CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth.
This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
Augsten
Martin
M
Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
Hägglöf
Christina
C
Olsson
Eleonor
E
Stolz
Claudia
C
Tsagozis
Panagiotis
P
Levchenko
Tetyana
T
Frederick
Mitchell J
MJ
Borg
Ake
A
Micke
Patrick
P
Egevad
Lars
L
Ostman
Arne
A
D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins