The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

Coffelt, S. B. et al. (2009) The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proceedings of the National Academy of Sciences of the United States of America, 106(10), pp. 3806-3811. (doi:10.1073/pnas.0900244106) (PMID:19234121) (PMCID:PMC2656161)

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Abstract

Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.

Item Type:Articles
Additional Information:This work was supported in part by National Institutes of Health grants 1P20RR20152–01 (to A.B.S.) and CA-1094551, CA-116199, and CA49639 (to F.C.M.); Susan G. Komen Breast Cancer Foundation grant BCTR0504372 (to K.W., J.L.D., and F.C.M.), and the W. M. Keck Foundation
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coffelt, Dr Seth
Authors: Coffelt, S. B., Marini, F. C., Watson, K., Zwezdaryk, K. J., Dembinski, J. L., LaMarca, H. L., Tomchuck, S. L., zu Bentrup, K. H., Danka, E. S., Henkle, S. L., and Scandurro, A. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:20 February 2009

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