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1 Program of Cell Biology and Genetics, Weill Graduate School of Medical Sciences, Cornell University Medical College, New York, New York; and 2 Department of Pathology and 3 Program of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Here, we report the role of Id genes and bone marrow-derived precursor cells in prostate tumor angiogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this model, the prostate-specific rat probasin promoter drives expression of the SV40 Tag, and transgenic mice develop spontaneous prostate adenocarcinoma (6) . TRAMP mice display low- and high-grade prostatic intraepithelial neoplasia and well-, moderate-, and poorly differentiated prostate adenocarcinomas (7) . Because there is such a dramatic variation in tumor grade in this model, this analysis allows us to determine whether tumor grade has any affect on angiogenic requirement for Id gene expression and/or bone marrow-derived precursor cells.
We show here that Id1–/– Id3+/– TRAMP mice display delayed tumor growth at 24 weeks compared with wild-type TRAMP mice. Id1 and Id3 were strongly expressed in the endothelial cells in poorly differentiated prostate adenocarcinoma but not in the endothelium in well-differentiated prostate adenocarcinoma, showing for the first time that there is a variation in the endothelium of prostate tumors depending on tumor grade. As anticipated from the expression analysis, in Id-deficient TRAMP mice, the poorly differentiated tumors showed extensive hemorrhage, whereas well-differentiated tumors exhibited none. Transplantation with Id wild-type bone marrow significantly reduced the hemorrhage in poorly differentiated prostate adenocarcinomas with bone marrow-derived endothelial cells contributing to 14% of its tumor blood vessels. However, in well-differentiated prostate adenocarcinomas, there was little evidence of bone marrow incorporation. These differences in the expression of Id genes in tumor endothelium, the effects of Id loss on tumor vasculature, and the recruitment of bone marrow-derived precursor cells in tumor blood vessels between well-differentiated and poorly differentiated prostate adenocarcinoma suggest that Id gene expression and the contribution of bone marrow-derived precursor cells into neovasculature vary depending on the tumor grade. This variation may provide a partial explanation for the neovascular heterogeneity between tumor stages.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Histologic Analysis, Immunohistochemistry, and In situ Hybridization.
Tumors were fixed in paraformaldehyde, and 8-µm paraffin sections were stained for H&E, mouse CD31 (rat antimouse CD31 monoclonal, 2.5 µg/mL; PharMingen, San Diego, CA), Id1 (rabbit polyclonal C-20, 1:150; Santa Cruz Biotechnology, Santa Cruz, CA), and VEGFR-1 and VEGFR-2 (mF-1 and DC101; Imclone Systems Inc., New York, NY). For polyclonal antibodies, we used the ABC kit (Vector Laboratories, Burlingame, CA) following the manufacturer’s instructions. For monoclonal antibodies we used the Vector MOM kit. Sections were processed for in situ hybridization with [32P]UTP-labeled antisense mouse Id1 and Id3, and mouse Ang2 RNA probes as described (4)
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Quantitation of Tumor Composition.
Sections from peripheral and central regions of a tumor were imaged at low magnification, and areas of tumor tissue and hemorrhage were evaluated using MetaMorph 6.1 program (Universal Imaging Software, Downingtown, PA). Ten to 15 sections were evaluated per each tumor sample.
Bone Marrow Transplantation and lacZ Detection.
Experimental procedures were carried out as described previously (3)
. Mice were lethally irradiated (950 rad) at age 12 weeks. Approximately 4 x 106 ß-galactosidase+ bone marrow cells isolated from Rosa-26 mice were injected into tail veins of each irradiated recipient mouse. The recipients were sacrificed when they developed palpable prostate tumors. Tissues were collected, fixed with 4% paraformaldehyde, and stained with 5-bromo-4-chloro-3 indolyl-ß-D-galactopyranosidase (X-gal) before embedded in paraffin.
Statistical Analysis.
Student’s t test was used to determine statistical significance between experimental groups. P < 0.05 was considered significant and is indicated with an asterisk. P values <0.01 and 0.001 are indicated by double and triple asterisks, respectively.
Human Prostate Adenocarcinoma.
Sections of human prostate adenocarcinoma samples were either purchased from Chemicon (TMA1202; Temecula, CA) or provided by Dr. William L. Gerald (Memorial Sloan-Kettering Cancer Center, New York, NY). Gleason grading system was used to decide the histologic grade of the samples. Gleason sum was deduced by adding the Gleason grades (range, 1 through 5) of two most prevalent glandular patterns of the tumor cells.
Microarray Analysis of Gene Expression.
Prostatic tissues were obtained from the Memorial Sloan-Kettering Cancer Center (New York, NY). Samples included 5 benign prostate tissues, 23 primary prostate cancers from patients with no therapy before surgery, 17 primary prostate cancers after 3 months of androgen ablation therapy, and 9 metastatic prostate cancers, including 3 that were progressing after 5 to 10 years of androgen ablation (8)
. Total RNA was extracted from frozen tissues, and cDNA was synthesized from total RNA. RNA target was synthesized, labeled, and assessed as described previously (8)
. Gene expression analysis was performed using Affymetrix U95 human gene arrays (Santa Clara, CA) using instruments and protocols recommended by the manufacturer.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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TRAMP mice were sacrificed at 12, 18, or 24 weeks. At 24 weeks, there was a significant delay in prostate tumor growth in Id1–/– Id3+/– TRAMP mice (Fig. 1A)
. Fifty-five percent of Id1/Id3 wild-type TRAMP mice (n = 20) developed large prostate tumors, grossly visible during dissection. Only 20% of Id1–/– Id3+/– TRAMP mice (n = 15) had grossly visible tumors at this time point, a statistically significant difference compared with wild-type TRAMP mice. A total of 84.2% of Id wild-type TRAMP mice (n = 19) and 72.7% of Id1–/– Id3+/– TRAMP mice (n = 11) developed either grossly visible or microscopic prostate tumors at this time (Fig. 1B)
, a measure of total tumor initiation. The difference was not statistically significant. Id1–/– Id3+/+ TRAMP mice (n = 10) and Id1+/– Id3+/– TRAMP mice (n = 15) also developed fewer grossly visible tumors, although no statistically significant difference from Id1/Id3 wild-type TRAMP mice was observed (data not shown). These results suggest that tumor progression but not tumor initiation is affected by Id loss, and this effect depends on Id gene dosage. Additional TRAMP mice were not sacrificed at any fixed time point but studied for their overall survive time. Survival curve comparison between TRAMP animals in an Id wild-type or knockout background showed no significant difference (Fig. 1C)
, indicating that the prostate tumorigenesis in the TRAMP mice is only temporarily delayed by Id deficiency.
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. In contrast, in poorly differentiated adenocarcinomas (n = 10), the nuclei of endothelial cells were strongly stained with the Id1 antibody (Fig. 2A)
. Tumor cells were weakly stained in most tumors. In situ hybridization analysis with an antisense Id1 probe confirmed the results of the immunohistochemistry (data not shown). In situ hybridization with an Id3 probe showed a similar expression pattern as Id1 in the endothelial cells (data not shown), and Id3 was not expressed in tumor cells. The expression pattern of the Id1 and Id3 genes suggests that in TRAMP mice, Id genes may play an important role in prostate tumor angiogenesis rather than contribute to tumorigenesis directly.
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. In contrast, in Id1–/– Id3+/– TRAMP mice, many tumors showed extensive hemorrhage throughout the tumors (Fig. 3B)
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). This suggests that tumor angiogenesis was compromised in poorly differentiated prostate adenocarcinomas in Id1–/– Id3+/– TRAMP mice.
During dissection, some grossly visible tumors in Id1–/– Id3+/– TRAMP mice were mostly white. Histologic analysis showed they were well-differentiated prostate adenocarcinomas. These tumors had relatively normal blood vessels and little hemorrhage, with no significant differences compared with the well-differentiated tumors in Id wild-type mice (Fig. 3
C–E). The well-differentiated lesions in the Id1–/– Id3+/– background had an average 0.6% area of hemorrhage, which is significantly less than that of poorly differentiated prostate tumors (P < 0.01). This result further indicated that angiogenesis in well-differentiated and poorly differentiated prostate tumors has inherent differences. The lack of effect of Id loss in well-differentiated tumors is consistent with the lack of Id1 expression observed in the endothelium of these tumors.
Bone Marrow Cells Contribute to the Blood Vessel Formation in Poorly Differentiated Prostate Adenocarcinomas but Not in Well-Differentiated Tumors.
In xenograft models, transplantation with wild-type bone marrow rescued the angiogenic deficiency in Id1–/– Id3+/– mice (3)
. To investigate whether bone marrow-derived precursor cells contribute to spontaneous prostate tumor vasculature, we transplanted Rosa-26 mouse bone marrow cells into TRAMP mice at 12 weeks and analyzed their prostates at 24 or 30 weeks.
In Id1–/– Id3+/– TRAMP mice that received a wild-type bone marrow transplant, poorly differentiated tumors showed significantly decreased hemorrhage (mean, 1.6%), compared with those without bone marrow transplant (mean, 9.2%) or those that received a bone marrow transplant from an Id1–/– Id3+/– donor (mean, 14.2%; Fig. 4A, B, and D
). This indicates that Id wild-type bone marrow-derived cells were able to rescue the angiogenic defect in Id1–/– Id3+/– TRAMP mice. Furthermore, hemorrhage increased in prostate tumors in Id wild-type mice transplanted with mutant bone marrow (mean, 7.4%; Fig. 4C and D
), implying Id-positive bone marrow-derived cells are necessary to maintain neovasculature in poorly differentiated tumors.
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. Staining with CD31 antibody confirmed the endothelial cell identity. However, X-gal staining in well-differentiated prostate tumors detected only 2.6% blue endothelial cells (Fig. 5B and C)
, suggesting the lack of significant bone marrow incorporation in well-differentiated tumors. In all of the mice that received a Rosa-26 bone marrow transplant, RBCs were lacZ positive, indicating the success of the bone marrow transplant and staining procedures.
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, consistent with comobilization and recruitment of CEPs and hematopoietic cells to tumor vasculature in the more advanced tumor stage. However, no cluster of bone marrow-derived hematopoietic cells were ever observed in well-differentiated prostate adenocarcinomas (Fig. 5E)
, showing an additional difference in bone marrow utilization between these two tumor stages.
In Human Prostate Adenocarcinoma, Id1 Expression Is Stronger in the Endothelium of Tumors with Higher Gleason Score.
To determine whether the aforementioned results are likely to apply to human prostate tumors, we assayed human samples with the Id antibody, which cross-reacts with human Id1.4
In human prostate adenocarcinoma samples with a low Gleason sum (2 to 4) indicative of a more well-differentiated tumor, Id1 immunohistochemistry showed no or weak staining in the neovasculature (Fig. 6A and D)
. In samples with higher Gleason sum (5 to 9; i.e., poorly differentiated tumors), Id1 expression was strong in the nucleus of tumor endothelium (Fig. 6B and D)
. There is a statistically significant trend that Id1 staining in neovasculature is stronger in tumors with higher Gleason sum (P < 0.01), indicating Id1 expression in the vasculature correlates with tumor grade. The similarity of the Id1 expression pattern in the endothelium of human prostate adenocarcinoma and in that of the TRAMP model suggests that Id gene involvement and bone marrow incorporation in neovasculature also may vary because of tumor grade in human prostate tumors.
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. A similar result was observed in murine samples, but this staining was determined to be nonspecific as shown by similar staining in Id1–/– control sections (data not shown). However, in samples from patients treated with neoadjuvant androgen ablation therapy, there was Id1 expression in the nuclei of basal layer cells (Fig. 6C)
. The Id1 mRNA levels in human prostate cancers assessed by microarray analysis (8)
also indicate that Id1 expression is low in untreated and androgen-resistant prostate cancer samples but is high in patient samples immediately after androgen ablation therapy (Fig. 6E)
. The most likely explanation for these results is that Id1 up-regulation is an early but temporary response to androgen deprivation. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There are established processes that contribute to tumor blood vessel formation: the sprouting and co-option of adjacent pre-existing vessels, and in recent years, increasing evidence indicates that tumor angiogenesis also is supported by bone marrow-derived precursor cells, including CEPs and hematopoietic stem cells (12) . Comobilization and recruitment of VEGFR-2+ CEPs and VEGFR-1+ hematopoietic cells facilitate the incorporation of CEPs into developing blood vessels. Bone marrow incorporation into tumor vasculature is a dynamic process during which the level of angiogenic factors such as VEGF and PIGF is elevated; metalloproteinases, especially matrix metalloproteinase-9, are activated; and bone marrow stromal cells subsequently release active cytokines like sKitL, which promote the proliferation and motility of CEPs and hematopoietic cells and increase their circulation in peripheral blood (13, 14, 15, 16) .
Id-deficient mice have a tumor angiogenesis defect caused by failed incorporation of bone marrow-derived precursor cells into tumor vasculature. This defect completely inhibits B6RV2 lymphoma growth after s.c. implantation, in which bone marrow-derived cells contribute to 95% of the blood vessels, showing bone marrow incorporation in neovasculature is essential in this xenograft tumor model (3) . In the Pten+/– tumor model, bone marrow-derived cells only contribute to 16% of vessels in spontaneous uterine carcinomas, but these vessels are essential to maintain the integrity of the vascular network (4) . This number may be an underestimate of the number of vessels that use these cells because their incorporation into the vessel is a dynamic process (3) , and only one time point was examined (4) . Unlike uterine carcinomas, however, bone marrow-derived cells do not contribute to the neovasculature in lymph hyperplasia in Pten+/– animals, showing tumor type-dependent bone marrow contribution to tumor endothelium (4) . Although Pten+/– Id1–/– Id3+/– mice exhibit an angiogenic defect in all of the tumor types that express Id1 in the endothelium, the effect on tumor growth varies with tumor type. This probably is caused by escape from angiogenic stress in some tumors, reminiscent of what has been observed in other tumor models (5 , 17) .
The TRAMP mouse provides a prostate tumor model in which tumors develop through histologically distinct stages. The expression of certain angiogenic factors, such as VEGF, is elevated in poorly differentiated versus well-differentiated prostate adenocarcinoma (18) . Id1 and Id3 are strongly expressed in the endothelium of poorly differentiated tumors but not that of well-differentiated tumors, illustrating a difference in the genetic composition of tumor vasculature, depending on tumor grade. The reduction in Id gene dosage also induced tumor grade-dependent differential effects on prostate tumor vasculature. In Id-deficient mice, poorly differentiated but not well-differentiated prostate adenocarcinoma showed extensive hemorrhage, indicating that Id loss only induces angiogenic defects at a more advanced tumor stage, consistent with the tumor grade-dependent Id expression pattern in blood vessels. These observations also are consistent with the fact that macroscopic tumors (usually enriched for rapidly growing poorly differentiated lesions) are observed at lower frequency in the Id knockout background compared with wild-type controls.
The failure to see any survival benefit in TRAMP mice in the Id knockout backgrounds may be interpreted simplistically as evidence that the severe antiangiogenic stress imposed by Id loss on prostate tumors (and all of the autochthonous tumors known to express Id1 or Id3 in the vessels) is not likely to be an effective clinical strategy. However, the extensive hemorrhage and necrosis observed in the poorly differentiated tumors on even modest Id reduction is reminiscent of that observed in mouse mammary tumor virus-HER-2/neu tumors (5) , and remarkably these tumors respond synergistically with chemotherapeutic intervention to effect the first complete remission of this transgenic tumor type. We suspect similar types of synergy between antiangiogenic stress and conventional chemotherapy will be seen with other tumors such as those modeled with TRAMP and intrauterine Pten+/– tumors, which show severely perturbed tumor integrity as a result of partial Id1,3 reduction. These types of synergistic effects also are likely to be observed in human cancers managed with antiangiogenic agents and conventional chemotherapy. In addition, since Id loss has been shown to dramatically suppress tumor metastasis even under conditions in which hemorrhagic primary tumor xenografts expand and ultimately kill the host (2) , it is possible that targeting Id alone will be effective in the management of metastatic disease.
Because mice deficient in Id gene expression fail to mobilize and recruit bone marrow-derived precursor cells, we wanted to investigate whether bone marrow incorporation into neovasculature depends on tumor stage. In poorly differentiated prostate tumors, we observed 
14% donor bone marrow-derived blood vessels, marked by lacZ-positive staining, generally surrounded by bone marrow-derived hematopoietic cells. Because only one time point was examined and bone marrow-derived cell contribution decreases over time, this may represent an underestimate of the number of vessels that use these cells (3)
. However, in well-differentiated prostate tumors, we never observed any bone marrow-derived endothelial cell or hematopoietic cell clusters, indicating that there is a difference in bone marrow incorporation and precursor cell recruitment in tumor vasculature in different tumor grades in the TRAMP model. It seems likely from this and other studies that Id-expressing bone marrow-derived precursors are recruited to the site of rapidly growing poorly differentiated tumors, perhaps in response to elevated levels of VEGF or other proangiogenic factors.
Human prostate tumor endothelium also shows a strikingly similar correlation of Id expression with tumor grade, indicating that the same mechanisms may be operational in human disease. Since its creation, the Gleason grading system has contributed significantly to prognostics of human prostate cancer (19) . Biopsy Gleason sum recently was shown as part of a pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy (20) . Because Id1 expression in neovasculature was low in samples with a low Gleason sum and higher in samples with Gleason sum >5, it will be intriguing to investigate whether Id1 expression in endothelium can serve as a prognostic marker for patients with prostate cancer. Id1 also was highly expressed in prostate tumor cells after 3 months of androgen ablation therapy, suggesting that Id1 expression is elevated as a direct response to androgen deprivation. Interestingly, it has been reported that Id1 overexpression can confer androgen-independent cell growth to LNCaP cells in culture (21) . This suggests that androgen ablation may initiate part of the program that facilitates androgen-independent cell growth. If Id1 is important in mediating this process, it is probably an early event because three tumors that recurred years after androgen ablation were Id1 negative.
In vivo selection of phage display libraries has been used to identify tumor-specific endothelial markers in humans (22) and to deliver drug and peptides to achieve anticancer activity in mice (23 , 24) . Tumor stage-specific vascular markers recently were revealed by phage display in pancreatic islet cell carcinoma and epidermal squamous cell cancer mouse models (25 , 26) . These studies showed that in multistage tumorigenesis, neovasculature in premalignant lesions is distinguishable from tumor vessels, consistent with our observation that the origin of the vasculature in prostate tumors is grade specific. We propose that the extent of bone marrow incorporation is one component for such neovasculature heterogeneity. Defining tumor angiogenesis according to tumor stages could significantly affect how we design and use angiogenesis inhibitors therapeutically. Further understanding of stage-specific neovasculature could provide important clues on how to target imaging agents and therapeutics to tumor vasculature in a more accurate and sensitive manner.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Robert Benezra, 1275 York Avenue, Box 241, New York, NY 10021. E-mail: r-benezra{at}ski.mskcc.org
Received 4/12/04. Revised 6/17/04. Accepted 6/30/04.
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REFERENCES |
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