Preferential production of latent transforming growth factor β‐2 by primary prostatic epithelial cells and its activation by prostate‐specific antigen

Abstract

Three mammalian isoforms of transforming growth factor-beta (TGFbeta) are known, TGFbeta1, 2, and 3, that have non-overlapping functions during development. However, their specific roles in cancers such as prostate cancer are less clear. Here we show that primary cultures of prostatic epithelial cells preferentially produce and activate the latent TGFbeta2 isoform. Paired cultures of normal and malignant prostate cells from prostate cancer patients produced predominantly the TGFbeta2 isoform, with 30- to 70-fold less TGFbeta1. By mono-Q ion exchange chromatography, three major peaks of latent TGFbeta2 activity were observed corresponding to the known small latent TGFbeta2 complex, the known large latent TGFbeta2 complex and a novel eluting peak of latent TGFbeta2. Although prostate cells are known to activate latent TGFbeta, the mechanism for activation is currently unclear. We investigated whether prostate specific antigen (PSA), a serine protease used as a clinical marker for prostate cancer, could play a role in the activation of latent TGFbeta. Unlike plasmin, a known activator of both latent TGFbeta1 and 2, PSA specifically activated the recombinant small latent form of TGFbeta2, but not TGFbeta1. Prostate epithelial cells, therefore, preferentially produce the TGFbeta2 isoform and PSA, a protease produced by the prostate, specifically targets the activation of this TGFbeta isoform. PSA-mediated activation of latent TGFbeta2 may be an important mechanism for autocrine TGFbeta regulation in the prostate and may potentially contribute to the formation of osteoblastic lesions in bone metastatic prostate cancer.

PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

“…28 PSA has been demonstrated to cleave several substrates important in bone, including insulinlike growth factor (IGF) binding proteins (BPs)-3 and -4, 16 parathyroid hormone-related protein, 17 and the small latent form of tumor growth factor-b2. 18 PSAmediated cleavage of parathyroid hormone-related protein which stimulates osteoclasts and is associated with osteolysis and humoral hypercalcemia of malignancy 29 leads to inactivation. 17 Cleavage of IGFBP-3 30 and PSA induces an osteoblastic bone phenotype AP Cumming et al -4 31 dissociates IGF-I from the IGF-IGFBP complex to stimulate osteoblast development.…”

“…17 Cleavage of IGFBP-3 30 and PSA induces an osteoblastic bone phenotype AP Cumming et al -4 31 dissociates IGF-I from the IGF-IGFBP complex to stimulate osteoblast development. 32 PSA-mediated proteolysis of the small latent tumor growth factor-b2 results in activation of tumor growth factor-b, 18 another important stimulator of new bone formation. 33,34 Bone histomorphometric parameters are indicative of bone reactions.…”

“…15 Furthermore, PSA may be involved in the development of osteoblastic bone metastasis frequently observed in advanced prostate cancer. Apart from its physiological substrates, PSA has been demonstrated in vitro to be able to cleave several additional substrates, [16][17][18] which may play a role in bone metastasis. The relevance of PSA in prostate cancer and the biological functions of the different forms of PSA in prostate cancer biology are still largely unknown.…”

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…Prostate cancer KLK1 Promotion of cell invasiveness; angiogenesis Emanueli et al, 2001;Giusti et al, 2005;Gao et al, 2010 KLK2 Tumor growth promotion; ECM degradation Deperthes et al, 1996;Takayama et al, 1997;Mikolajczyk et al, 1999;Rehault et al, 2001;Mize et al, 2008 PSA/KLK3 Tumor growth promotion; EMT-like changes; ECM degradation; angiogenesis; metastasis Webber et al, 1995;Cramer et al, 1996;Fortier et al, 1999;Sun et al, 2001;Yonou et al, 2001;Koistinen et al, 2002;Ishii et al, 2004;Pezzato et al, 2004;Romanov et al, 2004;Dallas et al, 2005;Veveris-Lowe et al, 2005;Goya et al, 2006;Nadiminty et al, 2006 KLK4 Tumor growth promotion; EMT-like changes; ECM degradation; metastasis Takayama et al, 2001;Matsumura et al, 2005;Veveris-Lowe et al, 2005;Beaufort et al, 2006;Gao et al, 2007;Klokk et al, 2007;Mize et al, 2008;Ramsay et al, 2008a;Wang et al, 2010 KLK7 EMT-like changes; promotion of cell invasiveness Mo et al, 2010 KLK14 Tumor growth promotion; ECM degradation Borgono et al, 2007b Breast cancer KLK1 Promotion of cell invasiveness; angiogenesis Emanueli et al, 2001;Wolf et al, 2001;Giusti et al, 2005 PSA/KLK3 Tumor suppressor Lai et al, 1996 KLK6 Tumor suppressor; inhibition of cells invasiveness; antiangiogenes...…”

“…Although the underlying mechanism of the PSA/KLK3-and KLK4-induced EMT has not been studied yet, TGF β 2 may represent their downstream mediator. Latent TGF β 2, which facilitates EMT-like changes, is a substrate of PSA/KLK3 (Dallas et al , 2005 ), for which KLK4 represents a potent activator (Takayama et al , 2001 ). Moreover, KLK7 has been demonstrated to induce EMT-like changes in prostate carcinoma 22RV1 and DU145 cells, increasing in this way their migration and invasion capacity (Mo et al , 2010 ).…”