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 language | English |
|---|---|
| Pages (from-to) | 1307-1329 |
| Number of pages | 23 |
| Journal | Molecular Oncology |
| Volume | 11 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 1 Oct 2017 |
Keywords
- cancer
- cancer-associated fibroblast
- kallikrein-related peptidase
- KLK
- prostate cancer
- tumour microenvironment
Cite this
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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 journal › Article › Research › peer-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 -