Prostate-Specific Antigen Induces Osteoplastic Changes by an Autonomous Mechanism

Yonou, Hiroyuki; Aoyagi, Yasuyuki; Kanomata, Naoki; Kamijo, Tomoyuki; Oda, Tatsuya; Yokose, Tomoyuki; Hasebe, Takahiro; Nagai, Kanji; Hatano, Tadashi; Ogawa, Yoshihide; Ochiai, Atsushi

doi:10.1006/bbrc.2001.6129

Cited by 35 publications

(41 citation statements)

References 21 publications

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“…Prostate cancer cells produce TGF-h which can be further activated by PSA (11). In addition, TGF-h secretion in SaOS-2 cells can be elevated by PSA (12). Growth stimulation of SaOS-2 cells by PSA can be inhibited by TGF-h antibody, suggesting that PSA-induced growth of osteoblasts is mediated, at least in part, by TGF-h (12).…”

Section: N70463mentioning

confidence: 99%

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Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2

Nadiminty

Lou

Lee

et al. 2006

Clinical Cancer Research

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Purpose: The high prevalence of osteoblastic bone metastases in prostate cancer involves the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serologic marker for prostate cancer. In this study, we examined the role of PSA in the induction of osteoblast differentiation. Experimental Design: Human cDNA containing a coding region for PSA was transfected into human osteosarcoma SaOS-2 cells. SaOS-2 cells were also treated with exogenously added PSA. We evaluated changes in global gene expression using cDNA arrays and Northern blot analysis resulting from expression of PSA in human osteosarcoma SaOS-2 cells. Results: SaOS-2 cells expressing PSA had markedly up-regulated expression of genes associated with osteoblast differentiation including runx-2 and osteocalcin compared with the controls. Consistent with these results, the stable clones expressing PSA showed increased mineralization and increased activity of alkaline phosphatase in vitro compared with controls, suggesting that these cells undergo osteoblast differentiation.We also found that osteoprotegerin expression was down-regulated and that the receptor activator of NF-nB ligand expression was up-regulated in cells expressing PSA compared with controls. Conclusions: Modulation of the expression of osteogenic genes and alteration of the balance between osteoprotegerin^receptor activator of NF-nB ligand by PSA suggests that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of the development of osteoblastic metastases in the heterogeneous mixture of osteolytic and osteoblastic lesions. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.Bone is the frequent site of many types of cancer metastasis including prostate cancer. Advanced prostate cancer is frequently accompanied by the development of unique bone metastases characterized as osteoblastic (bone forming), which results in significant complications including bone pain, fractures, and spinal cord compression, even hemiparesis, leading to morbidity with no curable treatment (1 -3). Although osteoblastic lesions are the most dominant bone metastases associated with prostate cancer, osteoclastic lesions (bone resorption) also infrequently occur in prostate bone metastases (4, 5). In contrast, cancers from other tissues that metastasize to bone are frequently associated with osteoclast formation. Osteoblastic characterization associated with prostate bone metastases suggests that factors derived from prostate cancer cells which influence bone remodeling may be unique from other types of cancer cells.Several osteogenic factors produced by prostate cancer cells have been identified including bone morphogenetic proteins (BMP; refs. 6, 7), endothelin-1 (8), insulin-like growth factors (IGF; ref. 9), parathyroid hormone -related peptide (10), transfor...

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Section: N70463mentioning

confidence: 99%

“…11), and prostatespecific antigen (PSA; refs. 11,12). Among them, only PSA is uniquely produced and secreted abundantly by prostate cancer cells, although recently, trace amounts of PSA were found to be produced by breast cancer cells.…”

mentioning

confidence: 99%

Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2

Nadiminty

Lou

Lee

et al. 2006

Clinical Cancer Research

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“…In our previous study, we demonstrated that PSA secreted by prostate cancer cells proteolytically activates latent TGF-␤1 by its serine protease activity (39). Several in vitro studies have shown that PSA also cleaves the IGF binding proteins (12,13) that modulate IGF function, generally by inhibiting it.…”

Section: Discussionmentioning

confidence: 98%

Growth Inhibition of Human Prostate Cancer Cells in Human Adult Bone Implanted into Nonobese Diabetic/Severe Combined Immunodeficient Mice by a Ligand-Specific Antibody to Human Insulin-Like Growth Factors

et al. 2004

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Advanced prostate cancer frequently involves the bone that has the largest content of insulin-like growth factors (IGFs). However, the role of bone-derived IGFs in bone metastasis of prostate cancer has not been studied extensively because of the lack of a reliable animal model. Therefore, we investigated whether a novel antibody directed against human IGF-I and IGF-II (KM1468) could inhibit the development of new bone tumors and the progression of established bone tumors in nonobese diabetic/severe combined immunodeficient mice implanted with human adult bone. We first confirmed that KM1468 bound specifically to human IGF-I, human IGF-II, and mouse IGF-II but not to insulin. It also blocked autophosphorylation of the type I IGF receptor induced by the binding of IGFs in human-type I IGF receptor-overexpressing BALB/c 3T3 cells, and it inhibited the IGF-stimulated growth of MDA PCa 2b cells in vitro. Then mice were injected intraperitoneally with KM1468 once weekly for 4 weeks either immediately or 4 weeks after inoculation of MDA PCa 2b cells. KM1468 markedly and dose-dependently suppressed the development of new bone tumors and the progression of established tumor foci, as determined by histomorphometry, and it also decreased serum prostatespecific antigen levels, compared with the control. This is the first report of an IGF ligand-specific inhibitory antibody that suppresses the growth of human prostate cancer cells in human adult bone. These results indicate that the IGF signaling axis is a potential target for prevention and treatment of bone metastases arising from prostate cancer.

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“…The proliferation of osteoblasts seems to be induced by a TGF β -mediated mechanism. This is indicated by the PSA/KLK3-dependent up-regulation of TGF β mRNA levels, as well as the inhibition of osteoblasts proliferation rate by anti-TGF β antibodies and serine proteases inhibitors (Yonou et al , 2001 ). Interestingly, enhanced expression of osteoblast differentiation-promoting genes and osteoblastic-like morphological alterations are induced in PSA/KLK3-transfected human osteosarcoma SaOs2 cells (Nadiminty et al , 2006 ).…”

Section: Kallikrein-related Peptidases and Tumor Progressionmentioning

confidence: 99%

“…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...…”

Section: Family Member Role In Pathobiology Referencesmentioning

confidence: 99%

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

Avgeris

Mavridis

Scorilas

2012

Biological Chemistry

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Tissue kallikrein (KLK1) and kallikrein-related peptidases (KLK2 -15) comprise a family of 15 highly conserved secreted serine proteases with similar structural characteristics and a wide spectrum of functional properties. Both gene expression and protein activity of KLKs are rigorously controlled at various levels via diverse mechanisms, including extensive steroid hormone regulation, to exert their broad physiological role. Nevertheless, deregulated expression, secretion, and function of KLK family members has been observed in several pathological conditions and, particularly, in endocrine-related human malignancies, including those of the prostate, breast, and ovary. The cancer-related abnormal activity of KLKs upon substrates such as growth factors, cell adhesion molecules, cell surface receptors, and extracellular matrix proteins facilitate both tumorigenesis and disease progression to the advanced stages. The well-documented relationship between KLK status and the clinical outcome of cancer patients has led to their identifi cation as promising diagnostic, prognostic, and treatment response monitoring biomarkers for these complex disease entities. The main objective of this review is to summarize the existing knowledge concerning the role of KLKs in prostate, breast, and ovarian cancers and to highlight their continually evolving biomarker capabilities that can provide signifi cant benefi ts for the management of cancer patients.

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Prostate-Specific Antigen Induces Osteoplastic Changes by an Autonomous Mechanism

Cited by 35 publications

References 21 publications

Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2

Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2

Growth Inhibition of Human Prostate Cancer Cells in Human Adult Bone Implanted into Nonobese Diabetic/Severe Combined Immunodeficient Mice by a Ligand-Specific Antibody to Human Insulin-Like Growth Factors

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

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