The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.
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.
Coffelt
Seth B
SB
Tumor Targeting Group, University of Sheffield School of Medicine, Sheffield, United Kingdom.
Marini
Frank C
FC
Watson
Keri
K
Zwezdaryk
Kevin J
KJ
Dembinski
Jennifer L
JL
LaMarca
Heather L
HL
Tomchuck
Suzanne L
SL
Honer zu Bentrup
Kerstin
K
Danka
Elizabeth S
ES
Henkle
Sarah L
SL
Scandurro
Aline B
AB
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D054804:Cathelicidins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D009500:Neutralization Tests; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D043925:Angiogenesis Inducing Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D002630:Chemotactic Factors; D018836:Inflammation Mediators; D043562:Receptors, G-Protein-Coupled