.JPG?ad=18503&adview=true)
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Departments of Urology [N. A., G. S. P., Z. G., R. E. R.], Pathology [M. S., G. V. T., J. S.], and Orthopedics [F. D.], and Jonsson Cancer Center [N. A., G. S. P., Z. G., R. E. R.], University of California-Los Angeles School of Medicine, Los Angeles, California 90095
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
50% of superficial tumors will continue to recur and as many as 30% will progress to muscle-invasive disease (3)
. Although radical cystectomy can salvage many patients with muscle-invasive cancers, a significant number go on to die from metastatic disease, for which there is currently no effective treatment. These data underscore the urgent necessity for better diagnostic and treatment strategies for superficial and invasive bladder cancers.
Given the sensitivity of bladder cancer to BCG immunotherapy, there is a particular need to identify bladder cancer antigens for cellular and monoclonal antibody-based targeted immunotherapies. EGFR, for example, is overexpressed by a significant percentage of muscle-invasive bladder cancers (4)
. A recent study demonstrated that monoclonal antibody directed against EGFR slowed growth of a human transitional cell cancer in an orthotopic mouse model (5)
. Similarly, new bladder cancer markers have been identified that not only demonstrate high specificity for TCC but that also show early promise as a clinical tool. One such marker, uroplakin II, is an urothelium-specific differentiation antigen that is expressed by 40% of TCCs (6)
. Detection of uroplakin-positive cells in human sera has been associated with metastatic spread of bladder cancer cells and may identify patients with micrometastatic spread prior to undergoing cystectomy (7)
.
PSCA is a glycosylphosphatidylinositol (GPI)-anchored 123-amino-acid glycoprotein related to the Ly-6/Thy-1 family of cell surface antigens (8) . PSCA expression in normal tissues is largely prostate-specific, but we recently reported finding PSCA transcripts and protein in transitional epithelium of the bladder and neuroendocrine cells of the stomach (9) . In situ hybridization and IHC analyses demonstrated PSCA expression in more than 80% of local and 100% of bone-metastatic prostate cancer specimens (9) . Importantly, the intensity of PSCA expression increased with tumor grade and stage, which suggests its potential as an immunotherapeutic target for high-risk and metastatic prostate cancer. Supporting this hypothesis, we recently demonstrated that monoclonal antibodies against PSCA can inhibit tumor growth and metastasis formation and can prolong survival in mice bearing human prostate cancer xenografts (10) . Also, Dannull et al. (11) recently reported that a PSCA-derived peptide could elicit a PSCA-specific T-cell response in a patient with metastatic prostate cancer.
Because PSCA is present at low levels in normal bladder, we asked whether PSCA is expressed in TCC. We also determined whether PSCA is overexpressed in bladder cancer compared with normal bladder and whether the level of expression correlates with bladder cancer stage or grade. We demonstrate that PSCA is expressed by a majority of both muscle-invasive and superficial tumors. Moreover, PSCA is overexpressed in virtually all nonmuscle invasive bladder tumors and in >30% of invasive and metastatic cancers. As with prostate cancer, expression increases with increasing tumor grade. Interestingly, the overexpression of PSCA that we observed in TCC is quantitatively more than that seen in prostate cancer with respect to tumor stage. These results support PSCA as a potential diagnostic and/or therapeutic target in bladder cancer.
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Immunohistochemistry
Methodology.
Specimens were stained using modifications of an immunoperoxidase technique previously described (12)
. Briefly, antigen retrieval was performed on paraffin sections using a commercial steamer and 0.01 M citrate buffer (pH 6.0). Slides were then washed in PBS and incubated with normal horse serum, diluted 1:20, for 10 min. PSCA monoclonal antibody 1G8 was generated in the CellPharm System 100 as described previously (9)
. Monoclonal antibodies to PSCA were diluted 1:20 in PBS. After 50 min of incubation with the primary antibody, slides were treated sequentially with rabbit antimouse immunoglobulin, swine antirabbit immunoglobulin, and rabbit antiswine immunoglobulin (all biotin conjugated). Slides were then incubated with streptavidin-peroxidase, and antibody localization was performed using the diaminobenzidene reaction. Positive and negative controls were performed on tissues obtained from mouse xenograft tumors that were derived from the human prostate cancer cell lines LAPC-9 and PC3, respectively. Negative controls for each stained section consisted of substitution of the primary antibody by a non-cross-reacting isotype-matched monoclonal antibody.
Scoring Methods.
Histopathological slides of the clinical specimens were read and scored by two pathologists (G. V. T., and J. S.) in a blinded fashion. There was a >90% inter- and intraobserver agreement. IHC intensity was graded on a scale of 0 to 3+ (0, no staining; 1+, mildly intense; 2+, moderately intense; 3+, severely intense). Staining density was quantified as the percentage of cells staining positive with the primary antibody, as follows: 0 = no staining, 1 = superficial staining, 2 = positive staining in <25% of the sample; 3 = positive staining in 25–50% of the sample; 4 = positive staining in >50% of the specimen; and 5 = positive staining throughout the sample. Intensity score (0 to 3+) was multiplied by the density score (0–5) to calculate an overall score (0–15). In this way, we were able to differentiate specimens that may have had focal areas of increased staining from those that had diffuse areas of increased staining (13)
. The overall score for each specimen was then categorically assigned to one of the following groups: 0–3 (little to no immunoreactivity), 4–7 (moderate immunoreactivity), and 8–15 (strong immunoreactivity). The above groupings attempt to stratify the overall PSCA immunoreactivity of each specimen for the purpose of comparison. Overexpression was considered to be present when the overall score was 
8, indicating that 50–100% of cells had moderate or intense staining. Within any given slide, adjacent areas of normal transitional epithelium were used as positive internal controls.
Northern Blot Analysis.
Fresh human tissues were obtained at the time of surgery, and RNA was prepared according to the manufacturer’s recommendations (Biotecx, Houston, TX). Nine samples were obtained: four benign and five malignant transitional cell tissues. All five malignant tissues were from patients with muscle-invasive disease. Normal bladder RNA was obtained from benign areas of cystectomy specimens of patients with focal muscle-ITCC. In none of these patients was there evidence, either pre- or postoperatively, of CIS. Northern blot analysis was then performed as described previously (14)
. Briefly, 10 µm of RNA from each sample were loaded onto a 1% agarose gel. Equal loading and RNA integrity was confirmed by ethidium bromide staining. After electrophoresis, RNA samples were transferred onto a nitrocellulose membrane. The PSCA probe was prepared from a cDNA fragment using random oligonucleotide primers (Amersham) and was labeled with [32P]dCTP. Equal loading of RNA was also confirmed by hybridization with an actin probe. The human prostate cancer cell lines LAPC-4 and LNCaP were used as positive and negative controls, respectively. Preparation of total RNA from cell lines was performed according to the manufacturer’s instructions (Biotecx). The human bladder cancer cell line HT1376 was also included in the analysis.
Confocal Microscopy.
Human bladder cancer cell line HT1376 cells were washed with PBS containing 1 mM MgCl2 and 0.1 mM CaCl2 (PBS/CM). Cells were incubated with the primary antibody, murine monoclonal anti-PSCA antibody 1G8, and subsequently with a secondary antibody, fluorescein-conjugated FITC goat antimouse IgG (1:200; Jackson Immunoresearch, West Grove, PA). The cells were then fixed with 2% paraformaldehyde in PBS/CM for 30 min. Next, the cells were incubated with 50 mM NH4Cl in PBS/CM for 10 min at room temperature and permeabilized for 10 min with 0.075% (w/v) saponin in PBS/CM containing 0.2% BSA. Nuclei were counterstained with propidium iodide (1 µg/ml; Sigma Chemical Co.). Optical sections were obtained by laser confocal microscopy.
Statistical Analysis.
Overall scores of PSCA staining were evaluated with respect to tissue histology using a one-way ANOVA-Sidak multiple comparison procedure, using overall score as the dependent variable and the histopathological subgroup as the factor. Table 3
was constructed in this manner. To evaluate the relationship between tumor grade and overall score within the subgroups STCC and ITCC, we performed a two-way ANOVA using the overall score as the dependent variable and the grade and subgroup as the two factors. The results of this analysis can be seen in Table 2
. For all analyses, P < 0.05 was considered statistically significant.
|
|
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
and 2
and illustrated in Fig. 1, A–H
. Thirty of 32 normal bladder specimens stained positively for PSCA. In these samples, PSCA expression was generally weak (i.e., 1+) and was localized almost exclusively to the superficial umbrella cell layer (i.e., density score of 1; Fig. 1A
). The mean intensity, density, and overall staining scores from normal tissues were 1.0, 1.0, and 1.1, respectively (Table 1)
. Expression of PSCA in normal bladders was significantly less than that found in CIS and both invasive and superficial tumors (P = 0.001; Table 3
).
|
|
; IHC data not shown). The mean intensity, density, and overall score for these samples was 1.8, 2.0, and 3.6, respectively. Although PSCA staining intensity and density tended to be higher in dysplastic than in normal bladder, this was not statistically significant (P = 0.782; Table 3
). In contrast, PSCA expression in CIS was intense and homogeneous in all but two specimens (19 of 21), with a mean intensity, density, and overall score of 2.7, 4.9, and 13.2, respectively (Table 1)
. Whereas PSCA staining in normal and dysplastic bladders was confined to the most superficial layers of urothelium, staining in CIS was detected in all of the neoplastic urothelial cell layers (Fig. 1B)
. Overall, CIS expressed significantly higher levels of PSCA than any other specimen category in this study (P < 0.05, compared with normal bladder, dysplasia, STCC, ITCC, and metastases; Table 3
).
Nonmuscle invasive tumors (stages Ta and T1) also displayed an overall strong positivity for PSCA expression (Fig. 1C)
. Twenty-nine (76%) of 38 samples overexpressed PSCA, defined as an overall score of 8 (Table 1)
. The mean intensity, density, and overall scores for Ta tumors were 2.0, 4.1, and 8.6, respectively, whereas T1 lesions scored 2.2, 4.6, and 10.7, respectively. As a group, superficial tumors stained more strongly than normal, dysplastic, and invasive samples (P = 0.001; Table 3
). PSCA expression increased significantly with worsening tumor grade in nonmuscle invasive tumors (Table 2)
. Grade 2 lesions had a mean overall staining score of 6.8 compared with a mean score of 11.2 for Grade 3 tumors (P < 0.001).
We detected PSCA expression in 42 (65%) of 65 muscle-invasive tumors, of which 21 (32%) exhibited the highest levels of expression (i.e., overall score, 8). Locally advanced tumors tended to express higher levels of PSCA than organ-confined lesions, although this trend did not reach statistical significance. T2 tumors had a mean overall score of 4.1, whereas T3 and T4 tumors had mean intensity versus density scores of 5.5 and 6.6, respectively (Table 1
; Fig. 1, D–F
). As with superficial tumors, PSCA expression in muscle-invasive cancers increased significantly with tumor grade (Table 2)
. Eight (67%) of 12 grade 2 tumors displayed no detectable PSCA expression, whereas only 14 (27%) of 53 grade 3 lesions showed no expression. The mean overall score for grade 2 muscle-invasive tumors was 2.1, compared with a score of 5.9 for grade 3 tumors (P < 0.001). Several poorly differentiated muscle-invasive TCCs contained foci of squamous cell differentiation. PSCA expression in these cases was particularly prominent, as depicted in Fig. 1F
. We also examined seven bladder cancer metastases. Four (57%) stained positive for PSCA (Fig. 1G)
, three of which were in the strongest immunoreactivity category (Table 1)
. The mean intensity, density, and overall scores for metastases were 1.4, 2.3, and 6.3, respectively. These results demonstrate that PSCA is expressed by a majority of TCCs. Expression is greatest in CIS and superficial tumors but is also extremely high in >30% of muscle-invasive and metastatic lesions. Importantly, within the subgroups STCC and ITCC, higher levels of PSCA expression correlate significantly with increasing tumor grade.
PSCA Protein Is Expressed on the Cell Surface of Bladder Cancer Cells.
To confirm that PSCA localizes to the cell surface of bladder cancer cells, we stained nonpermeabilized HT1376 bladder cancer cells and examined them by confocal microscopy. PSCA monoclonal antibody 1G8 detected PSCA expression in a subpopulation of these cells. As seen in Fig. 1H
, PSCA protein expression is localized to the cell surface.
PSCA mRNA Expression in Normal and Malignant Urothelium.
Northern blot analysis was performed on four normal and five invasive transitional cell cancer samples (Fig. 1I)
. As predicted, low levels of PSCA mRNA expression were detected in three of four normal bladder specimens. PSCA mRNA was also detected in three (60%) of five muscle-invasive tumors and an invasive transitional cell cancer cell line (HT1376). Consistent with the IHC findings, two of these invasive cancers (i.e., 40%) overexpressed PSCA when compared with normal bladder. The level of PSCA expression in these two cases was similar to that seen in LAPC 9, a prostate cancer xenograft. The corresponding IHC stain for a patient with a muscle-invasive transitional cell tumor of the renal pelvis is shown in Fig. 1E
(lane with asterisk) and confirms the intense expression detected by Northern analysis. Of all of the tissues examined in this study, this was the only sample to be obtained from a site other than the bladder.
|
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
PSCA expression was strongest and most common in superficial, nonmuscle invasive tumors. PSCA expression was detected in all but one case of superficial transitional cell cancer and all cases of CIS. Similarly, 90% of CIS specimens and 76% of nonmuscle invasive cancers overexpressed PSCA. In contrast, 35% of invasive cancers had no detectable expression of PSCA, and only 32% overexpressed it. It is unlikely that the failure to detect expression in many invasive cancers was antibody- or antigen-related, because a similar percentage of tumors had no expression on Northern analysis. It is also unlikely that loss of expression can be attributed to a loss of differentiation in muscle-invasive tumors, as was recently proposed by Bahrenberg et al., because the highest levels of PSCA expression were found in CIS, a poorly differentiated and aggressive lesion. Similarly, PSCA expression was higher in poorly differentiated nonmuscle invasive tumors than in differentiated superficial ones. Although it is possible that the loss of PSCA expression is associated with invasion, 32% of invasive and 43% of metastatic tumors overexpressed PSCA. Additional studies will be needed to understand PSCA gene regulation during the process of bladder cancer invasion.
As noted above, increasing levels of PSCA expression correlated with increasing tumor grade in both superficial and muscle-invasive tumors. One possible mechanism for PSCA overexpression is that it may result from PSCA gene amplification. PSCA maps distal to the MYC oncogene on chromosome 8q24.2 (8) . In prostate cancer, PSCA overexpression is associated with PSCA and MYC coamplification (17) . Christoph et al. (18) and Sauter et al. (19) have shown that low-level MYC amplification is a common feature of both nonmuscle-invasive and invasive bladder cancers and correlates with worsening tumor grade. Fluorescent in situ studies of bladder cancers should clarify whether PSCA overexpression is caused by gene amplification. Also, it will be interesting to determine whether PSCA overexpression correlates with MYC amplification.
We observed intense PSCA staining in poorly differentiated transitional cell tumors with squamous features, which suggests that PSCA expression may be associated with squamous differentiation. We recently created a transgenic mouse model using the PSCA promoter to drive green fluorescent protein (GFP) expression.5 In this model, we noted GFP expression in keratinized skin as well as in the adult urothelium of a single founder line. Likewise, Bahrenberg et al. (16) recently reported that PSCA is expressed by keratinocytes in tissue culture, although we have not seen PSCA expression in adult skin. These observations suggest that PSCA may be a marker of both transitional and squamous differentiation patterns in the bladder and may provide another possible mechanism whereby PSCA expression levels may increase in poorly differentiated bladder tumors.
Our results differ somewhat from those reported recently by Bahrenberg et al. (16) . Similar to Bahrenberg, we saw dramatically increased levels of PSCA expression in superficial tumors. Likewise, we saw lesser overall expression of PSCA in muscle-invasive tumors. However, unlike Bahrenberg, we found that a majority of invasive and metastatic tumors expressed PSCA and >30% overexpressed it. In addition, although Bahrenberg et al. concluded that PSCA expression was a marker of differentiated bladder tumors, we found that PSCA expression was highest in poorly differentiated invasive and superficial tumors. One possible reason for these differences is that the study of Bahrenberg et al. did not include cases of CIS or high-grade superficial cancer. Also, their study was small and included only two well-differentiated (presumably superficial) and eight poorly differentiated (presumably invasive) cancers.
Another difference between this study and that of Bahrenberg is that we primarily evaluated PSCA protein expression, whereas the latter looked at mRNA levels exclusively. Importantly, Bahrenberg et al. reported finding several PSCA splice variants. One of these, denoted 
(1–17), results in the substitution of the 17-amino-acid signal sequence of exon 1 with a new 31-amino-acid sequence. This splice variant is transcribed and would be predicted to contain the epitope in exon 2 that is recognized by PSCA monoclonal antibody 1G8. It is possible, therefore, that, in at least some instances, our immunostaining would have detected a PSCA splice variant. That said, we did not detect any aberrant messages by Northern analysis, and we were clearly able to correlate PSCA mRNA and protein expression in a patient with muscle-invasive TCC. Also, our Northern analysis was consistent with the IHC data, showing expression in 60% of cases and overexpression in 40%.
Confocal microscopy studies demonstrated cell surface expression of PSCA in a subset of cells from the bladder cancer cell line HT1376. IHC analysis of PSCA shows cell surface as well as apparent cytoplasmic staining of PSCA in benign and malignant transitional epithelia (Fig. 1, A–G)
. One possible explanation for this is that anti-PSCA antibody can recognize PSCA peptide precursors that reside in the cytoplasm. In addition, it is possible that the positive staining that appears in the cytoplasm is actually from the overlying cell membrane. We have observed similar results with prostate cancer vis-a-vis confocal/immunofluorescent and IHC data (9)
. These data seem to indicate that PSCA is a novel cell surface marker for TCC.
Our results suggest that PSCA may have a number of potential uses in the diagnosis and treatment of human TCC. Because neoplastic transitional cells are naturally sloughed from the bladder, differential expression of PSCA in voided samples might form the basis for a diagnostic test. Detection of PSCA on the surface of circulating cells in blood and bone marrow might be useful in identifying some patients with bladder cancer micrometastases, particularly those whose primary tumors express PSCA. We have recently shown that immunomagnetic beads conjugated with PSCA monoclonal antibodies can detect as few as 1 in 107 PSCA-positive cells in bone marrow.6 Similar approaches have been tested using uroplakin II as a marker of metastatic transitional cells (7) .
PSCA might also be a valuable target for bladder cancer immunotherapy. One potential approach is to use monoclonal antibodies intravesically to treat localized disease (particularly CIS) or systemically to treat advanced disease. We have recently shown that naked PSCA antibodies inhibit prostate cancer tumorigenesis and metastasis, which suggests that they may have utility in TCC as well (10) . Similar approaches have been reported in bladder cancer using antibodies against EGFR systemically and against the MUC 1 mucin antigen intravesically (5 , 20) . PSCA might also be useful for local or systemic vaccine approaches. Dannull et al. (11) recently demonstrated that amino acids 14–22 of PSCA can elicit a PSCA-specific T-cell response in a patient with prostate cancer. Given the profound immunosensitvity of bladder cancer to nonspecific agents such as BCG, this is a particularly promising approach, especially in the local setting.
In summary, we have shown in this study that PSCA is expressed by a majority of superficial and muscle-invasive transitional cell tumors. Furthermore, PSCA is overexpressed in a majority of superficial tumors and a significant percentage of invasive and metastatic transitional cell cancers. These results suggest that PSCA may be a valuable target for bladder cancer diagnosis and therapy.
|
FOOTNOTES |
|---|
1 Supported in part by grants from the NIH K08 CA74169, the Cancer Research Institute, and CaPCURE. 
2 N. A. and G. S. P. contributed equally to this work.
3 To whom requests for reprints should be addressed, at the Department of Urology, UCLA, 66-134 Center for the Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1738. E-mail: rreiter{at}mednet.ucla.edu
4 The abbreviations used are: TCC, transitional cell carcinoma; PSCA, prostate stem cell antigen; ITCC, invasive TCC; STCC, superficial TCC; CIS, carcinoma in situ; IHC, immunohistochemical; BCG, Calmette-Guerin bacillus; EGFR, epidermal growth factor receptor.
5 T. Watabe, R. E. Reiter, M. Lin, A. A. Donjacour, G. R. Cunha, and O. N. Witte. In situ visualization of a growth responsive subset of epithelial cells associated with prostate development, regeneration and tumorigenesis, submitted for publication.
6 Z. Gu and R. E. Reiter, unpublished data.
Received 2/ 2/01. Accepted 4/27/01.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  Z. Gu, J. Yamashiro, E. Kono, and R. E. Reiter 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., October 15, 2005; 65(20): 9495 - 9500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nakamoto, H. Okada, T. Nakajima, A. Ikuta, K. Yasuda, and H. Kanzaki Progesterone induces the fibulin-1 expression in human endometrial stromal cells Hum. Reprod., June 1, 2005; 20(6): 1447 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Lam, J. Yamashiro, I. P. Shintaku, R. L. Vessella, R. B. Jenkins, S. Horvath, J. W. Said, and R. E. Reiter Prostate Stem Cell Antigen Is Overexpressed in Prostate Cancer Metastases Clin. Cancer Res., April 1, 2005; 11(7): 2591 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhigang and S. Wenlv Prostate Stem Cell Antigen (PSCA) Expression in Human Prostate Cancer Tissues: Implications for Prostate Carcinogenesis and Progression of Prostate Cancer Jpn. J. Clin. Oncol., July 1, 2004; 34(7): 414 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P.T. Higgins, L. Wang, N. Kambham, K. Montgomery, V. Mason, S. U. Vogelmann, K. V. Lemley, P. O. Brown, J. D. Brooks, and M. van de Rijn Gene Expression in the Normal Adult Human Kidney Assessed by Complementary DNA Microarray Mol. Biol. Cell, February 1, 2004; 15(2): 649 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jain, A. Lam, I. Vivanco, M. F. Carey, and R. E. Reiter Identification of an Androgen-Dependent Enhancer within the Prostate Stem Cell Antigen Gene Mol. Endocrinol., October 1, 2002; 16(10): 2323 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ross, S. D. Spencer, I. Holcomb, C. Tan, J. Hongo, B. Devaux, L. Rangell, G. A. Keller, P. Schow, R. M. Steeves, et al. Prostate Stem Cell Antigen as Therapy Target: Tissue Expression and in Vivo Efficacy of an Immunoconjugate Cancer Res., May 1, 2002; 62(9): 2546 - 2553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Watabe, M. Lin, H. Ide, A. A. Donjacour, G. R. Cunha, O. N. Witte, and R. E. Reiter Growth, regeneration, and tumorigenesis of the prostate activates the PSCA promoter PNAS, January 8, 2002; 99(1): 401 - 406. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
