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Mol Oncol. 2017 Oct;11(10):1307-1329. doi: 10.1002/1878-0261.12075. Epub 2017 Aug 10.

Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells.

Author information

1
Australian Prostate Cancer Research Centre - Queensland, Translational Research Institute, Queensland University of Technology (QUT), Woolloongabba, Australia.
2
Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Kelvin Grove, Australia.
3
Regenerative Dentistry and Oral Biology, Oral Health Centre, University of Queensland, Herston, Australia.
4
Aquesta Pathology, Toowong, Australia.
5
School of Medicine, University of Queensland, Herston, Australia.
6
Australian Prostate Cancer BioResource, The Prostate Cancer Research Program, Monash University, Clayton, Australia.
7
Prostate Research Group, Cancer Program - Biomedicine Discovery Institute Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Australia.
8
Cancer Biology and Care Program, Translational Research Institute, Mater Research Institute - The University of Queensland, Woolloongabba, Australia.
9
Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Parkville, Australia.
10
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.

Abstract

The reciprocal communication between cancer cells and their microenvironment is critical in cancer progression. Although involvement of cancer-associated fibroblasts (CAF) in cancer progression is long established, the molecular mechanisms leading to differentiation of CAFs from normal fibroblasts are poorly understood. Here, we report that kallikrein-related peptidase-4 (KLK4) promotes CAF differentiation. KLK4 is highly expressed in prostate epithelial cells of premalignant (prostatic intraepithelial neoplasia) and malignant lesions compared to normal prostate epithelia, especially at the peristromal interface. KLK4 induced CAF-like features in the prostate-derived WPMY1 normal stromal cell line, including increased expression of alpha-smooth muscle actin, ESR1 and SFRP1. KLK4 activated protease-activated receptor-1 in WPMY1 cells increasing expression of several factors (FGF1, TAGLN, LOX, IL8, VEGFA) involved in prostate cancer progression. In addition, KLK4 induced WPMY1 cell proliferation and secretome changes, which in turn stimulated HUVEC cell proliferation that could be blocked by a VEGFA antibody. Importantly, the genes dysregulated by KLK4 treatment of WPMY1 cells were also differentially expressed between patient-derived CAFs compared to matched nonmalignant fibroblasts and were further increased by KLK4 treatment. Taken together, we propose that epithelial-derived KLK4 promotes tumour progression by actively promoting CAF differentiation in the prostate stromal microenvironment.

KEYWORDS:

KLK ; cancer; cancer-associated fibroblast; kallikrein-related peptidase; prostate cancer; tumour microenvironment

PMID:
28510269
PMCID:
PMC5623815
DOI:
10.1002/1878-0261.12075
[Indexed for MEDLINE]
Free PMC Article

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