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

Thomas Kryza, Lakmali M. Silva, Nathalie Bock, Ruth A. Fuhrman-Luck, Carson R. Stephens, Jin Gao, Hema Samaratunga, Australian Prostate Cancer BioResource, Mitchell G. Lawrence, John D. Hooper, Ying Dong, Gail P. Risbridger, Judith A. Clements

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1307-1329
Number of pages23
JournalMolecular Oncology
Volume11
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Keywords

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

Cite this

Kryza, T., Silva, L. M., Bock, N., Fuhrman-Luck, R. A., Stephens, C. R., Gao, J., ... Clements, J. A. (2017). Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells. Molecular Oncology, 11(10), 1307-1329. https://doi.org/10.1002/1878-0261.12075
Kryza, Thomas ; Silva, Lakmali M. ; Bock, Nathalie ; Fuhrman-Luck, Ruth A. ; Stephens, Carson R. ; Gao, Jin ; Samaratunga, Hema ; Australian Prostate Cancer BioResource ; Lawrence, Mitchell G. ; Hooper, John D. ; Dong, Ying ; Risbridger, Gail P. ; Clements, Judith A. / Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells. In: Molecular Oncology. 2017 ; Vol. 11, No. 10. pp. 1307-1329.
@article{8bf0f7f6f63d4773afb4fa681b1e1391,
title = "Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells",
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 = "cancer, cancer-associated fibroblast, kallikrein-related peptidase, KLK, prostate cancer, tumour microenvironment",
author = "Thomas Kryza and Silva, {Lakmali M.} and Nathalie Bock and Fuhrman-Luck, {Ruth A.} and Stephens, {Carson R.} and Jin Gao and Hema Samaratunga and {Australian Prostate Cancer BioResource} and Lawrence, {Mitchell G.} and Hooper, {John D.} and Ying Dong and Risbridger, {Gail P.} and Clements, {Judith A.}",
year = "2017",
month = "10",
day = "1",
doi = "10.1002/1878-0261.12075",
language = "English",
volume = "11",
pages = "1307--1329",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "John Wiley & Sons",
number = "10",

}

Kryza, T, Silva, LM, Bock, N, Fuhrman-Luck, RA, Stephens, CR, Gao, J, Samaratunga, H, Australian Prostate Cancer BioResource, Lawrence, MG, Hooper, JD, Dong, Y, Risbridger, GP & Clements, JA 2017, 'Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells' Molecular Oncology, vol. 11, no. 10, pp. 1307-1329. https://doi.org/10.1002/1878-0261.12075

Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells. / Kryza, Thomas; Silva, Lakmali M.; Bock, Nathalie; Fuhrman-Luck, Ruth A.; Stephens, Carson R.; Gao, Jin; Samaratunga, Hema; Australian Prostate Cancer BioResource ; Lawrence, Mitchell G.; Hooper, John D.; Dong, Ying; Risbridger, Gail P.; Clements, Judith A.

In: Molecular Oncology, Vol. 11, No. 10, 01.10.2017, p. 1307-1329.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells

AU - Kryza, Thomas

AU - Silva, Lakmali M.

AU - Bock, Nathalie

AU - Fuhrman-Luck, Ruth A.

AU - Stephens, Carson R.

AU - Gao, Jin

AU - Samaratunga, Hema

AU - Australian Prostate Cancer BioResource

AU - Lawrence, Mitchell G.

AU - Hooper, John D.

AU - Dong, Ying

AU - Risbridger, Gail P.

AU - Clements, Judith A.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

KW - cancer

KW - cancer-associated fibroblast

KW - kallikrein-related peptidase

KW - KLK

KW - prostate cancer

KW - tumour microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85030219544&partnerID=8YFLogxK

U2 - 10.1002/1878-0261.12075

DO - 10.1002/1878-0261.12075

M3 - Article

VL - 11

SP - 1307

EP - 1329

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 10

ER -