Secreted frizzled-related protein 4 inhibits proliferation and metastatic potential in prostate cancer.
BACKGROUND
Secreted frizzled-related proteins (sFRP4) inhibits Wnt signaling and thus cellular proliferation in androgen-independent prostate cancer cells in vitro. However, increased expression of membranous sFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease. Here, we investigated the phenotype of sFRP4 overexpression in an androgen-dependent prostate cancer model.


METHODS
An sFRP4-overexpressing androgen-dependent (LNCaP) prostate cancer model was established to assess changes in cellular proliferation, the expression, and subcellular localization of adhesion molecules and cellular invasiveness, and compared with the findings in sFRP4-overexpressing androgen-independent cells (PC3).


RESULTS
sFRP4 overexpression in both cell line models resulted in a morphologic change to a more epithelioid cell type with increased localization of beta-catenin and cadherins (E-cadherin in LNCaP, N-cadherin in PC3) to the cell membrane. Functionally, sFRP4 overexpression was associated with a decreased rate of proliferation (P = 0.0005), decreased anchorage-independent growth (P < 0.001), and decreased invasiveness in PC3 cells (P < 0.0001). Furthermore, increased membranous sFRP4 expression was associated with increased membranous beta-catenin expression (P = 0.02) in a cohort of 224 localized human androgen-dependent prostate cancers.


CONCLUSIONS
These data suggest that sFRP4 is an inhibitor of prostate cancer growth and invasion in vitro independent of androgen receptor (AR) signaling with correlative evidence in human androgen-dependent disease suggesting similar changes in the clinical setting. Consequently, potential therapeutic strategies to modulate Wnt signaling by sFRP4 will be relevant to both localized androgen-dependent prostate cancer and advanced metastatic disease.
Horvath
Lisa G
LG
Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia.
Lelliott
Jayne E
JE
Kench
James G
JG
Lee
C-Soon
CS
Williams
Elizabeth D
ED
Saunders
Darren N
DN
Grygiel
John J
JJ
Sutherland
Robert L
RL
Henshall
Susan M
SM
D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000503:physiopathology* / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D015820:Cadherins; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D051153:Wnt Proteins; D051176:beta Catenin; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins