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Tumor Biology |
Flinders Cancer Centre, Departments of Surgery [M. W. J., J. S. R., S. E. H., C. R., D. J. H., W. D. T.] and Anatomical Pathology [J. S.], Flinders Medical Centre and Flinders University of South Australia, Bedford Park, SA 5042, Australia
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recently, VEGF expression has been demonstrated in prostate tumors and in LNCaP, PC3, and DU145 prostate cancer cell lines (5 , 20, 21, 22) . Monoclonal antibodies that neutralize VEGF retard both the growth and metastatic spread of DU145 prostate cancer xenografts in severe combined immune-deficient mice and decrease the growth of LNCaP tumors in nude mice, suggesting that VEGF is a critical factor for the progression of prostate cancer (23 , 24) . Additionally, expression of VEGFR-1 and R-2 by malignant cells within prostate tumors has been reported. Collectively, these observations suggest that VEGF may influence disease progression by direct mediation of prostate tumor cells (25) .
In this study, we report that VEGFR-1 and R-2 are expressed by LNCaP, PC3, and DU145 cells, and that their expression is colocalized with VEGF to malignant epithelial cells and blood vessels in human prostate tumors. Additionally, we show that stimulation of LNCaP cells with rhVEGF165 induces DNA synthesis and recruits quiescent cells into the S-phase of the cell cycle via signaling through VEGFR-2. These findings suggest that VEGF may regulate both angiogenesis and tumor cell growth via autocrine and/or paracrine mechanisms in prostate cancer.
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MATERIALS AND METHODS |
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Protein Extraction and Immunoblot Analysis.
Immunoblot analysis was performed as described previously (5)
. Briefly, 20 µg of protein from whole cell extracts of LNCaP, PC3, DU145, and MS-1 cells and whole tissue extracts of 6 frozen prostate carcinoma specimens (3 from men with clinically localized disease and 3 from men with advanced, metastatic disease) were analyzed using affinity-purified rabbit polyclonal antisera for VEGFR-1 (C-17; 0.8 µg/ml) and VEGFR-2 (C-1158; 2 µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA) and affinity-isolated, peroxidase-conjugated, antirabbit antisera (1:2000 dilution; Silenus Laboratories, Melbourne, Australia). Immunoreactivity was detected using enhanced chemiluminescence (Amersham International, Buckinghamshire, United Kingdom) according to the manufacturer’s instructions and recorded on Hyperfilm-ECL detection film (Amersham International).
Immunohistochemistry.
Immunohistochemistry was performed as described previously (5)
. Five-µm sections were blocked for endogenous peroxidase activity, and microwave antigen retrieval was used to enhance immunoreactivity (27)
. Serial sections of each tumor were analyzed using affinity-purified rabbit polyclonal antisera for VEGF (A-20; 500 ng/ml), VEGFR-1 (C-17; 2 µg/ml), and VEGFR-2 (C-1158; 4 µg/ml; Santa Cruz Biotechnology) and biotinylated goat antirabbit IgG (1:400 dilution; Vector Laboratories, Burlingame, CA), followed by an avidin-biotin complex (1:400 dilution; Vectastain ABC kit; Vector Laboratories). Immunoreactivity was visualized with 3',3'-diaminobenzidine tetrahydrochloride (Sigma Chemical Co., St. Louis, MO), and specimens were counterstained with hematoxylin prior to mounting for light microscopy. Negative controls included omission of the primary antibody, and substitution of primary antibody with nonimmune rabbit serum at equivalent immunoglobulin concentration. Additionally, peptide competition experiments were performed for VEGF and VEGFR-1 antisera using 10:1 (w/w) absorptions with the antigenic peptides used to produce the antibodies (Santa Cruz Biotechnology). Immunopositive controls included frozen sections of human placenta and the MS-1 cell line.
[3H]Thymidine Incorporation.
LNCaP cells were plated at a density of 8 x 103 cells/well in serum-free RPMI 1640 into 96-well culture plates (Falcon, Franklin Lakes, NJ) and cultured for 72 h. Medium was then replaced with RPMI 1640 containing [3H]thymidine (6.7 Ci/mmol/ml; ICN Pharmaceuticals, Costa Mesa, CA) and one or other of the following reagents: rhVEGF165 (0.1–100 ng/ml; R&D Systems, Minneapolis, MN); anti-VEGFR-2 neutralizing monoclonal antibody (1 µg/ml; Imclone Systems, New York, NY); rhVEGF165 and anti-VEGFR-2 antibody together; or 5% FBS and cultured for an additional 20 h. Sixteen replicate wells were used for each experimental condition. Cells were then trypsinized for 20 min and harvested onto glass fiber filters, and the radioactivity incorporated was measured using a Packard Matrix 9600 Direct Beta Counter (Packard Instrument Company, Meriden, CT). MS-1 cells were exposed to the same conditions as above, except that cells were plated at a density of 2 x 103 cells/well in RPMI 1640 containing 1% FBS for 24 h and then changed to serum-free RPMI 1640 for 72 h prior to the addition of treatments. Statistical analysis (paired samples t test) was performed using the software Statistical Package for the Social Sciences Version 10.0 (SPSS, Chicago, IL).
Flow Cytometric Analysis of Cell Cycle Distribution.
The cell cycle parameters for LNCaP cells were determined by flow cytometry of propidium iodide-stained cells (28)
. Briefly, subconfluent LNCaP cells cultured in 100-mm culture dishes were synchronized in G0-G1 by serum deprivation. The cells were then cultured in either serum-free RPMI 1640, RPMI 1640 containing 10 ng/ml rhVEGF165, or RPMI 1640 containing 5% FBS and harvested at 24 and 48 h. The experiment was performed using four replicates for each variable at each time point. The replicates for each variable at each time point were pooled, and 2 x 106 cells taken from each pooled cell population were then washed in PBS containing 5 mM EDTA and fixed in 70% ethanol at 4°C for 1 h. Cells were resuspended using PBS containing 2% FBS and 5 mM EDTA, and the cellular DNA was stained with 20 µg/ml propidium iodide and 10 µg/ml RNase A in PBS for 20 min at room temperature. The cells were then examined by flow cytometry (Becton/Dickinson FACS Scanner, San Jose, CA) to determine distribution within the cell cycle. The percentage of the cells present in G0-G1 and S-phase were determined using the ModFIT software package (Verity Software House, Topsham, ME).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2A
). VEGFR-1 protein was also present in tumor specimen P87 at Mr 160,000 and LNCaP cell preparations at Mr 180,000. VEGFR-2 was detected at Mr 180,000 in 2 of the prostate tumor specimens (Fig. 1B)
. In contrast, all of the prostate cancer cells expressed VEGFR-2 protein at Mr 150,000 (Fig. 2C)
. VEGFR-1 and R-2 immunoreactive proteins were also present in both the tumor preparations and cancer cell lines at molecular weights below that predicted by their respective amino acid sequences (14
, 29)
, possibly representing degradation products of the receptor proteins.
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VEGFR-1 and R-2 immunoreactivity was either weak or not detected in normal glands. In contrast, the staining intensity of both receptors was increased in PIN and in cancer foci of Gleason patterns 2, 3, and 4, with moderate to strong immunoreactivity observed in the majority of specimens (Table 1
; Fig. 3
). However, immunostaining for VEGFR-1 and R-2 was absent or weak in cancer foci of Gleason pattern 5, except in specimen 387, which had strong staining for VEGFR-1 (Table 1)
. No differences in the staining profiles for VEGFR-1 and R-2 in the primary cancer tissues were observed between patients diagnosed with localized or disseminated disease.
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. Additionally, endothelial cells of blood vessels in both benign and malignant regions of the tumors, as well as inflammatory cells both within and outside blood vessels, were immunoreactive for VEGFR-1 and R-2 (data not shown). No immunoreactivity was observed in sections where the primary antibody was substituted with nonimmune rabbit serum or in sections incubated with VEGFR-1 and VEGF antiserum absorbed with their respective peptides (Fig. 3)
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VEGF Induction of DNA Synthesis and Recruitment into S-Phase in LNCaP Cells.
The VEGF signaling axis was investigated in LNCaP cells using [3H]thymidine incorporation and flow cytometry. After serum deprivation, exposure of LNCaP and MS-1 endothelial cells to rhVEGF165 resulted in dose-dependent increases in [3H]thymidine uptake over 24 h when compared with untreated cells, with maximal increases of 50 and 125% observed at 10 ng/ml rhVEGF165, respectively (Fig. 4)
. Five % FBS supplementation produced a 3-fold increase in [3H]thymidine uptake compared with untreated LNCaP cells (data not shown). Culture of LNCaP cells with 10 ng/ml rhVEGF165 and 1 µg/ml of anti-VEGFR-2 monoclonal antibody resulted in no change in [3H]thymidine incorporation when compared with untreated cells, suggesting that VEGF stimulation of LNCaP cells is mediated by VEGFR-2 (Fig. 5A)
. Similarly, in MS-1 cells, culture with 10 ng/ml rhVEGF165 and 1 µg/ml of anti-VEGFR-2 monoclonal antibody significantly reduced [3H]thymidine incorporation induced by 10 ng/ml rhVEGF165 alone (Fig. 5B)
. Additionally, culture of serum-deprived LNCaP cells with 1 µg/ml of anti-VEGFR-2 monoclonal antibody over 5 days resulted in a 20% decrease in [3H]thymidine incorporation compared with untreated cells (data not shown).
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. Addition of 5% FBS induced an 8-fold increase in the proportion of cells in S-phase.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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On the basis of these studies, we investigated the expression of VEGFR-1 and R-2 in prostate tumors and assessed the functional significance of VEGFR-1 and R-2 expression by prostate cancer cells. Visual assessment of clinically localized and metastatic prostate cancer specimens indicated that the intensity of immunostaining for both VEGFR-1 and R-2 is increased in PIN and in the malignant epithelium of well and moderately differentiated tumors when compared with normal glandular epithelium. However, we observed weak or absent immunostaining for both receptors in the majority of cancers with Gleason pattern 5, suggesting that VEGF receptor expression may be down-regulated in poorly differentiated tumors. VEGF expression has been demonstrated previously in the malignant epithelium of well and moderately differentiated prostate cancer, with decreased expression observed in poorly differentiated tumors (21) , an observation confirmed by us in this cohort of prostate tumors. In addition, in this report we demonstrate that VEGF is consistently expressed in malignant epithelial cells in cancer foci that are immunoreactive for VEGFR-1 and/or R-2, suggesting a potential autocrine role for VEGF in prostate cancer.
The mechanism for VEGF receptor up-regulation in neoplastic and malignant cells of the prostate is unknown. Hypoxia has been demonstrated to regulate the expression of VEGF, VEGFR-1, and R-2 in a number of cell types both in vivo and in vitro (35 , 36) . Although the literature regarding hypoxia in prostate cancer is sparse, Movsas et al. (37) demonstrated that the prostate glands of men with early stage prostate cancer have lower O2 levels compared with histologically normal prostates, and that the absolute O2 tension is inversely correlated with the staining intensity of VEGF (38) . It is possible that local hypoxia directly induces VEGF, VEGFR-1, and R-2, which would account for the colocalization of these proteins in cancer foci.
On the basis of the amino acid sequences of VEGFR-1 and R-2, the molecular weights of these proteins are predicted to be Mr 145,000 and Mr 150,000, respectively (14 , 29) . Both receptors have multiple potential N-glycosylation sites and undergo progressive glycosylation prior to presentation at the cell surface. However, pulse-chase investigations of NIH3T3 cells stably transfected with VEGFR-1 and R-2 indicate that fully glycosylated VEGF receptors are rapidly degraded after presentation at the cell surface (39) . Our immunoblot analysis of VEGFR-1 found that the nonglycosylated form (Mr 145,000) predominated in all of the prostate cancer specimens and cancer cell line preparations, with the exception of LNCaP cells, which also contained fully glycosylated VEGFR-1 at Mr 180,000. VEGFR-2 was detected in 2 of the 6 prostate cancer specimens at a molecular weight suggestive of semiglycosylated protein (Mr 180,000). In contrast, the prostate cancer cell lines displayed 2 VEGFR-2 immunoreactive bands of approximately Mr 150,000–155,000, most likely representing nonglycosylated and semiglycosylated VEGFR-2 protein. The reason for the absence of nonglycosylated VEGFR-2 in the prostate cancer specimens is unclear; however, this may be attributable to degradation of the protein either during or after the collection of the cancer specimens, because all 6 specimens contained low molecular weight VEGFR-2 immunoreactive bands.
The colocalization of VEGF and its receptors to individual prostate cancer cells suggests the presence of a VEGF autocrine signaling loop. Stimulation of DNA synthesis by VEGF has been demonstrated in nonendothelial cells such as BeWo choriocarcinoma cells, which express VEGFR-1 and R-2 (16) . Additionally, the coexpression of VEGF and VEGFR-1 in tumor cells of pulmonary adenocarcinoma is correlated with poor survival (34) . In the current study, rhVEGF165 was used to treat LNCaP prostate cancer cells to demonstrate that VEGF can stimulate DNA synthesis and recruit cells into S-phase of the cell cycle. In this and other studies, VEGF induction of cell proliferation appears to be mediated by VEGFR-2 (32) . In porcine aortic endothelial cells transfected with either VEGFR-1 or R-2, VEGF induces higher levels of receptor autophosphorylation in cells expressing VEGFR-2 and initiates a range of cellular responses, including proliferation, which are not seen in cells expressing VEGFR-1 (12) . Additionally, stimulation of NIH3T3 cells that express VEGFR-1 results in weak tyrosine phosphorylation in the absence of mitogenesis (40) . In the current study, neutralization of VEGFR-2 abolished the induction of DNA synthesis by rhVEGF165 in LNCaP cells, supporting the contention that VEGFR-2 mediates VEGF induction of cell growth. Although not studied here, VEGF binding to VEGFR-1 may mediate other physiological responses in prostate tumor cells. In monocytes, which express only VEGFR-1, VEGF induces cell migration and the production of tissue factor, whereas production of matrix metalloproteinases 1, 3, and 9 in smooth muscle cells may also be mediated via the VEGFR-1 receptor (41 , 42) . Interestingly, VEGFR-1 demonstrates higher affinity ligand binding than R-2 and may act competitively to regulate VEGF-induced mitogenesis (12) . Consequently, binding of VEGF to both VEGFR-1 and R-2 expressed by prostate tumor cells may have implications for a variety of processes involved in tumor progression, including stimulation of tumor cell proliferation, degradation of extracellular matrix, and tumor cell migration.
The action of VEGF in prostate physiology is unlikely to be restricted to malignant epithelial cells. Indeed, we detected staining for VEGF, VEGFR-1, and R-2 in stromal fibromuscular cells, confirming the previous finding of Ferrer (25) . The expression of VEGF and its receptors has also been noted in the smooth muscle cells of the uterus and invasive breast carcinoma, whereas colonic smooth muscle cells express only VEGF, suggesting that VEGF receptor expression may be a feature of smooth muscle derived from reproductive tissues (19 , 43) . These observations may reflect steroid hormone regulation of the VEGF signaling pathway in reproductive tissues, believed to underpin the angiogenic development associated with the menstrual cycle, and contribute to the growth and maintenance of the vasculature of the normal prostate (44 , 45) . In support of this contention, steroid hormones, including estrogens, progestins, and androgens, have been demonstrated to regulate VEGF expression in both stromal cells and malignant and nonmalignant epithelial cells derived from reproductive tissues (22 , 46, 47, 48, 49, 50, 51) , and exposure of pituitary endothelial cells to 17ß-estradiol results in significantly increased levels of VEGFR-2 in these cells, suggesting that sex steroids are also capable of regulating VEGF receptor expression (52) .
In summary, this study has demonstrated coexpression of VEGF, VEGFR-1, and R-2 in human prostate tumor cells and has shown that VEGFR-1 and R-2 immunoreactivity is increased in PIN and prostate cancer compared with normal epithelial cells. Additionally, we have provided evidence that the VEGF pathway is functional in the LNCaP prostate cancer cell line, suggesting that VEGF acts as a multifunctional cytokine in prostate tumors, capable of promoting angiogenesis and autocrine regulation of tumor growth. Further investigation of the biological consequences of VEGF and VEGFR expression in prostate tumor cells may yield valuable new insights into the growth of prostate cancer.
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FOOTNOTES |
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1 Supported by the National Health and Medical Research Council of Australia, the Anti-Cancer Foundation of South Australia, and Flinders Medical Centre Foundation. 
2 To whom requests for reprints should be addressed, at Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Hanson Institute, P. O. Box 14 Rundle Mall, Frome Road, Adelaide, S.A. 5000, Australia. Phone: 61-8-82223225; Fax: 61-8-82223035; E-mail: wayne.tilley{at}imvs.sa.gov.au
3 The abbreviations used are: VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; rhVEGF, recombinant human; FBS, fetal bovine serum; PIN, prostatic intraepithelial neoplasia.
Received 11/ 6/00. Accepted 12/ 4/01.
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