, Stop Z1100, Austin, TX 78712 (e-mail: william.matsui@austin.utexas.edu).

Current address of Zeshaan A. Rasheed: AstraZeneca, One MedImmune Way, Gaithersburg, MD 20868.

Support was provided by The Pancreatic Cancer Action Network-AACR 10-70-25-RASH (Z.A.R.), The V Foundation (Z.A.R.), National Institutes of Health R01CA150142 (W.M.), R01CA193887 (W.M.), and The Lustgarten Foundation (W.M.).

Asma Begum, Ross H. McMillan, Yu-Tai Chang, Vesselin R. Penchev, NV Rajeshkumar, Anirban Maitra, Michael G. Goggins, James R. Eshelman, Christopher L. Wolfgang, Zeshaan A. Rasheed, and William Matsui do not have competing financial interests.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pancreasjournal.com).

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