Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. Although PSCA is thought to be involved in intracellular signaling, much remains unknown about its physiological function and regulatory mechanism in normal and cancer cells. It is up-regulated in several major cancers including prostate, bladder, and pancreatic cancers. The expression of PSCA is positively correlated with advanced clinical stage and metastasis in prostate cancers and is also associated with malignant progression of premalignant prostate lesions. Therefore, PSCA has been proposed as a biomarker of diagnosis and prognosis, as well as a target of therapy for these cancers. In addition, PSCA has also shown clinical potential in immunotherapy as a prostate-specific antigen, which, when presented by dendritic cells, may elicit strong tumor-specific immunity. In contrast, PSCA is down-regulated in esophageal and gastric cancer and may have a tumor-suppressing function in the gastric epithelium. Recent exciting findings that genetic variations of PSCA conferred increased risks of gastric cancer and bladder cancer have opened up a new avenue of research about the pathological function of PSCA. PSCA seems to be a Jekyll and Hyde molecule that plays differential roles, tumor promoting or suppressing, depending on the cellular context. Clin Cancer Res; 16(14); 3533–8. ©2010 AACR.

Prostate stem cell antigen (PSCA) is a small, glycosylphosphatidylinositol (GPI)-anchored cell surface protein belonging to the Thy-1/Ly-6 family. It shares 30% homology with stem cell antigen type 2 (SCA-2), a surface marker of immature lymphocytes (1). In human, the PSCA is expressed in the epithelial cells of prostate, urinary bladder, kidney, skin, esophagus, stomach, and placenta (14). Although it was originally designated as a “stem cell antigen” for similarity to SCA-2, PSCA is now known to be expressed mainly in differentiating cells rather than stem cells, which was shown by studies on prostate and gastric epithelial cells (5, 6). Other than the expression patterns, the physiological functions of the PSCA remain an enigma. PSCA knockout mice were viable and showed no gross abnormal phenotype (7). The Thy-1/Ly-6 family to which PSCA belongs does not seem to offer many clues, because the family members show a remarkable functional diversity ranging from T-cell activation (8) to apoptosis regulation in the nervous system (9).

Initially PSCA was identified and isolated as a tumor antigen overexpressed in prostate cancer (1), and subsequent investigations have revealed that it is also up-regulated in urinary bladder cancer, renal cell carcinoma, pancreatic cancer, hydatidiform mole, and ovarian mucinous tumor (1014). Remarkably, it is down-regulated in esophageal and gastric cancers (2, 6).

Although little is known about the regulatory mechanism of PSCA expression, it is certain that androgen is involved in the PSCA regulation, at least in prostate epithelium, because an androgen responsive element was identified in its promoter region (15). Transgenic mice introduced with PSCA promoter-driven green fluorescent protein (GFP) constructs showed that the GFP expression was influenced by puberty, castration, and androgen restoration (16). In human, complete androgen ablation suppresses PSCA mRNA expression in human prostate carcinoma in vivo (17). In the bladder carcinoma cell line RT112, PSCA expression was stimulated by a culture dish surface that causes aggregation of cells, and by phorbol ester in a cycloheximide- and actinomycin-inhibitable manner, indicating that its expression is regulated by mechanisms related to the adhesion of epithelial cells and by some pathways involving protein kinase C and newly synthesized protein(s); see ref. 18. PSCA was recently reported to be down-regulated in telomerase-transduced urothelial cells (19), suggesting that PSCA may be regulated by some telomerase-related mechanism.

Although members of the GPI-anchor proteins have the GPI-moiety, a common feature for the family members, they have diverse structures and functions (20). In mammals, GPI-anchored proteins lacking a transmembrane domain are believed to be located in the lipid raft (Fig. 1), which is still a somewhat hypothetic microdomain on the surface of the outer cell membrane; however, several pieces of biological evidence support its existence and propose that it is detergent-insoluble and enriched for sphingolipids and cholesterol (20). The structure of PSCA suggests at least two distinct mechanisms of its potential function. The first possibility is that PSCA may form a complex with another protein that has a transmembrane domain and intracellular domain to activate a downstream target. In this regard, it is interesting to note that on the basis of a protein motif scan, (http://myhits.isb-sib.ch/cgi-bin/motif_scan) PSCA contains an activin type I and II extracellular receptor domain, which binds to the transforming growth factor beta (TGF-β) superfamily of ligands and plays important roles in many cellular functions (21). Evolutionally, the Ly-6 family and activin receptor family are closely related and cluster together at the family level (22). It would be interesting to test whether TGF-β family ligand binds to PSCA and whether there are transmembrane proteins on the cell surface that partner with PSCA and transmit signals. The second potential mechanism of PSCA function is through the cleavage of the GPI anchor by phospholipase C, which will release PSCA from membrane into secretion and act through a receptor-mediated signaling pathway. There have been no reports of any proteins that bind to PSCA and the identification of such proteins would shed significant light into the biologic function of PSCA.

Fig. 1.

Presumptive PSCA signaling pathway and PSCA-targeted immunotherapy. In the prostate epithelium, PSCA expression is induced by androgen through the binding of androgen-androgen receptor complex to androgen responsive element (ARE) located at the upstream of the gene. Its expression is also up-regulated by cell-cell contact in vitro. It was reported that introduction of human telomerase reverse transcriptase (hTERT) to urothelial cells suppresses PSCA expression. After translation, PSCA is sorted to endoplasmic reticulum, in which it is attached with GPI and transported to the outer surface of the cell membrane, where it is anchored to the outer lipid layer via fatty-acid chain of the GPI-moiety. As other GPI-anchored proteins, PSCA is believed to be located to a specialized microdomain, the so-called lipid raft, in the cell membrane. PSCA may play multiple roles in cell-death induction, tumor progression, and tumor suppression. However, the ligand of PSCA is not yet identified and the downstream signaling pathway and the physiological function are unknown. PSCA-targeted immunotherapy could be a new therapeutic option for hormone therapy-refractory prostate cancer. Possible strategies include direct cytotoxic effects by anti-PSCA antibody or by T cells with T-cell receptor genetically fused to anti-PSCA antibody, and induction of tumor specific immunity by DCs loaded with PSCA peptide.

Fig. 1.

Presumptive PSCA signaling pathway and PSCA-targeted immunotherapy. In the prostate epithelium, PSCA expression is induced by androgen through the binding of androgen-androgen receptor complex to androgen responsive element (ARE) located at the upstream of the gene. Its expression is also up-regulated by cell-cell contact in vitro. It was reported that introduction of human telomerase reverse transcriptase (hTERT) to urothelial cells suppresses PSCA expression. After translation, PSCA is sorted to endoplasmic reticulum, in which it is attached with GPI and transported to the outer surface of the cell membrane, where it is anchored to the outer lipid layer via fatty-acid chain of the GPI-moiety. As other GPI-anchored proteins, PSCA is believed to be located to a specialized microdomain, the so-called lipid raft, in the cell membrane. PSCA may play multiple roles in cell-death induction, tumor progression, and tumor suppression. However, the ligand of PSCA is not yet identified and the downstream signaling pathway and the physiological function are unknown. PSCA-targeted immunotherapy could be a new therapeutic option for hormone therapy-refractory prostate cancer. Possible strategies include direct cytotoxic effects by anti-PSCA antibody or by T cells with T-cell receptor genetically fused to anti-PSCA antibody, and induction of tumor specific immunity by DCs loaded with PSCA peptide.

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A mouse monoclonal anti-PSCA antibody 1G8 inhibited tumor growth, prevented metastasis, and prolonged the survival of mice harboring inoculated human prostate cancer xenografts (23), which is probably through inducing caspase-independent cell death by cross-linking the PSCA proteins (24). On the other hand, PSCA was found to prevent the subpopulation of choroid cells in chicken brain from cell death by modulating a signaling pathway involving α7-containing nicotinic acetylcholine receptors (9). In addition, PSCA showed cell growth inhibition activity for a gastric cancer cell line without a significant induction of cell death (6). These paradoxical observations, together with the up- and down-regulation of PSCA in different human tissues, suggest that PSCA may be oncogenic for some epithelial cells and also be a tumor suppressor for others. This kind of Jekyll and Hyde molecule is not unprecedented. For example, in normal epithelium, Mucin 1 (MUC1) is protective against potentially tumorigenic environmental insults, but after significant epithelial damage that results in the loss of cell polarity and change in the membrane proteins' distribution, it becomes promotive for cancer cell growth and survival (25). Likewise, the Wilms' tumor 1 (WT1; ref. 26) and NOTCH gene (27) may function either as an oncogene or a tumor suppressor depending on the cellular context and the crosstalk with other cellular molecules and pathways.

In sum, although mechanistic details are unknown, the accumulated findings suggest that PSCA has a functional diversity depending on both tissue types and cell status, normal or malignant.

Clinical application of PSCA in prostate cancer

Because PSCA was originally isolated as a tumor antigen overexpressed in prostate cancer, investigation for its clinical application has mainly focused on prostate cancer. PSCA expression was detected in about 90% of primary prostate cancers, and the expression level is positively correlated with advanced clinical stage, invasion to seminal vesicle and prostate capsule, and progression to androgen-independence (1, 3, 28, 29). PSCA expression was also detected in the metastatic sites at bone, lymph node, and liver (65 to 100%, dependent on the organs and reports; refs. 3, 30). One study reported increased PSCA-gene copy number in 71% (five of seven cases) of prostate cancer with MYC gene amplification, and both genes were located in the same Chr. 8q amplicon, suggesting that gene amplification is the major cause of the overexpression of PSCA in prostate cancer (31). PSCA is approximately 15 Mb distal to Myc oncogene on 8q24, which is one of the most frequently amplified regions in human cancers (32). It is conceivable that increased copy number of PSCA is the major cause of the observed PSCA overexpression in some tumors. A study on 117 prostate biopsy specimens of prostate intraepithelial neoplasia (PIN) revealed that PSCA expression was higher in high-grade PIN (HGPIN), a premalignant condition, than in low-grade PIN. Moreover, the expression levels were elevated in the PIN lesions that subsequently progressed to cancer compared with those that did not progress (33). This value of PSCA expression in predicting cancer progression was also observed in patients with benign prostatic hyperplasia (34, 35).

PSCA also seems to be a useful marker for a detection of metastasis and circulating tumor cells (CTC). More than 90% of lymph node and bone specimens with metastasis were positive for PSCA expression (36). PSCA expression was not detectable in peripheral blood samples of 71 nonmalignant controls and 41 cases of prostate cancer confined to the organ, but detectable in 8 of 17 prostate cancers of extraprostate invasion (37). However, another study on blood samples showed a lower sensitivity for the castration-refractory prostate cancer cases (38). Combined use of other molecules, e.g., prostate-specific antigen (PSA), may overcome this limitation. The presence of PSCA transcripts in the peripheral blood was also a significant predictor of biochemical recurrence after radical prostatectomy in high-risk prostate cancer (39).

The PSCA expression also could be used as an index in the evaluation of therapeutic effect. After treatment of HGPIN with flutamide, an androgen receptor antagonist, 66 patients who showed reduction of PSCA mRNA in the prostate tissue did not develop cancer on follow-up, whereas 11 of 13 cases with increased PSCA expression levels developed cancer afterward (40). The reduction of PSCA expression in the prostate tissue was also shown in localized prostate cancer cases after external beam radiotherapy (41).

In addition to its potential applications as a diagnosis and prognosis biomarker, PSCA has been suggested as a therapeutic target. Current standard treatments for patients with localized prostate cancer are radiation, hormonal therapy, and radical prostatectomy. For patients with metastases, an androgen-ablation therapy is the first choice, which has shown a benefit in 70 to 80% of the cases (42). When the prostate cancer becomes refractory to the hormone therapy, PSCA gene-based strategies may offer a new therapeutic option.

The first step of mounting an immune response is the antigen presentation by dendritic cells (DC). Vaccination with tumor antigen-loaded DC is hypothesized to be a powerful therapeutic strategy to potentiate a tumor-specific immunity induction, and several studies have been conducted to identify a prostate cancer-specific tumor antigen suitable for the loading (43). Effect of PSCA peptide-loaded DC has already been evaluated in a phase I-II trial for patients with hormone- and chemotherapy-refractory prostate cancer (44). Of 12 patients entered into the trial, 5 patients developed delayed-type hypersensitivity reaction, indicating that the patients had obtained the tumor antigen-specific immunity. The patients tended to be free of disease progression and showed superior overall survival (median survival, 22 months) compared with the remaining patients (8 months). In another phase I-II study in advanced patients with hormone-refractory prostate cancer, DC loaded with a mixture of peptides from four prostate-specific antigens, PSCA, PSA, PSMA, and PAP, were shown to elicit strong cytotoxic T-cell response against all these tested tumor antigens. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time (45). In light of the recent approval of the first anticancer vaccine, Provenge (Dendreon Corporation, Seattle, WA), against advanced prostate cancer by the U.S. Food and Drug Administration (FDA), the clinical potential of PSCA as a tumor antigen in immunotherapy is promising.

Some other strategies for immunotherapy involving the PSCA gene have been tested preclinically. Introduction of a PSCA-expression plasmid into mice harboring transplanted prostate cancer cells inhibited tumor growth via generating PSCA-specific CD8+ T-cell immune response (DNA vaccination; refs. 4648). T-cell containing chimeric T-cell receptor (TCR), which was generated by fusing an anti-PSCA antibody single-chain fragment to the β-chain of TCR, showed potent cytotoxicity against PSCA-positive tumor cells (49).

Cytotoxic therapy targeting PSCA is another potential clinical application. As described before, anti-PSCA monoclonal antibody 1G8 exhibited tumor growth inhibition, metastasis prevention, and prolongation of the survival of mice inoculated with human prostate cancer xenografts (23, 24). Humanized 1G8 was generated by grafting complementarity determining regions to the anti-p185 4D5va (trastuzumab) framework and the radioiodinated antibody was shown to have specificity for PSCA. The localization of 1G8 to the prostate cancer xenograft was shown in mouse bodies with high-contrast micro positron emission tomography (microPET) imaging (5052).

Clinical application in other cancers

PSCA has also been investigated as a biomarker for other cancers. In urinary bladder cancer, immunocytochemical study of PSCA was applied to voided urine specimens and the sensitivity of transitional cell carcinoma detection was 80% for PSCA immunocytochemistry alone compared with 46.7% for cytology alone. Combining cytology with PSCA staining increased the sensitivity to 84% without decreasing the specificity significantly, suggesting that immunocytochemical analysis of PSCA on voided urine samples may provide a simple and quantitative adjunct marker for cytological diagnosis of urothelial bladder cancer (53). On the other hand, despite its up-regulation in urinary bladder cancer over normal urothelium, PSCA had significantly higher expression in superficial than in invasive bladder cancer (P < 0.001), and there was a significant inverse relationship between PSCA expression and recurrence in superficial bladder cancer (54).

Pancreatic cancer has aberrantly up-regulated PSCA in nearly 60% of cases, whereas the gene is not expressed in normal pancreatic duct (12). PSCA was proposed as a specific biomarker of pancreatic adenocarcinoma cells in cytologic examination of fine-needle aspiration specimens (55) and as a biomarker for the detection of CTCs in peripheral blood of pancreatic cancer patients (56). Elevation of immunoglobulin G (IgG) reactive to PSCA-derived peptides was shown in 80% of pancreatic cancer, but only in 18% of subjects without the cancer (57). Radiolabeled and bioconjugated anti-PSCA antibodies have been tested for diagnostic imaging of pancreatic cancer (58, 59). As in prostate cancer, an anti-PSCA antibody 1G8 showed an inhibitory effect on tumor growth and progression in a mouse model of a pancreatic cancer xenograft (60). It should be noted, however, that PSCA may have a dual function, oncogenic and tumor suppressive, depending on the tissue types and malignant status of the cells. A close evaluation of a potential adverse effect on various organs may be required in the development of a PSCA-targeting systemic therapy.

PSCA as a cancer susceptibility gene: genome-wide association study

Although PSCA has been identified for more than a decade, the investigations have been largely superficial and have focused on its potential application as a biomarker and therapeutic target, as described above. However, several unexpected, exciting findings from a totally different field of research, genome-wide association studies (GWAS), have injected fresh life into the research of PSCA. We found a significant association of a functional single nucleotide polymorphism (SNP) in the PSCA gene rs2294008 with the risk of gastric and bladder cancers in two separate GWAS (6, 61). Two recent case control studies confirmed the association of this SNP with gastric and bladder cancer in the Chinese population (62, 63). The rs2294008 SNP is a missense SNP that alters the start codon of PSCA. In addition, in vitro reporter assays showed that the risk allele reduced the transcriptional activity of the PSCA promoter in both gastric and bladder cell lines (6, 61). Analysis of PSCA mRNA expression in 16 adjacent normal bladder tissues showed a significant correlation of the risk allele with low expression, consistent with in vitro data (63). These findings are congruous with the notion that PSCA may act as a tumor suppressor (6). No cases of somatic or germline mutations in the PSCA gene have been reported in any cancers to date. It is perplexing that the risk allele is the same and the reduced transcriptional activity is consistent in both gastric and bladder cancers, even though the PSCA gene is down-regulated in gastric cancer but up-regulated in bladder cancer. Nevertheless, these findings have opened up a new avenue of research about the pathological role of PSCA and created a new application of PSCA in cancer risk prediction.

Future directions

PSCA is up-regulated in prostate, urinary bladder, and pancreatic cancers and its clinical utility has been shown in the diagnosis and prognosis of these cancers. PSCA has also been investigated as a potential target for tumor-targeted immunity and for direct suppression by anti-PSCA antibody. Moreover, the PSCA germline genetic variation has been associated with the risk of specific cancers including gastric and urinary bladder cancers. However, it should be stressed that our knowledge of the physiological and pathological functions of PSCA is still quite limited. It seems that PSCA is a Jekyll and Hyde molecule with dual functions depending on the context of tissue specificity and pathophysiological conditions. There are many challenges and opportunities ahead. The priority of research is to find the physiological functions of PSCA, its ligand, and its downstream signaling cascade. To determine the regulatory mechanisms of its expression in different normal and tumor tissues is essential to decipher its dual role of tumor promoting and suppressing functions. The functional consequence of the risk allele of rs2294008 on PSCA protein function and cellular trafficking and the biological mechanisms for the increased cancer risks associated with rs2294008 are a completely new territory. It will be of interest to know whether genetic variations in PSCS are associated with other cancers and whether there are somatic mutations of the PSCA gene in certain cancers. The clinical applications of PSCA need to be further validated and explored. The next decade of research on PSCA will undoubtedly be exciting and fruitful.

No potential conflicts of interest were disclosed.

Grant Support: J. Gu, NIH R01CA131335; T. Yoshida, The program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation; X. Wu, NIH U01CA127615, R01CA74880, and P50CA91846.

1
Reiter
RE
,
Gu
Z
,
Watabe
T
, et al
. 
Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer
.
Proc Natl Acad Sci U S A
1998
;
95
:
1735
40
.
2
Bahrenberg
G
,
Brauers
A
,
Joost
HG
, et al
. 
Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors
.
Biochem Biophys Res Commun
2000
;
275
:
783
8
.
3
Gu
Z
,
Thomas
G
,
Yamashiro
J
, et al
. 
Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer
.
Oncogene
2000
;
19
:
1288
96
.
4
de Nooij-van Dalen
AG
,
van Dongen
GA
,
Smeets
SJ
, et al
. 
Characterization of the human Ly-6 antigens, the newly annotated member Ly-6K included, as molecular markers for head-and-neck squamous cell carcinoma
.
Int J Cancer
2003
;
103
:
768
74
.
5
Tran
CP
,
Lin
C
,
Yamashiro
J
, et al
. 
Prostate stem cell antigen is a marker of late intermediate prostate epithelial cells
.
Mol Cancer Res
2002
;
1
:
113
21
.
6
Sakamoto
H
,
Yoshimura
K
,
Saeki
N
, et al
. 
Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer
.
Nat Genet
2008
;
40
:
730
40
.
7
Moore
ML
,
Teitell
MA
,
Kim
Y
, et al
. 
Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation
.
Prostate
2008
;
68
:
139
51
.
8
Bamezai
A
. 
Mouse Ly-6 proteins and their extended family: markers of cell differentiation and regulators of cell signaling
.
Arch Immunol Ther Exp (Warsz)
2004
;
52
:
255
66
.
9
Hruska
M
,
Keefe
J
,
Wert
D
, et al
. 
Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes α7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons
.
J Neurosci
2009
;
29
:
14847
54
.
10
Amara
N
,
Palapattu
GS
,
Schrage
M
, et al
. 
Prostate stem cell antigen is overexpressed in human transitional cell carcinoma
.
Cancer Res
2001
;
61
:
4660
5
.
11
Elsamman
EM
,
Fukumori
T
,
Tanimoto
S
, et al
. 
The expression of prostate stem cell antigen in human clear cell renal cell carcinoma: a quantitative reverse transcriptase-polymerase chain reaction analysis
.
BJU Int
2006
;
98
:
668
73
.
12
Argani
P
,
Rosty
C
,
Reiter
RE
, et al
. 
Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma
.
Cancer Res
2001
;
61
:
4320
4
.
13
Feng
HC
,
Tsao
SW
,
Ngan
HY
, et al
. 
Overexpression of prostate stem cell antigen is associated with gestational trophoblastic neoplasia
.
Histopathology
2008
;
52
:
167
74
.
14
Cao
D
,
Ji
H
,
Ronnett
BM
. 
Expression of mesothelin, fascin, and prostate stem cell antigen in primary ovarian mucinous tumors and their utility in differentiating primary ovarian mucinous tumors from metastatic pancreatic mucinous carcinomas in the ovary
.
Int J Gynecol Pathol
2005
;
24
:
67
72
.
15
Jain
A
,
Lam
A
,
Vivanco
I
, et al
. 
Identification of an androgen-dependent enhancer within the prostate stem cell antigen gene
.
Mol Endocrinol
2002
;
16
:
2323
37
.
16
Watabe
T
,
Lin
M
,
Ide
H
, et al
. 
Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter
.
Proc Natl Acad Sci U S A
2002
;
99
:
401
6
.
17
Zhigang
Z
,
Wenlu
S
. 
Complete androgen ablation suppresses prostate stem cell antigen (PSCA) mRNA expression in human prostate carcinoma
.
Prostate
2005
;
65
:
299
305
.
18
Bahrenberg
G
,
Brauers
A
,
Joost
HG
, et al
. 
PSCA expression is regulated by phorbol ester and cell adhesion in the bladder carcinoma cell line RT112
.
Cancer Lett
2001
;
168
:
37
43
.
19
Chapman
EJ
,
Kelly
G
,
Knowles
MA
. 
Genes involved in differentiation, stem cell renewal, and tumorigenesis are modulated in telomerase-immortalized human urothelial cells
.
Mol Cancer Res
2008
;
6
:
1154
68
.
20
Chatterjee
S
,
Mayor
S
. 
The GPI-anchor and protein sorting
.
Cell Mol Life Sci
2001
;
58
:
1969
87
.
21
Tsuchida
K
,
Nakatani
M
,
Hitachi
K
, et al
. 
Activin signaling as an emerging target for therapeutic interventions
.
Cell Commun Signal
2009
;
7
:
15
.
22
Gupta
A
,
Van Vlijmen
HW
,
Singh
J
. 
A classification of disulfide patterns and its relationship to protein structure and function
.
Protein Sci
2004
;
13
:
2045
58
.
23
Saffran
DC
,
Raitano
AB
,
Hubert
RS
, et al
. 
Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts
.
Proc Natl Acad Sci U S A
2001
;
98
:
2658
63
.
24
Gu
Z
,
Yamashiro
J
,
Kono
E
, et al
. 
Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism
.
Cancer Res
2005
;
65
:
9495
500
.
25
Kufe
DW
. 
Mucins in cancer: function, prognosis and therapy
.
Nat Rev Cancer
2009
;
9
:
874
85
.
26
Yang
L
,
Han
Y
,
Suarez Saiz
F
, et al
. 
A tumor suppressor and oncogene: the WT1 story
.
Leukemia
2007
;
21
:
868
76
.
27
Radtke
F
,
Raj
K
. 
The role of Notch in tumorigenesis: oncogene or tumour suppressor?
Nat Rev Cancer
2003
;
3
:
756
67
.
28
Han
KR
,
Seligson
DB
,
Liu
X
, et al
. 
Prostate stem cell antigen expression is associated with gleason score, seminal vesicle invasion and capsular invasion in prostate cancer
.
J Urol
2004
;
171
:
1117
21
.
29
Zhigang
Z
,
Wenlv
S
. 
Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer
.
World J Surg Oncol
2004
;
2
:
13
.
30
Lam
JS
,
Yamashiro
J
,
Shintaku
IP
, et al
. 
Prostate stem cell antigen is overexpressed in prostate cancer metastases
.
Clin Cancer Res
2005
;
11
:
2591
6
.
31
Reiter
RE
,
Sato
I
,
Thomas
G
, et al
. 
Coamplification of prostate stem cell antigen (PSCA) and MYC in locally advanced prostate cancer
.
Genes Chromosomes Cancer
2000
;
27
:
95
103
.
32
Meyer
N
,
Penn
LZ
. 
Reflecting on 25 years with MYC
.
Nat Rev Cancer
2008
;
8
:
976
90
.
33
Zhigang
Z
,
Wenlu
S
. 
Prostate stem cell antigen (PSCA) mRNA expression in prostatic intraepithelial neoplasia: implications for the development of prostate cancer
.
Prostate
2007
;
67
:
1143
51
.
34
Zhigang
Z
,
Wenlu
S
. 
The association of prostate stem cell antigen (PSCA) mRNA expression and subsequent prostate cancer risk in men with benign prostatic hyperplasia following transurethral resection of the prostate
.
Prostate
2008
;
68
:
190
9
.
35
Zhao
Z
,
Liu
J
,
Li
S
, et al
. 
Prostate stem cell antigen mRNA expression in preoperatively negative biopsy specimens predicts subsequent cancer after transurethral resection of the prostate for benign prostatic hyperplasia
.
Prostate
2009
;
69
:
1292
302
.
36
Ananias
HJ
,
van den Heuvel
MC
,
Helfrich
W
, et al
. 
Expression of the gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in lymph node and bone metastases of prostate cancer
.
Prostate
2009
;
69
:
1101
8
.
37
Hara
N
,
Kasahara
T
,
Kawasaki
T
, et al
. 
Reverse transcription-polymerase chain reaction detection of prostate-specific antigen, prostate-specific membrane antigen, and prostate stem cell antigen in one milliliter of peripheral blood: value for the staging of prostate cancer
.
Clin Cancer Res
2002
;
8
:
1794
9
.
38
Helo
P
,
Cronin
AM
,
Danila
DC
, et al
. 
Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with CellSearch assay and association with bone metastases and with survival
.
Clin Chem
2009
;
55
:
765
73
.
39
Joung
JY
,
Cho
KS
,
Kim
JE
, et al
. 
Prostate stem cell antigen mRNA in peripheral blood as a potential predictor of biochemical recurrence in high-risk prostate cancer
.
J Surg Oncol
2010
;
101
:
145
8
.
40
Zhigang
Z
,
Wenlu
S
. 
Flutamide reduced prostate cancer development and prostate stem cell antigen mRNA expression in high grade prostatic intraepithelial neoplasia
.
Int J Cancer
2008
;
122
:
864
70
.
41
Zhigang
Z
,
Wenlu
S
. 
External beam radiotherapy (EBRT) suppressed prostate stem cell antigen (PSCA) mRNA expression in clinically localized prostate cancer
.
Prostate
2007
;
67
:
653
60
.
42
Damber
JE
,
Aus
G
. 
Prostate cancer
.
Lancet
2008
;
371
:
1710
21
.
43
Matera
L
. 
The choice of the antigen in the dendritic cell-based vaccine therapy for prostate cancer
.
Cancer Treat Rev
2009
;
36
:
131
41
.
44
Thomas-Kaskel
AK
,
Zeiser
R
,
Jochim
R
, et al
. 
Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival
.
Int J Cancer
2006
;
119
:
2428
34
.
45
Waeckerle-Men
Y
,
Uetz-von Allmen
E
,
Fopp
M
, et al
. 
Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma
.
Cancer Immunol Immunother
2006
;
55
:
1524
33
.
46
Zhang
X
,
Yu
C
,
Zhao
J
, et al
. 
Vaccination with a DNA vaccine based on human PSCA and HSP70 adjuvant enhances the antigen-specific CD8+ T-cell response and inhibits the PSCA+ tumors growth in mice
.
J Gene Med
2007
;
9
:
715
26
.
47
Garcia-Hernandez Mde
L
,
Gray
A
,
Hubby
B
, et al
. 
Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity
.
Cancer Res
2008
;
68
:
861
9
.
48
Ahmad
S
,
Casey
G
,
Sweeney
P
, et al
. 
Prostate stem cell antigen DNA vaccination breaks tolerance to self-antigen and inhibits prostate cancer growth
.
Mol Ther
2009
;
17
:
1101
8
.
49
Morgenroth
A
,
Cartellieri
M
,
Schmitz
M
, et al
. 
Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells
.
Prostate
2007
;
67
:
1121
31
.
50
Olafsen
T
,
Gu
Z
,
Sherman
MA
, et al
. 
Targeting, imaging, and therapy using a humanized antiprostate stem cell antigen (PSCA) antibody
.
J Immunother
2007
;
30
:
396
405
.
51
Leyton
JV
,
Olafsen
T
,
Lepin
EJ
, et al
. 
Humanized radioiodinated minibody for imaging of prostate stem cell antigen-expressing tumors
.
Clin Cancer Res
2008
;
14
:
7488
96
.
52
Leyton
JV
,
Olafsen
T
,
Sherman
MA
, et al
. 
Engineered humanized diabodies for microPET imaging of prostate stem cell antigen-expressing tumors
.
Protein Eng Des Sel
2009
;
22
:
209
16
.
53
Cheng
L
,
Reiter
RE
,
Jin
Y
, et al
. 
Immunocytochemical analysis of prostate stem cell antigen as adjunct marker for detection of urothelial transitional cell carcinoma in voided urine specimens
.
J Urol
2003
;
169
:
2094
100
.
54
Elsamman
E
,
Fukumori
T
,
Kasai
T
, et al
. 
Prostate stem cell antigen predicts tumour recurrence in superficial transitional cell carcinoma of the urinary bladder
.
BJU Int
2006
;
97
:
1202
7
.
55
McCarthy
DM
,
Maitra
A
,
Argani
P
, et al
. 
Novel markers of pancreatic adenocarcinoma in fine-needle aspiration: mesothelin and prostate stem cell antigen labeling increases accuracy in cytologically borderline cases
.
Appl Immunohistochem Mol Morphol
2003
;
11
:
238
43
.
56
Lukyanchuk
VV
,
Friess
H
,
Kleeff
J
, et al
. 
Detection of circulating tumor cells by cytokeratin 20 and prostate stem cell antigen RT-PCR in blood of patients with gastrointestinal cancers
.
Anticancer Res
2003
;
23
:
2711
6
.
57
Tanaka
M
,
Komatsu
N
,
Terakawa
N
, et al
. 
Increased levels of IgG antibodies against peptides of the prostate stem cell antigen in the plasma of pancreatic cancer patients
.
Oncol Rep
2007
;
18
:
161
6
.
58
Foss
CA
,
Fox
JJ
,
Feldmann
G
, et al
. 
Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen: initial imaging in experimental models of pancreatic cancer
.
Mol Imaging
2007
;
6
:
131
9
.
59
Yong
KT
,
Ding
H
,
Roy
I
, et al
. 
Imaging pancreatic cancer using bioconjugated InP quantum dots
.
ACS Nano
2009
;
3
:
502
10
.
60
Wente
MN
,
Jain
A
,
Kono
E
, et al
. 
Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer
.
Pancreas
2005
;
31
:
119
25
.
61
Wu
X
,
Ye
Y
,
Kiemeney
LA
, et al
. 
Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer
.
Nat Genet
2009
;
41
:
991
5
.
62
Lu
Y
,
Chen
J
,
Ding
Y
, et al
. 
Genetic variation of PSCA gene is associated with the risk of both diffuse- and intestinal-gastric cancer in a Chinese population
.
Int J Cancer
2010
,
Epub 2010 Feb 3
.
63
Wang
S
,
Tang
J
,
Wang
M
,
Yuan
L
,
Zhang
Z
. 
Genetic variation in PSCA and bladder cancer susceptibility in a Chinese population
.
Carcinogenesis
2010
;
31
:
621
4
.