Original Article
Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels
N Engl J Med 2010; 363:1621-1630October 21, 2010
- Abstract
Background
In adult humans, the follicle-stimulating hormone (FSH) receptor is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. It is minimally expressed by the endothelial cells of gonadal blood vessels.
Methods
We used immunohistochemical and immunoblotting techniques involving four separate FSH-receptor-specific monoclonal antibodies that recognize different FSH receptor epitopes and in situ hybridization to detect FSH receptor in tissue samples from patients with a wide range of tumors. Immunoelectron microscopy was used to detect FSH receptor in mouse tumors.
Results
In all 1336 patients examined, FSH receptor was expressed by endothelial cells in tumors of all grades, including early T1 tumors. The tumors were located in the prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, testis, and ovary. In specimens obtained during surgery performed to remove tumors, the FSH receptor was not expressed in the normal tissues located more than 10 mm from the tumors. The tumor lymphatic vessels did not express FSH receptor. The endothelial cells that expressed FSH receptor were located at the periphery of the tumors in a layer that was approximately 10 mm thick; this layer extended both into and outside of the tumor. Immunoelectron microscopy in mice with xenograft tumors, after perfusion with anti–FSH-receptor antibodies coupled to colloidal gold, showed that the FSH receptor is exposed on the luminal endothelial surface and can bind and internalize circulating ligands.
Conclusions
FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of tumors. (Funded by INSERM.)
Media in This Article
Figure 1
Expression of Follicle-Stimulating Hormone (FSH) Receptor by Vascular Endothelial Cells in Human Prostate Tumors.Figure 2
Immunoblotting and In Situ Hybridization Confirmation of the Identity of the Antigen Recognized in Tumors by the FSHR323 Antibody.Article Activity
- Article
The follicle-stimulating hormone (FSH) receptor is a glycosylated transmembrane protein that binds FSH and belongs to the family of G-protein-coupled receptors. FSH, a key hormone in mammalian reproduction, is produced mainly in the anterior pituitary gland, and the target organs are the ovary and testis. In females, FSH stimulates follicular maturation and estrogen production through aromatization of androgens.1 In males, FSH stimulates Sertoli-cell proliferation in immature testes and maintains normal spermatogenesis in adults.2
In adult humans and animals, the FSH receptor is known to be expressed only in the testicular Sertoli cells and the ovarian granulosa cells,3,4 and it is expressed in low levels in the endothelial cells of the ovary5 and testis.6 In the testis, the FSH receptor mediates the translocation of FSH across the blood-testis endothelial barrier by a process of receptor-mediated transcytosis.6 We conducted a study to assess endothelial-cell expression of the FSH receptor in blood vessels in a wide range of human cancers.
Methods
Tissue Specimens
Tumor specimens (see Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) were obtained from 1336 patients immediately after surgery. The patients did not receive cytotoxic agents or hormones before surgery. The specimens were fixed in formalin and embedded in paraffin. Five study investigators performed histologic analysis of each tumor specimen. Gleason scores and stages for prostate tumors were assigned according to the World Health Organization guidelines.7 (The Gleason score is the sum of the two most common histologic patterns or grades in a prostate tumor, each of which is graded on a scale of 1 to 5, with 5 being the most cytologically aggressive.) The other tumor types were graded histologically according to the standards of the American Joint Committee on Cancer.8
The protocol was approved by the institutional review board or ethics committee at each study site. Written informed consent was obtained at the time of surgery from all living donors from whom samples were obtained. Control samples consisted of normal tissue that routinely accompanies tumors removed by surgery. Donors of normal tissue also provided written informed consent.
Antibodies
Two FSH-receptor antibodies, FSHR18 and FSHR323, were purified from hybridomas (American Type Culture Collection numbers CRL-2688 and CRL-2689). Two other FSH-receptor antibodies, FSHR190 and FSHR225, were provided by another researcher. The antibodies were shown to be monospecific for the FSH receptor by the following three independent methods: immunoblotting of cell extracts from ovarian specimens and of lysates of cell cultures transfected with FSH-receptor complementary DNA (cDNA), coimmunoprecipitation of radiolabeled FSH from cells that express the FSH receptor, and immunohistochemical detection of the FSH receptor in cells known to be targets for the FSH in human tissues (granulosa cells in the ovary and Sertoli cells in the testis).5
In Situ Hybridization and Confocal Microscopy
In situ hybridization was performed with the use of a biotinylated cDNA antisense oligonucleotide probe9 (for details, see the Supplementary Appendix). Indirect immunofluorescence confocal microscopy was performed on paraformaldehyde-fixed cryostat sections obtained from unfixed frozen prostate specimens or on paraffin-embedded sections. The FSH receptor was detected with the use of the FSHR323 antibody (for details, see the Supplementary Appendix).
Immunoprecipitation, Electrophoresis, and Western Blotting
Frozen tissue was solubilized in TRIS buffer (pH 7.4) containing 0.4 M sodium chloride and 1.2% Triton X-100 (for details, see the Supplementary Appendix), and the FSHR323 antibody was added to the supernatant. The complexes were captured on protein-A Sepharose beads and analyzed by means of sodium dodecyl sulfate–polyacrylamide-gel electrophoresis (SDS-PAGE), followed by immunoblotting with the use of the FSHR18 antibody.
Immunoelectron Microscopy
Tumors were generated by injecting nude mice with LNCaP human prostate-cancer cells (for details, see the Supplementary Appendix). The blood was removed by systemic perfusion, and anti-FSH-receptor antibodies coupled to colloidal gold were systemically introduced by means of perfusion for 20 minutes. The vasculature was washed and processed for electron microscopy.6
Results
Expression of FSH Receptor by Endothelial Cells in Prostate Tumors
Our initial analysis was performed in human prostate tumors with the use of the anti–FSH-receptor monoclonal antibody FSHR323. Immunohistochemical analysis of paraffin-embedded sections revealed strong staining of endothelial cells in tumors (Figure 1AFigure 1
Expression of Follicle-Stimulating Hormone (FSH) Receptor by Vascular Endothelial Cells in Human Prostate Tumors.). The FSH-receptor-positive blood vessels were located at the periphery of the tumors, as detailed below. No staining of endothelial cells was visible in normal prostate tissue (Figure 1B), which was located more than 10 mm outside the tumors in specimens obtained by total prostatectomy. A faint FSH-receptor signal was visible occasionally in the tumor cells (Figure 1A). No staining occurred when tissue sections obtained from patients with prostate cancer were incubated with nonimmune mouse IgG2a of the same isotype as FSHR323 (Figure 1A in the Supplementary Appendix), or when the primary antibody was omitted (Figure 1B in the Supplementary Appendix). The endothelial cells were identified as belonging to blood vessels by costaining them with an antibody against the vascular endothelial marker, von Willebrand factor (Figure 1F, 1G, and 1H). The lymphatic vessels in tumors, identified with the use of the monoclonal antibody D2-40, did not express the FSH receptor (Figure 1D and 1E). The identity of the antigen recognized in tumor endothelial cells by the FSHR323 antibody was confirmed by immunohistochemical analysis with two other well-characterized monoclonal antibodies, FSHR190 and FSHR225, which bound epitopes of the FSH receptor that are different from those recognized by FSHR3235 and revealed a staining pattern identical to that of FSHR323 (Figure 2 in the Supplementary Appendix).The identity of the antigen was further confirmed by immunoprecipitation followed by detection with an independent monoclonal antibody. Prostate-tumor extract was immunoprecipitated with the use of the FSHR323 antibody, subjected to SDS-PAGE, and analyzed by means of immunoblotting with the use of FSHR18, which recognizes an epitope that is different from that recognized by FSHR323.5 An 87-kD band corresponding to the known molecular weight of the mature glycosylated FSH receptor5 was detected in the prostate-cancer tissue (Figure 2AFigure 2
Immunoblotting and In Situ Hybridization Confirmation of the Identity of the Antigen Recognized in Tumors by the FSHR323 Antibody.). No FSH-receptor signal was visible in extracts from normal-appearing prostate tissue obtained from patients with prostate cancer (Figure 2A). It is extremely improbable that a protein other than the FSH receptor contains both epitopes recognized by the two antibodies and has the same molecular weight as the FSH receptor. In situ hybridization confirmed the expression of FSH-receptor RNA in the tumor endothelial cells (Figure 2B and 2C). Thus, all three techniques used (immunohistochemical analysis with the use of three independent antibodies, immunoblotting, and in situ hybridization) identified the FSH receptor.The same consistent expression of the FSH receptor by the endothelial cells of tumor blood vessels was detected in tissue specimens obtained from all 773 patients with prostate cancer who were evaluated, and the absence of expression was confirmed in all associated normal tissues. The lowest Gleason score in the tumors analyzed was 5; this score characterizes tumors of low malignant potential. Among the 773 tumors analyzed, 41% had Gleason scores of 5 or 6. The most advanced tumors analyzed had the highest Gleason score, 10. FSH-receptor–positive blood vessels were also detected in approximately 20% of benign prostatic hyperplasia specimens, in vessels surrounding hyperplastic glands (Figure 1C). In contrast to the findings in the tumors, the FSH-receptor–positive vessels were present throughout the hyperplastic areas, not only at the periphery. The anatomical location of benign prostatic hyperplasia differed from the sites of most prostate tumors10 and thus, FSH-receptor–based imaging could be used to distinguish the two conditions.
Expression of FSH Receptor by Endothelial Cells in Other Cancers and Nonmalignant Tissues
Immunohistochemical studies similar to those described above were performed for 10 other tumor types in a total of 563 patients (for details, see Table 1 in the Supplementary Appendix). Approximately 70% of the tumors were grade I or II, approximately 25% were grade III, and the remaining tumors were grade IV. Examples of other types of tumors are shown in Figure 3Figure 3
Tumor Tissues from Other Types of Human Cancers and Inflammatory Tissues.. In each of the tumors analyzed, without exception, we detected consistent expression of the FSH receptor by endothelial cells. As we found with the prostate tumors, occasional cancer cells were also faintly stained in breast tumors and exocrine pancreatic tumors (data not shown).In all normal control samples, which were obtained from the same sections as the tumor samples, the endothelial cells of blood vessels were negative for the FSH receptor (Figure 3 in the Supplementary Appendix), with the exception of a faint FSH-receptor signal that was barely visible in the blood vessels of testes and ovaries (Figure 4 in the Supplementary Appendix), which are known to express the FSH receptor.5,6
We also analyzed nonmalignant inflammatory, regenerative, and proliferative tissues and found that expression of the FSH receptor is not a general feature of such tissue responses. In samples from patients with rheumatoid arthritis (Figure 3B, panel e), chronic pancreatitis (Figure 3B, panel f), Crohn's disease, and wound healing (Figure 5A, 5B, and 5C in the Supplementary Appendix), no FSH-receptor expression was detected in the endothelial cells. In placental endothelial cells, high levels of FSH receptor were expressed in all vessels (Figure 5D in the Supplementary Appendix).
Localization of FSH Receptor at Tumor Periphery
A general characteristic of the vessels with endothelial cells that expressed the FSH receptor in prostate tumors was that they were located at the periphery of the tumors, in shells that had a thickness of approximately 10 mm (range, 7 to 15) and extended a few millimeters both inside and outside the tumor in the apparently normal tissue. No FSH receptor-expressing vessels were detected in the deeper areas of the tumors. Figure 4Figure 4
FSH-Receptor Expression According to Vessel Location. shows the distribution of the vessels expressing the FSH receptor.The same shell-type distribution of endothelial cells expressing the FSH receptor was observed in all 11 tumor types examined, with the exception of renal-cell carcinomas; in the latter type, in approximately 30%, the FSH receptor was expressed uniformly in the vessels throughout the tumor, and in approximately 40%, the FSH receptor was expressed only at the exterior of the tumor. The percentage of vessels expressing the FSH receptor reached a maximum of 40 to 100% at the demarcation line between the tumor and the normal tissue and decreased gradually to zero both toward the interior and away from the tumor. The values for both shell thickness and maximum percentage of FSH-receptor–positive vessels were lowest in tumors of the exocrine pancreas and hepatocarcinomas; intermediate in tumors of the urinary bladder, ovary, lung, and stomach; and highest in tumors of the prostate, kidney, colon, breast, and testis. The thickness of the shell did not appear to be related to the size of the tumor.
Exposure of FSH Receptor on the Luminal Surface of the Tumor Epithelium
Tumor-specific endothelial receptors could be candidates for tumor imaging and therapy because they may be directly accessible to intravenously delivered agents, which may also accumulate in the tumors after crossing the endothelial cells.
In Situ Animal Model
To assess whether endothelial FSH receptors are accessible to intravenously delivered ligands, we used an in situ animal model: mice that carried LNCaP human xenograft tumors. The tumor endothelial cells in these mice express the FSH receptor (Figure 6 in the Supplementary Appendix). After perfusion of these mice for 20 minutes with anti-FSH-receptor antibodies coupled to colloidal gold, immunoelectron microscopy showed that in tumors, gold particles were attached to the luminal aspect of the endothelium, on the plasmalemma proper (Figure 5AFigure 5
Anti–FSH-Receptor Antibodies Coupled to Perfused Colloidal Gold in the Vasculature of Tumor-Bearing Mice.), on the diaphragms of fenestrae (Figure 5B), and in the coated pits (Figure 5C). Particles were also visible in the interior of the endothelial cells in coated vesicles (Figure 5D), endocytic vesicles (Figure 5E), and infrequently in multivesicular bodies (Figure 5F). No tracer was detected in the intercellular junctions of the endothelial layer (Figure 5G), indicating that no intercellular transport occurred. Particles were also visible in the lumen of channels that connect the luminal and abluminal fronts of the endothelium and in the subendothelial space adjacent to these structures (Figure 7A in the Supplementary Appendix). Accumulations of gold particles were infrequently visible in the interstitial space (Figure 7B in the Supplementary Appendix).In contrast to the findings in the tumor endothelial cells, extremely rare gold particles were observed in endothelial cells of normal organs (lung and prostate) obtained from the same animals. Most microscopical fields did not show any particles in the lung tissue (Figure 5H) or the prostate tissue. The most likely explanation for their presence is that they were the few unbound particles in the blood vessels that had not been removed by washing, and they were subsequently cross-linked by glutaraldehyde to the endothelial-cell surface. In the tumors, the gold particles were visible on all examined endothelial cells in all blood-vessel profiles; by contrast, in testes, the particles were present in only approximately 10% of the vessels, on the endothelial-cell plasma membranes, and in coated pits, and at much lower density than in the tumor blood vessels. Isolated gold particles were also visible in rare cases in the subendothelial space of the testes.
Discussion
We report FSH-receptor expression by endothelial cells of blood vessels in a wide range of tumors in all 1336 patients examined. Two previous studies showed immunohistochemical detection of the FSH receptor in the tumor cells of prostate adenocarcinomas.11,12 The presence of the FSH receptor in the endothelial cells was not mentioned, possibly because specimens from the peripheral areas had not been examined. This supposition cannot be verified because the antibodies are no longer available.
The location of the FSH-receptor–positive vessels in the normal tissue immediately adjacent to the tumor is consistent with the view that the tumor cells in the invasive front attract surrounding blood vessels toward the tumor, and during this process, FSH-receptor expression is activated. Another possibility is suggested by the observation that in breast tumors in humans, endothelial cells proliferate at the tumor periphery but not in the interior.13 Accordingly, FSH-receptor expression by endothelial cells may be associated with their proliferation in this particular location.
If it becomes possible to exploit FSH-receptor expression for imaging purposes, the location of the FSH-receptor signal at the boundary between the tumoral and the normal tissues should make it useful for defining the target volume for radiation therapy or surgery.
If it can be shown that intravenously administered antibodies can detect tumor endothelial cells, the presence of FSH receptor on the surface of these cells in a wide range of tumors makes it a potential target for both tumor imaging and therapy. As shown in Figure 4 in the Supplementary Appendix, FSH-receptor density on the gonadal endothelial cells is much lower than that in tumors, and therefore, it may be possible to find a therapeutic window so that the gonadal vessels are not substantially affected. The Sertoli and granulosa cells, which express high levels of FSH receptor, could be spared if the toxic agents targeted at the FSH receptor were delivered in a particulate form that would not cross the blood-gonadal endothelial barrier. The volume that can be targeted by FSH receptor represents a substantial fraction of the volume of small tumors (e.g., a 3-mm-thick peripheral layer inside a tumor with a 2-cm diameter accounts for 66% of its volume, leaving an unstained core with a 14-mm diameter). The functional relevance of the volume that can be targeted may be even greater than its geometric contribution because of a more intense proliferation of cancer cells at the tumor periphery.14-19
Our in situ experiments cannot be considered to be a proof-of-principle demonstration that the FSH receptor expressed on tumor-associated blood vessels can be exploited clinically. We removed the blood from the mice before perfusing gold-labeled antibodies into vasculature. Our model does not mimic a clinical application in humans.
The binding of FSH to FSH receptor in ovarian granulosa cells induces an increase in hypoxia-inducible factor 1α protein levels under normoxic conditions, which in turn leads to up-regulation of vascular endothelial growth factor (VEGF).20 This observation provides support for the speculation that FSH-receptor expression could induce VEGF and VEGF receptor 2 (VEGFR-2) signaling in tumor endothelial cells and thus promote angiogenesis. The fact that FSH and FSH-receptor signaling is known to generate activated Gq/11 protein21 suggests yet another biologic role for the presence of the FSH receptor in tumor endothelial cells. Gq/11 has been shown to induce VEGFR-2 signaling in human umbilical-vein endothelial cells, even in the absence of VEGF.22 This effect may substantially enhance the proliferation and migration of endothelial cells in cancer independently of VEGF availability. For both mechanisms, we speculate that blocking FSH-receptor signaling could be a new antitumor strategy.
In conclusion, we found that the FSH receptor, which was present on the endothelial surface of blood vessels at the periphery of a wide range of tumors, was accessible to agents injected intravenously.
Supported by INSERM.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Sylvette Reposo and Pascale Soyeux-Porte for excellent technical assistance, Drs. Karen Leroy and Jeanne Tran Van Nhieu for some of the liver and colon antibodies, Dr. Hugues Loosfelt for the FSHR190 and FSHR225 specimens, Dr. Xavier Decrouy for assistance with confocal microscopy, Dr. Christo Christov for assistance with electron microscopy, and Dr. Francis Vachereau for the LNCaP xenografts.
Source Information
From Mount Sinai School of Medicine, New York (A.R.); and INSERM Unité 753, Villejuif (C.P.), Val-de-Grâce Hospital, Paris (P.C.), Tenon Hospital, Paris (M.A.), INSERM Unité 955-Eq 07, Université Paris-Est, Créteil (Y.A., M.T.V.H., N.G.), Beaujon Hospital, Clichy (A.C.), and Centre Hospitalier Universitaire de Poitiers, Poitiers (G.F.) — all in France.
Address reprint requests to Dr. Ghinea at INSERM Unité 955-Eq 07, 8 rue du Général Sarrail, Université Paris-Est, Créteil, France, or at nicolae.ghinea@inserm.fr.
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