| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Department of Cell Biology [P. J. K., B. A. F., N. M. G.] and Scott Department of Urology [N. M. G.], Baylor College of Medicine, Houston, Texas 77030; Mineral Metabolism Laboratory, Jerry L. Pettis Memorial Veterans Administration Medical Center, Loma Linda, California 92357 [S. M.]; and Division of Endocrinology, Department of Pediatrics, University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [P. C.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Deregulation of the IGF axis has been specifically implicated in clinical prostate cancer. Recent epidemiological studies have demonstrated that elevated serum IGF-I, in particular, is associated with prostate cancer risk (5, 6, 7) . In a prospective case-control study of men participating in the Physician’s Health Study, it was found that men with serum IGF-I concentrations in the upper quartile were at increased risk of developing clinically evident prostate cancer within the next 5–10 years. The study also indicated that plasma IGF-I concentration may be a better predictor of prostate cancer than serum PSA (5) . The levels of IGFBP-2 and IGFBP-3 are also found to be altered in the serum and prostate tissue of prostate cancer patients. In these patients, levels of IGFBP-2 are often increased, whereas levels of IGFBP-3 are often decreased (8, 9, 10, 11, 12) . Because IGFBP-3 is a substrate for PSA, a member of the kallikrein family of serine proteases, it is postulated that rising PSA levels during the natural history of prostate cancer facilitate disease progression by proteolytically cleaving IGFBP-3, thereby increasing the level of bioavailable IGF at the cellular level (13) .
Despite the evidence establishing a close relationship between the IGF axis and prostate cancer, it has been difficult to comprehensively examine changes in the IGF axis at the molecular level throughout the natural history of clinical disease, in part due to the paucity of clinical samples representing the earliest forms of this disease as well as the heterogeneity of both the disease and of the patient population. We have, therefore, used the autochthonous Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model to facilitate molecular characterization of the changes in the IGF axis during the initiation, progression, and metastasis of prostate cancer as well as in androgen-independent disease (14, 15, 16) .
The TRAMP model was previously generated using the minimal PB -426/+28 regulatory sequence to specifically target SV40 early gene (Tag) expression to prostatic epithelium (14) commencing at sexual maturity. By 10–12 weeks of age, TRAMP mice generally develop PIN and/or well-differentiated prostate cancer. All TRAMP mice ultimately develop prostatic adenocarcinoma that metastasizes to distant sites, primarily the lymph nodes and lungs. This generally occurs by 24–30 weeks of age in [C57BL/6 x FVB]F1 TRAMP mice (14 , 15) . Following androgen ablation, 20–35% of TRAMP mice remain tumor free, whereas 65–80% develop androgen-independent disease. Tumors that develop in castrated mice uniformly progress to poorly differentiated adenocarcinoma. Castrated mice that develop tumors also exhibit twice the incidence of metastasis (16) . Here we report evidence that local expression of IGF-I in the prostate correlates with, and may in fact facilitate, early disease progression. Furthermore, we demonstrate that independence from IGF1R-mediated signaling correlates with—and may, therefore, be a prerequisite for—metastasis and androgen independence.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
QRT-PCR.
Total RNA was isolated from tissues by the cesium chloride method (17)
. The reverse transcription-PCR reaction was performed with modifications of the procedure described by Orly et al. (18)
. Briefly, RNA (1 µg) was reverse transcribed for 1 h at 37°C using 100 ng of oligo dT [pd(T)12–18] primers (Pharmacia, Piscataway, NJ) and 200 units of Moloney Murine Leukemia Virus reverse transcriptase (Life Technologies, Inc., Grand Island, NY) in a 100-µl reaction containing 1x First Strand Buffer (Life Technologies, Inc.), 600 µM dNTPs (Life Technologies, Inc.), 1 mM DTT (Life Technologies, Inc.), and 100 units of RNase inhibitor (Boehringer Mannheim, Indianapolis, IN). The RT reaction was terminated by heating for 15 min at 95°C. Ninety µl of the RT reaction mixture (900 ng of input RNA) was added to 60 µl of RT master mix containing 1x First Strand Buffer, 600 µM dNTPs, 100 ng/µl oligo dT, and 1 mM DTT to achieve a final concentration of 200 µM dNTPs in the PCR reaction. The diluted RT reaction mixture was added to 300 µl of the PCR master mix containing 1x PCR buffer (Promega, Madison, WI), 0.5 µM of the appropriate oligonucleotide forward and reverse primer pair (Fig. 1A)
, 12.5 µCi [
-32P]dCTP (3000 Ci/mmol, ICN Biochemicals, Irvine, CA), 0.85 units Taq DNA polymerase (Promega) as well as 0.5 µM oligonucleotide forward and reverse primers for the ribosomal protein L19 (RPL19) as an internal control (Fig. 1A)
. The concentration of MgCl2 added to the PCR master mix was dependent on the experimental primer set used: IGF-I, 2 mM; IGF-II, 2.5 mM; IGF1R, 2.5 mM; or IGF2R, 2 mM. Each PCR reaction mixture was aliquoted into eight tubes (50 µl each) for reaction termination at various cycles (14
, 16
, 18
, 20
, 22
, 24
, 26 , and 28)
. PCR was performed using a denaturing temperature of 94°C (1 min), an annealing temperature of 62°C (IGF-I), 65°C (IGF-II and IGF2R), or 68°C (IGF1R) for 2 min, and extension temperature of 72°C (3 min) using a DNA engine (MJ Research, Inc., Watertown, MA). All of the PCR reactions were terminated over a range of cycles to determine the ratio of IGF:L19 within the log phase of the reaction. IGF2R, however, was amplified by only 20 cycles of PCR because preliminary studies demonstrated this to be within the log phase of each reaction for both IGF2R and L19 primer sets. The radiolabeled PCR products (15 µl) were mixed with 5x tracking dye (3 µl; Ref. 19
) and were separated on a 5% polyacrylamide gel in 0.5x Tris-borate-EDTA buffer. The gels were dried under vacuum and heat (1 h at 80°C) and the amplified products were quantitated using phosphoimage analysis (Storm 860, Molecular Dynamics, Sunnyvale, CA). To determine the log phase of each PCR reaction, the volume of each phosphoimaged band was plotted against the number of PCR cycles. The reported ratio of IGF:L19 was generated by calculating the average of three points extrapolated from the plotted data according to the equation N = No2n, where N is the volume after amplification, No is the initial volume, and n is the number of cycles. A representative autoradiograph of a QRT-PCR gel and the graphical representation of the phosphoimage analysis is shown in Fig. 1, B and C
. Each of the data points in Figs. 2
3
4
5
represents the mean of 3–6 mice. The PCR product amplified from each set of primers (IGF-I, IGF-II, IGF1R, and IGF2R) was subcloned, and DNA sequence verified that the primers amplified the appropriate cDNA.
|
|
|
|
|
WLBs.
Serum IGFBP levels were measured in samples (4 µl) which were separated by nonreducing 10% SDS-PAGE overnight at constant voltage and were electroblotted onto nitrocellulose. The membranes were then sequentially washed with NP40, 1% BSA, and Tween 20; incubated with 106 cpm each of 125I-IGF-I and -IGF-II (Amersham Life Sciences, Arlington, Heights, IL) for 12 h; washed with Tween Tris-buffered salinex 3; dried; and exposed to film for 4 days as described previously (11)
. SDS-PAGE reagents were purchased from Bio-Rad (Richmond, CA). Phenylmethylsulfonyl fluoride (PMSF), EDTA, pepstatin, and aprotinin were obtained from Sigma (St. Louis, MO).
Western Immunoblots.
Serum (4 µl) from mice was handled as described for the WLBs and was subjected to electrophoresis overnight through 10% nonreducing SDS-PAGE at constant voltage. Gels were electroblotted onto nitrocellulose; blocked with 5% nonfat dry milk in Tris-buffered saline; probed with a rabbit antibovine IGFBP-2 antibody (UBI, Lake Placid, NY) that is specific to IGFBP-2 of all mammalian species without cross-reactivity with other IGFBPs; and detected using a peroxidase-linked enhanced chemiluminescence detection system as described previously (23)
.
Densitometric and Statistical Analysis.
Densitometric measurement of immunoblots and WLBs were performed using a Bio-Rad GS-670 Imaging densitometer (Bio-Rad, Melville, NY). When applicable, mean ± SE are shown. Student t tests were used for statistical analysis.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. As shown in Fig. 2
, expression of IGF-I mRNA in the prostate did not change significantly between 12 and 30 weeks of age in nontransgenic mice. Although the IGF-I mRNA level in prostate was lower on a per cell basis in 12-week-old TRAMP mice than in 12-week-old nontransgenic mice, the relative level of IGF-I mRNA was observed to increase gradually during cancer progression. In fact, significantly higher levels of IGF-I mRNA were observed in the tumors from 30-week-old TRAMP mice and metastatic lesions from TRAMP mice (200% and 250%, respectively; P < 0.05) when compared with levels in the prostates from 12-week-old TRAMP mice.
To examine the expression of IGF-I in androgen-independent disease, RNA was isolated from tumors of TRAMP mice castrated at 12 weeks of age and sacrificed at 12 weeks postcastration. The majority of castrated TRAMP mice, 77% in this study, developed tumors by 12 weeks postcastration. In contrast to the data obtained from the intact TRAMP mice, expression of IGF-I mRNA remained at nontransgenic or precastration levels in the prostate tumors of the castrated TRAMP mice as well as in the accompanying metastatic lesions (Fig. 2)
. These data indicate that the development of prostate cancer in intact TRAMP mice is distinct from androgen-independent disease with respect to the regulation of IGF-I expression in the prostate.
As demonstrated in Fig. 3
, the expression of IGF1R mRNA was not observed to change significantly during primary cancer progression in intact TRAMP tumors. It is interesting to note, however, that although expression of IGF1R mRNA remained at nontransgenic levels in the tumors from intact TRAMP mice, expression of IGF1R mRNA was significantly reduced (P < 0.05) in tumors from castrated TRAMP mice (85%) as well as in metastatic lesions (97%) when compared with prostate levels in nontransgenic mice. These observations implicate a selection against expression of IGF1R in advanced and disseminated disease.
Although expression of IGF-II mRNA in the prostate did not change significantly with age in nontransgenic mice, IGF-II mRNA levels were significantly reduced (75–95%; P < 0.05) in the prostates of TRAMP mice when compared with nontransgenic mice (Fig. 4)
. This decrease (80%) in expression of IGF-II mRNA was observed as early as 12 weeks of age in TRAMP mice and persisted as the cancer progressed. Expression of IGF-II mRNA was also significantly reduced (P < 0.05) in tumors from castrated TRAMP mice (80%) as well as in metastatic lesions (75–95%) when compared with IGF-II mRNA levels in prostates of nontransgenic mice.
As shown in Fig. 5
, changes in expression of IGF2R mRNA did not occur during prostate cancer progression in the TRAMP model. Similar to the pattern of expression of IGF1R mRNA, expression of IGF2R mRNA remained at nontransgenic levels during cancer progression in tumors from intact TRAMP mice. Expression of IGF2R mRNA was significantly reduced (P < 0.05) in tumors from castrated TRAMP mice (62%) and in metastatic lesions (47–66%) when compared with prostate levels in nontransgenic mice, which suggests that—like IGF1R and IGF-II—reduced expression of IGF2R correlates with advanced disease.
Analysis of Serum IGF-I Levels during Cancer Progression in TRAMP Mice.
Radioimmunoassays were used to determine whether changes in the concentration of serum IGF-I correlated with prostate cancer progression in an independent cohort of TRAMP and nontransgenic mice. As shown in Fig. 6
, the serum IGF-I concentration in nontransgenic mice increased between 6 weeks of age (178 ± 8 ng/ml) and 18 weeks of age (232 ± 36 ng/ml) reaching a maximal level by 18 weeks of age. In contrast, the serum IGF-I concentration in TRAMP mice reached a level corresponding to the maximal nontransgenic level by 12 weeks of age, a time when the serum IGF-I concentration in TRAMP mice (260 ± 17 ng/ml) was significantly different (P < 0.01) from the concentration in nontransgenic mice (173 ± 11 ng/ml). Thus, precociously elevated levels of IGF-I were observed in TRAMP mice as early as 12 weeks of age, which suggests that IGF-I may be important in early disease progression.
|
Analysis of Serum IGFBPs Levels during Prostate Cancer Progression in TRAMP Mice.
To assess whether changes in serum IGFBPs were induced by the prostatic tumors, we subjected serum samples of control (n = 9), TRAMP (n = 9), and castrated TRAMP (n = 4) mice to WLB with radiolabeled IGFs and to WIB with an IGFBP-2 specific antibody. Using this method, we observed no differences in any of the serum IGFBPs between control and TRAMP mice prior to 24 weeks of age, at which time serum IGFBP-2 levels were approximately 2-fold higher than in control mice (P < 0.05; Fig. 7
). This is similar to reports in human prostate cancer patients (10
, 11) . It was interesting to note that a 50% reduction in serum IGFBP-3 level was observed as a consequence of castration of TRAMP mice, a finding remarkably similar to that reported previously in castrated baboons (24)
.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
We observed that the expression of IGF-I mRNA in the prostate increased with prostate cancer progression in intact TRAMP mice. This is consistent with previously reported observations that the SV40 early genes, specifically large Tag, are known to influence the transcription of IGF-I (26) . This is accomplished, in part, by preventing the binding of an inhibitory E2F complex to the IGF-I promoter (27) . Although IGF-I is important in the development of prostate cancer, it has previously been demonstrated that when the insulin gene regulatory region was used to target Tag to the pancreas expression of IGF-II but not expression of IGF-I was found to be increased (28) , which indicated that IGF-II is important in the development of pancreatic cancer and suggests that up-regulation of IGF-I is not a general property of the transgene but rather a consequence of the transformation of prostate epithelial cells.
Concurrent with the observed increase in expression of prostatic IGF-I, serum IGF-I was found to be precociously elevated in TRAMP mice early in cancer progression. Although the level of prostatic IGF-I mRNA per cell was found to be reduced, it should be noted that the prostates of TRAMP mice are, on average, 20% larger by wet weight than those of nontransgenic littermates at 12 weeks of age (16) . It is possible that those cells expressing IGF-I may have a growth advantage, and that the observed increase in serum IGF-I may reflect the increased number of IGF-I expressing prostatic epithelial cells. It is interesting to note that the increase in serum IGF-I levels coincided with the time at which the majority of TRAMP mice displayed either PIN and/or well-differentiated prostate cancer. Hence, the integrity of the prostate ductal structures may have been compromised as proposed for the mechanism whereby PSA enters the circulation (29) , and the small foci of invasive cells could have allowed IGF-I to "leak" into the circulation. Because no significant changes in serum IGFBP levels were observed in intact TRAMP mice until 24 weeks of age, this essentially rules out the possibility that elevations in serum IGF-I were an artifact caused by binding protein interference in the assay. This further indicates that the observed increase in serum IGF-I was probably due to prostatic IGF-I and not due to a systemic response.
It is curious that, as prostatic IGF-I levels continued to rise in the TRAMP mice, the serum IGF-I levels did not rise above the level observed in nontransgenic adults. The level of serum IGF-I in TRAMP mice is most likely maintained via a feedback loop because IGF-I is known to negatively regulate secretion of growth hormone by the pituitary, and hepatic expression of IGF-I—the major source of serum IGF-I—is primarily responsive to growth hormone (2 , 3) . Therefore, serum IGF-I, synthesized by the prostate, possibly down-regulates the secretion of pituitary growth hormone and thereby decreases IGF-I secretion by the liver to maintain serum IGF-I at an optimal level.
Although our data suggest that prostatic IGF-I contributes to serum IGF-I, this finding does not preclude the possibility that the prostate is also a direct target of circulating IGF-I and that elevated basal levels of serum IGF-I may directly contribute to early prostate cancer progression. It was demonstrated (30) that systemic administration of IGF-I to rats for 1 week resulted in an increase in the mean wet weight of the prostate gland. Likewise, acromegaly patients with elevated growth hormone and IGF-I serum levels also have increased prostate volumes, and when these patients are treated with octreotide to suppress GH/IGF-I levels, prostate volumes were observed to decrease (31) . On the basis of these observations, it should be interesting to determine whether genetic differences in serum IGF-I bioavailability contribute to a predisposition to prostate cancer. In fact, it has been demonstrated that African-American men have a higher incidence of clinically significant prostate cancer than Caucasian-American men (32) . Although both populations exhibit similar basal levels of serum IGF-I, African-American men generally have lower levels of IGFBP-3, the major binding protein in the serum (33) . Hence, African-American men may be predisposed to prostate cancer because they actually have a higher level of bioavailable IGF-I in their serum and/or tissues. By crossing TRAMP mice with mice that have systemic alterations in IGF-I levels, for example, lit/lit mice that have reduced serum IGF-I levels (34) and MT-GHRH transgenic mice that have elevated serum IGF-I levels (35) , it should be possible to further test this hypothesis.
It is interesting to note that expression of IGF1R, IGF-II, and IGF2R mRNA was significantly reduced (85–96%, 75–95%, 47–66%, respectively; P < 0.05) in both metastatic and androgen-independent disease. The dramatic reduction (85–96%, P < 0.05) in IGF1R expression in these poorly differentiated tumors is particularly interesting because it supports the hypothesis that the loss of IGF1R expression may be associated with the loss of differentiation and increased tumorigenicity (36) . Thus, the data from the TRAMP model suggest that organ-confined disease seems to be IGF-I-dependent, whereas metastatic and androgen-independent disease are IGF1R-independent. Although this study focused on mRNA expression, future studies will examine signaling molecules downstream of the IGF1R to determine the functional consequence of the loss of IGF1R mRNA expression in metastatic and androgen-independent disease.
The IGF2R gene is lost in a variety of cancers including liver and breast tumors and is thought to be a tumor suppressor gene (37 , 38) , and IGF2R expression is significantly reduced (47–66%, P < 0.05) in metastatic and androgen-independent disease in the TRAMP model. There are a number of possible events that could arise as a consequence of the loss of IGF2R expression. Because IGF2R regulates intracellular trafficking of lysosomal enzymes including cathepsins that are IGFBP proteases (39) , the loss of IGF2R expression could result in increased cathepsin activity that may proteolytically cleave the IGFBPs and thereby increase the bioavailability of the IGFs. In addition, increased secretion of cathepsins may, in part, facilitate metastasis by degradation of basement membranes (39) . Because IGF2R is also involved in the activation of latent TGFß (37 , 38) , the loss of IGF2R expression would reduce TGFß activity. Curiously, it has been demonstrated previously (40) that levels of TGFß can be elevated in prostate cancer, which indicates that TGFß must be activated by an alternate mechanism in prostate cancer cells lacking IGF2R.
It is tempting to speculate on a mechanism whereby IGF-I contributes to the initiation and progression of prostate cancer. One possibility is that elevated levels of IGF-I may promote angiogenesis because it is known to induce VEGF (41)
. In fact, in our model, the increase in serum IGF-I seems to correlate with the increase in mean vessel density associated with the development of high-grade PIN lesions.4
Given this relationship (Fig. 8)
, we propose that IGF-I is involved in the "angiogenic switch" (42)
leading to prostatic neovascularization. Although it is unclear whether the elevated levels of serum IGF-I in prostate cancer patients is of prostatic origin, it is possible that both systemic and prostatic IGF-I may contribute to the initiation and/or progression of the disease, which could explain why men with elevated baseline levels of serum IGF-I may be predisposed to prostate cancer.
|
In summary, our results using TRAMP mice support the epidemiological data that elevated serum IGF-I correlates with prostate cancer progression and that the prostate can be a source of IGF-I. Furthermore, our data demonstrate that specific changes in the IGF axis correlate with the initiation and/or early progression of the disease. To directly test this hypothesis, we have now generated transgenic mice targeting the DES-IGF-I ligand [which has a reduced affinity for the IGFBPs (43) ] to the prostate under the control of the prostate epithelial cell-specific rat PB promoter. Preliminary observations with the PB-DES mice demonstrate that they develop PIN-like lesions, which supports the hypothesis that deregulated IGF-I expression in the prostate is causally related to neoplastic transformation,5 and we anticipate that these mice will allow us to better characterize the consequence of IGF-I deregulation. The TRAMP model also predicts that the loss of IGF1R is a hallmark of advanced androgen-independent and metastatic disease and provides the rationale that therapies designed to reduce IGF-I levels, as with a somatostatin analogue, may be efficacious prior to androgen ablation therapy or the occurrence of metastasis but will mostly likely not be effective in patients with metastatic disease or those who have undergone androgen ablation therapy. Lastly, because the data from the TRAMP model predict that the loss of IGF1R and IGF2R is a hallmark of advanced androgen-independent and metastatic disease, these molecules should be examined as possible prognostic tools to differentiate between patients whose cancer will remain dormant and those whose cancer will progress to advanced disease.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by Specialized Program of Research Excellence CA58204 (to N. M. G.), CaP CURE (to N. M. G.), National Research Service Award CA74589 (to P. J. K.), Wyland F. Leadbetter Fellowship from the American Foundation for Urologic Disease (to B. A. F.), NIH R01 AR31062 (to S. M.), NIH 2R01 DK47591 (to P. C.), and American Cancer Society Idea Development Award (to P. C.). 
2 To whom requests for reprints should be addressed, at Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, M626, Houston, TX 77030.
3 The abbreviations used are: IGF, insulin-like growth factor; IGF1R, type-1 IGF receptor; IGF2R, type-2 IGF receptor; IGFBP, IGF-binding protein; PSA, prostate-specific antigen; PB, probasin; TRAMP, transgenic adenocarcinoma of mouse prostate; PIN, prostatic intraepithelial neoplasia; RT, reverse transcription; QRT-PCR, quantitative RT-PCR; WLB, Western ligand blot/blotting; WIB, Western immunoblot/immunoblotting; Tag, T antigen; TGFß, transforming growth factor ß; VEGF, vascular endothelial growth factor.
Received 10/12/98. Accepted 3/ 4/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  S. Li, D. Zhang, L. Yang, J. V. Burnier, N. Wang, R. Lin, E. R. Lee, R. I. Glazer, and P. Brodt The IGF-I Receptor Can Alter the Matrix Metalloproteinase Repertoire of Tumor Cells through Transcriptional Regulation of PKC-{alpha} Mol. Endocrinol., December 1, 2009; 23(12): 2013 - 2025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, M. J.L. Bonorden, G.-x. Li, H.-J. Lee, H. Hu, Y. Zhang, J. D. Liao, M. P. Cleary, and J. Lu Methyl-Selenium Compounds Inhibit Prostate Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model with Survival Benefit Cancer Prevention Research, May 1, 2009; 2(5): 484 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Adhami, I. A. Siddiqui, S. Sarfaraz, S. I. Khwaja, B. B. Hafeez, N. Ahmad, and H. Mukhtar Effective Prostate Cancer Chemopreventive Intervention with Green Tea Polyphenols in the TRAMP Model Depends on the Stage of the Disease Clin. Cancer Res., March 15, 2009; 15(6): 1947 - 1953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Schayek, K. Haugk, S. Sun, L. D. True, S. R. Plymate, and H. Werner Tumor Suppressor BRCA1 Is Expressed in Prostate Cancer and Controls Insulin-like Growth Factor I Receptor (IGF-IR) Gene Transcription in an Androgen Receptor-Dependent Manner Clin. Cancer Res., March 1, 2009; 15(5): 1558 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Svensson, J. Kindblom, R. Shao, S. Moverare-Skrtic, M. K Lagerquist, N. Andersson, K. Sjogren, K. Venken, D. Vanderschueren, J.-O. Jansson, et al. Liver-derived IGF1 enhances the androgenic response in prostate J. Endocrinol., December 1, 2008; 199(3): 489 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Anzo, L. J. Cobb, D. L. Hwang, H. Mehta, J. W. Said, S. Yakar, D. LeRoith, and P. Cohen Targeted Deletion of Hepatic Igf1 in TRAMP Mice Leads to Dramatic Alterations in the Circulating Insulin-Like Growth Factor Axis but Does Not Reduce Tumor Progression Cancer Res., May 1, 2008; 68(9): 3342 - 3349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Sutherland, S. E. Knoblaugh, P. J. Kaplan-Lefko, F. Wang, M. Holzenberger, and N. M. Greenberg Conditional Deletion of Insulin-like Growth Factor-I Receptor in Prostate Epithelium Cancer Res., May 1, 2008; 68(9): 3495 - 3504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pandini, M. Genua, F. Frasca, S. Squatrito, R. Vigneri, and A. Belfiore 17{beta}-Estradiol Up-regulates the Insulin-like Growth Factor Receptor through a Nongenotropic Pathway in Prostate Cancer Cells Cancer Res., September 15, 2007; 67(18): 8932 - 8941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Zorn, K. J. Wojno, M. T. McCabe, R. Kuefer, J. E. Gschwend, and M. L. Day 5-Aza-2'-Deoxycytidine Delays Androgen-Independent Disease and Improves Survival in the Transgenic Adenocarcinoma of the Mouse Prostate Mouse Model of Prostate Cancer Clin. Cancer Res., April 1, 2007; 13(7): 2136 - 2143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Severi, H. A. Morris, R. J. MacInnis, D. R. English, W. D. Tilley, J. L. Hopper, P. Boyle, and G. G. Giles Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev., June 1, 2006; 15(6): 1137 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Tsuchiya, L. Wang, H. Suzuki, T. Segawa, H. Fukuda, S. Narita, M. Shimbo, T. Kamoto, K. Mitsumori, T. Ichikawa, et al. Impact of IGF-I and CYP19 Gene Polymorphisms on the Survival of Patients With Metastatic Prostate Cancer J. Clin. Oncol., May 1, 2006; 24(13): 1982 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Le, J. T. Arnold, K. K. McFann, and M. R. Blackman DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E952 - E960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cheng, D. O. Stram, K. L. Penney, M. Pike, L. Le Marchand, L. N. Kolonel, J. Hirschhorn, D. Altshuler, B. E. Henderson, and M. L. Freedman Common Genetic Variation in IGF1 and Prostate Cancer Risk in the Multiethnic Cohort J Natl Cancer Inst, January 18, 2006; 98(2): 123 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Goel, L. Moro, M. King, N. Teider, M. Centrella, T. L. McCarthy, M. Holgado-Madruga, A. J. Wong, E. Marra, and L. R. Languino {beta}1 Integrins Modulate Cell Adhesion by Regulating Insulin-Like Growth Factor-II Levels in the Microenvironment Cancer Res., January 1, 2006; 66(1): 331 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Freedland, W. J. Aronson, B. Trock, P. Cohen, C. J. Kane, C. L. Amling, J. C. Presti Jr., M. K. Terris, and for the Shared Equal Access Regional Cancer Hospit Racial Differences in Prognostic Value of Adult Height for Biochemical Progression Following Radical Prostatectomy Clin. Cancer Res., November 1, 2005; 11(21): 7735 - 7742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Huss, D. R. Gray, N. M. Greenberg, J. L. Mohler, and G. J. Smith Breast Cancer Resistance Protein-Mediated Efflux of Androgen in Putative Benign and Malignant Prostate Stem Cells Cancer Res., August 1, 2005; 65(15): 6640 - 6650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Goel, M. Breen, J. Zhang, I. Das, S. Aznavoorian-Cheshire, N. M. Greenberg, A. Elgavish, and L. R. Languino {beta}1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts Cancer Res., August 1, 2005; 65(15): 6692 - 6700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-W. Lee, L. Ma, X. Yan, B. Liu, X.-k. Zhang, and P. Cohen Rapid Apoptosis Induction by IGFBP-3 Involves an Insulin-like Growth Factor-independent Nucleomitochondrial Translocation of RXR{alpha}/Nur77 J. Biol. Chem., April 29, 2005; 280(17): 16942 - 16948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pandini, R. Mineo, F. Frasca, C. T. Roberts Jr., M. Marcelli, R. Vigneri, and A. Belfiore Androgens Up-regulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells Cancer Res., March 1, 2005; 65(5): 1849 - 1857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Krueckl, R. A. Sikes, N. M. Edlund, R. H. Bell, A. Hurtado-Coll, L. Fazli, M. E. Gleave, and M. E. Cox Increased Insulin-Like Growth Factor I Receptor Expression and Signaling Are Components of Androgen-Independent Progression in a Lineage-Derived Prostate Cancer Progression Model Cancer Res., December 1, 2004; 64(23): 8620 - 8629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Adhami, I. A. Siddiqui, N. Ahmad, S. Gupta, and H. Mukhtar Oral Consumption of Green Tea Polyphenols Inhibits Insulin-Like Growth Factor-I-Induced Signaling in an Autochthonous Mouse Model of Prostate Cancer Cancer Res., December 1, 2004; 64(23): 8715 - 8722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rubinstein, G. Idelman, S. R. Plymate, G. Narla, S. L. Friedman, and H. Werner Transcriptional Activation of the Insulin-Like Growth Factor I Receptor Gene by the Kruppel-Like Factor 6 (KLF6) Tumor Suppressor Protein: Potential Interactions between KLF6 and p53 Endocrinology, August 1, 2004; 145(8): 3769 - 3777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Freeman, B. E. Welm, R. D. Gangula, J. M. Rosen, M. Ittmann, N. M. Greenberg, and D. M. Spencer Inducible Prostate Intraepithelial Neoplasia with Reversible Hyperplasia in Conditional FGFR1-Expressing Mice Cancer Res., December 1, 2003; 63(23): 8256 - 8263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Song, S. C. Cornelius, M. Reiss, and D. Danielpour Insulin-like Growth Factor-I Inhibits Transcriptional Responses of Transforming Growth Factor-{beta} by Phosphatidylinositol 3-Kinase/Akt-dependent Suppression of the Activation of Smad3 but Not Smad2 J. Biol. Chem., October 3, 2003; 278(40): 38342 - 38351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wu, G. Tortolero-Luna, H. Zhao, D. Phatak, M. R. Spitz, and M. Follen Serum Levels of Insulin-like Growth Factor I and Risk of Squamous Intraepithelial Lesions of the Cervix Clin. Cancer Res., August 1, 2003; 9(9): 3356 - 3361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Woodson, J. A. Tangrea, M. Pollak, T. D. Copeland, P. R. Taylor, J. Virtamo, and D. Albanes Serum Insulin-like Growth Factor I: Tumor Marker or Etiologic Factor? A Prospective Study of Prostate Cancer among Finnish Men Cancer Res., July 15, 2003; 63(14): 3991 - 3994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kiyama, K. Morrison, T. Zellweger, M. Akbari, M. Cox, D. Yu, H. Miyake, and M. E. Gleave Castration-Induced Increases in Insulin-Like Growth Factor-Binding Protein 2 Promotes Proliferation of Androgen-independent Human Prostate LNCaP Tumors Cancer Res., July 1, 2003; 63(13): 3575 - 3584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Ngo, R. J. Barnard, P. Cohen, S. Freedland, C. Tran, F. deGregorio, Y. I. Elshimali, D. Heber, and W. J. Aronson Effect of Isocaloric Low-fat Diet on Human LAPC-4 Prostate Cancer Xenografts in Severe Combined Immunodeficient Mice and the Insulin-like Growth Factor Axis Clin. Cancer Res., July 1, 2003; 9(7): 2734 - 2743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wang, V. L. DeGroff, and S. K. Clinton Tomato and Soy Polyphenols Reduce Insulin-Like Growth Factor-I-Stimulated Rat Prostate Cancer Cell Proliferation and Apoptotic Resistance In Vitro via Inhibition of Intracellular Signaling Pathways Involving Tyrosine Kinase J. Nutr., July 1, 2003; 133(7): 2367 - 2376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Nanni, G. Nicoletti, C. De Giovanni, S. Croci, A. Astolfi, L. Landuzzi, E. Di Carlo, M. Iezzi, P. Musiani, and P.-L. Lollini Development of Rhabdomyosarcoma in HER-2/neu Transgenic p53 Mutant Mice Cancer Res., June 1, 2003; 63(11): 2728 - 2732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Letsch, A. V. Schally, R. Busto, A. M. Bajo, and J. L. Varga Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers PNAS, February 4, 2003; 100(3): 1250 - 1255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Binder, Th. Hagemann, B. Husen, M. Schulz, and A. Einspanier Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases Mol. Hum. Reprod., September 1, 2002; 8(9): 789 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Papandreou, D. D. Daliani, P. F. Thall, S.-M. Tu, X. Wang, A. Reyes, P. Troncoso, and C. J. Logothetis Results of a Phase II Study With Doxorubicin, Etoposide, and Cisplatin in Patients With Fully Characterized Small-Cell Carcinoma of the Prostate J. Clin. Oncol., July 15, 2002; 20(14): 3072 - 3080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. O. Hellawell, G. D. H. Turner, D. R. Davies, R. Poulsom, S. F. Brewster, and V. M. Macaulay Expression of the Type 1 Insulin-like Growth Factor Receptor Is Up-Regulated in Primary Prostate Cancer and Commonly Persists in Metastatic Disease Cancer Res., May 1, 2002; 62(10): 2942 - 2950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Schwarze, S. E. DePrimo, L. M. Grabert, V. X. Fu, J. D. Brooks, and D. F. Jarrard Novel Pathways Associated with Bypassing Cellular Senescence in Human Prostate Epithelial Cells J. Biol. Chem., April 19, 2002; 277(17): 14877 - 14883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Lamartiniere, M. S. Cotroneo, W. A. Fritz, J. Wang, R. Mentor-Marcel, and A. Elgavish Genistein Chemoprevention: Timing and Mechanisms of Action in Murine Mammary and Prostate J. Nutr., March 1, 2002; 132(3): 552S - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter? Cancer Res., December 1, 2001; 61(24): 8601 - 8610. [Full Text] [PDF]
|
|
|
|
|
|
M. Ruiz, P. Troncoso, C. Bruns, and M. Bar-Eli Activator Protein 2{alpha} Transcription Factor Expression Is Associated with Luminal Differentiation and Is Lost in Prostate Cancer Clin. Cancer Res., December 1, 2001; 7(12): 4086 - 4095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Hayward, Y. Wang, M. Cao, Y. K. Hom, B. Zhang, G. D. Grossfeld, D. Sudilovsky, and G. R. Cunha Malignant Transformation in a Nontumorigenic Human Prostatic Epithelial Cell Line Cancer Res., November 1, 2001; 61(22): 8135 - 8142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gupta, K. Hastak, N. Ahmad, J. S. Lewin, and H. Mukhtar Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols PNAS, August 10, 2001; (2001) 171326098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Damon, S. R. Plymate, J. M. Carroll, C. C. Sprenger, C. Dechsukhum, J. L. Ware, and C. T. Roberts Jr. Transcriptional Regulation of Insulin-Like Growth Factor-I Receptor Gene Expression in Prostate Cancer Cells Endocrinology, January 1, 2001; 142(1): 21 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Harman, E. J. Metter, M. R. Blackman, P. K. Landis, and H. B. Carter Serum Levels of Insulin-Like Growth Factor I (IGF-I), IGF-II, IGF-Binding Protein-3, and Prostate-Specific Antigen as Predictors of Clinical Prostate Cancer J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4258 - 4265. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Abate-Shen and M. M. Shen Molecular genetics of prostate cancer Genes & Dev., October 1, 2000; 14(19): 2410 - 2434. [Full Text]
|
|
|
|
|
|
H. M. Khandwala, I. E. McCutcheon, A. Flyvbjerg, and K. E. Friend The Effects of Insulin-Like Growth Factors on Tumorigenesis and Neoplastic Growth Endocr. Rev., June 1, 2000; 21(3): 215 - 244. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Chott, Z. Sun, D. Morganstern, J. Pan, T. Li, M. Susani, I. Mosberger, M. P. Upton, G. J. Bubley, and S. P. Balk Tyrosine Kinases Expressed in Vivo by Human Prostate Cancer Bone Marrow Metastases and Loss of the Type 1 Insulin-Like Growth Factor Receptor Am. J. Pathol., October 1, 1999; 155(4): 1271 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gupta, K. Hastak, N. Ahmad, J. S. Lewin, and H. Mukhtar Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols PNAS, August 28, 2001; 98(18): 10350 - 10355. [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 |
, significant difference (P < 0.05) from TM by Fisher’s protected least significant difference ANOVA.
