Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases (original) (raw)
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Endokrynologia Polska, 2013
Introduction: Follicle stimulating hormone receptors (FSHR) are well known to be expressed in gonads and in gonadal tumours. Recently, their incidence has also been revealed in endocrine non-gonadal tumours such as adrenal and pituitary tumours. Moreover, FSHR immunostaining has also been reported in endothelium of intra-and peritumoral blood vessels of a large series of cancers. The present paper reports on the incidence of FSHR in both tumoral cells and some intratumoral blood vessels of neuroendocrine tumours (NETs). Material and methods: Sixteen NETs samples were taken from 14 patients. The tumour samples were immunostained using the antibody raised against 1-190 amino acid sequence from the human FSH-R and anti-Ki67 antibody. Results: In all the samples examined, the majority of tumoral cells were immunostained with anti-FSHR antibody. Positive immunostaining concerned also the intratumoral blood vessels endothelia in a half of the examined samples. Immunopositive blood vessels were found more often in tumours with higher Ki-67 index. Conclusion: FSHR expressed in NETs, if they are functional, may mediate the signals which can enhance further tumour growth.
Thyroid Research, 2015
In normal conditions FSHR are expressed in granulosa cells of the ovary and Sertoli cells of the testis. They can be expressed also in gonadal tumours. However, recently the expression of FSHR was found in tumoral cells and intra-tumoral blood vessels of many other tumours, including thyroid tumours. Aim of this study was to see whether the expression of FSHR can be useful in the differentiation of benign and malignant thyroid lesions. 44 samples of surgically excised thyroids were immunostained with anti- FSHR antibody raised against 1-190 amino acid sequence from the human FSHR. Non-neoplastic thyroid follicles (i.e. the follicles situated outside the tumour) do not show the immunostaining for FSHR. The same concerns the majority of follicular adenomas. In contrast, 87.5% of follicular cancers, the same percentage of papillary cancers and all the examined undifferentiated cancers showed the FSHR immunopositivity of tumoral cells. A tendency towards the higher frequency of FSHR - positive blood vessels also concerns malignant thyroid tumours. The ectopic FSHR immunostaining seems to be useful to differentiate malignant from benign lesions, especially follicular cancers from follicular adenomas. However, the further studies on larger material are needed.
Journal of Cellular and Molecular Medicine, 2012
Sunitinib is an anti-angiogenic receptor tyrosine kinase inhibitor used to treat advanced metastatic renal cell carcinoma and other types of cancer. Sutent is effective in only approximately 70% of clear cell renal cell carcinoma (CCRCC) patients, has significant adverse side effects and no method is available to predict which patients will not respond. Our purpose was to explore the possibility of introducing an effective prediction method based on a marker of the tumour vasculature, the follicle stimulating hormone receptor (FSHR). Fifty patients diagnosed with advanced metastatic CCRCC have been subjected to surgery for removal of the primary tumour and were subsequently treated with sunitinib. After three months of therapy the patients were categorized as 'responsive', 'stable' or 'non-responsive' based on the RECIST guidelines. The blood vessel density and the percentage of FSHR-positive vessels were determined by immunofluorescence on sections from the primary tumours removed by surgery, prior to the sunitinib treatment. The percentage of FSHRstained vessels was on average fivefold higher for the patients who responded to the treatment in comparison with the stable group and almost eightfold higher than in the non-responsive group. The percentage allowed the detection of responders with 87-100% sensitivity and specificity. No significant differences were detected in the total density of vessels among the three groups. The data suggest that FSHR expression levels in the blood vessels of CCRCC primary tumours can be used to predict, with high sensitivity and specificity, the patients who will respond to sunitinib therapy.
Immunohistochemical detection of FSH receptors in pituitary adenomas and adrenal tumors
Folia Histochemica et Cytobiologica, 2012
Follicle stimulating hormone (FSH) receptors (FSHR) are physiologically expressed in the ovary and testis. It is well known that FSHR are also expressed in gonadal cancers, but the data on their incidence in extra-gonadal tumors are scarce. Recently, the expression of FSHR in the vascular endothelium within different human cancers was found, but nothing is known on FSHR appearance in non-gonadal endocrine tumors. The present paper reports on the immunohistochemical detection of FSHR in human pituitary adenomas and adrenal tumors. The study included samples of 28 pituitary adenomas and 36 adrenal tumors. Moreover, 2 samples of non-tumoral adrenal glands were also studied. FSH receptor immunostaining was performed on paraffin sections using the rabbit anti-human FSH-R polyclonal antibody raised against 1-190 amino acid sequence from the human FSH-R (sc-13935). The pituitary adenomas were immunostained to reveal the pituitary hormones and the proliferation marker Ki-67. In the pituitary adenomas, positive immunostaining with anti-FSHR antibody occurred in the adenoma cells cytoplasm and endothelia of the intra- and peritumoral blood vessels. The cytoplasmic immunostaining was found in the majority of investigated tumors but the intensity of staining was weak to moderate. There is some tendency towards the higher cytoplasmic FSHR score in tumors with higher Ki-67 index (atypical adenomas). In contrast to the cytoplasm, the FSHR immunostaining in blood vessels is strong and concerns all the investigated samples. Strong FSHR immunostaining is present in the endothelium of intra- and/or peritumoral blood vessels in the majority of pheochromocytomas, approximatively one half of the adrenocortical adenomas and both cases of the adrenal cancers. The immunostaining is detectable also in the tumoral cell cytoplasm in all but one examined pheochromocytomas. All the investigated adrenocortical adenomas presented strong immunostaining of cell membranes. No immunostained cell membranes were found. in adrenal cancers. The positive immunostaining was found in glandular cells, but not in blood vessels, of non-tumoral adrenal cortex and medulla. Immunostaining of FSHR often occurs in the endothelium of intra- and/or peritumoral blood vessels of pituitary adenomas and benign and malignant adrenal tumors. The immunostaining may be also present in tumoral cells. A role of FSHR expression in these tumors (stimulation of angiogenesis? stimulation of cell growth?) needs further studies to be clarified.
PET of Follicle-Stimulating Hormone Receptor: Broad Applicability to Cancer Imaging
Molecular pharmaceutics, 2015
Selective overexpression of follicle-stimulating hormone receptor (FSHR) inside the vascular endothelium of tumors has been confirmed to play critical roles in angiogenesis, tumor invasion, and metastases. The expression level of FSHR correlates strongly with the response of tumors to antiangiogenic therapies. In this study, an immunoPET tracer was developed for imaging of FSHR in different cancer types. A monoclonal antibody (FSHR-mAb) against FSHR was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and used for subsequent (64)Cu-labeling. NOTA-FSHR-mAb preserved FSHR specificity/affinity, confirmed by flow cytometry measurements. (64)Cu-labeling was successfully conducted with decent yields (∼25%) and high specific activity (0.93 GBq/mg). The uptake of (64)Cu-NOTA-FSHR-mAb was 3.6 ± 0.8, 13.2 ± 0.7, and 14.6 ± 0.4 %ID/g in FSHR-positive CAOV-3 tumors at 4, 24, and 48 h postinjection, respectively (n = 3), significantly high...
Antibody Selection for Cancer Target Validation of FSH-Receptor in Immunohistochemical Settings
Antibodies, 2017
Background: The follicle-stimulating hormone (FSH)-receptor (FSHR) has been reported to be an attractive target for antibody therapy in human cancer. However, divergent immunohistochemical (IHC) findings have been reported for FSHR expression in tumor tissues, which could be due to the specificity of the antibodies used. Methods: Three frequently used antibodies (sc-7798, sc-13935, and FSHR323) were validated for their suitability in an immunohistochemical study for FSHR expression in different tissues. As quality control, two potential therapeutic anti-hFSHR Ylanthia ® antibodies (Y010913, Y010916) were used. The specificity criteria for selection of antibodies were binding to native hFSHR of different sources, and no binding to non-related proteins. The ability of antibodies to stain the paraffin-embedded Flp-In Chinese hamster ovary (CHO)/FSHR cells was tested after application of different epitope retrieval methods. Results: From the five tested anti-hFSHR antibodies, only Y010913, Y010916, and FSHR323 showed specific binding to native, cell-presented hFSHR. Since Ylanthia ® antibodies were selected to specifically recognize native FSHR, as required for a potential therapeutic antibody candidate, FSHR323 was the only antibody to detect the receptor in IHC/histochemical settings on transfected cells, and at markedly lower, physiological concentrations (ex., in Sertoli cells of human testes). The pattern of FSH323 staining noticed for ovarian, prostatic, and renal adenocarcinomas indicated that FSHR was expressed mainly in the peripheral tumor blood vessels. Conclusion: Of all published IHC antibodies tested, only antibody FSHR323 proved suitable for target validation of hFSHR in an IHC setting for cancer. Our studies could not confirm the previously reported FSHR overexpression in ovarian and prostate cancer cells. Instead, specific overexpression in peripheral tumor blood vessels could be confirmed after thorough validation of the antibodies used.
Endokrynologia Polska, 2014
Introduction: In our earlier study, we found that pituitary adenomas, like other human tumours, express ectopically follicle stimulating hormone receptors (FSHR) in intratumoural blood vessels endothelia and/or tumoural cells. The aim of the present paper was to provide more detailed data on FSHR expression in different subtypes of pituitary adenomas and to evaluate its possible role as a prognostic and/ or predictive biomarker in these tumours. Material and methods: Forty two pituitary adenomas, surgically removed, were immunostained with antibodies against the pituitary hormones, antigen Ki-67 and 1-190 fragment of FSHR. Results: The positive FSHR immunostaining was found in blood vessels endothelia of 88% of adenomas and in tumoural cells of 40% adenomas. In tumoural cells, the incidence of at least moderate FSHR immunostaining is significantly higher in invasive tumours (68%) compared to non-invasive (12%) ones, and higher (albeit not statistically significantly) in invasive-proliferating adenomas (Ki-67 > 3%, grade 2b) compared to invasive but non-proliferating (Ki-67 < 3%, grade 2a) ones. Conclusions: The present study confirms that pituitary adenomas ectopically express FSHR in intratumoural blood vessels endothelia and tumoural cells. Moreover, the expression in tumoural cells is prevalent in invasive and proliferating adenomas vs. non-invasive and non-proliferating tumours.
International Journal of Cancer, 2002
The role of FSHR expression in ovarian cancer development is not clear. We examined quantitative expression of FSHR in different types of OET, presumed precursor lesions and peritoneal implants and further discussed FSH as a key growth-promotion factor for the process of ovarian epithelial tumorigenesis. Thirty-five primary OET specimens, including 5 serous cystadenomas, 4 papillary serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs and 2 carcinomas) were obtained from several morphologically different areas, including benignlooking, borderline and cancerous areas in the same OETs, and from the remaining ovarian tissue and contralateral ovaries. Competitive RT-PCR was performed to measure the quantitative expression of FSHR in each tissue sample. FSHR expression levels were compared among nonpaired samples and within paired samples. We found that OSE had the lowest FSHR expression, whereas antral follicles had the highest level. Within benign OETs, papillary serous cystadenomas have 4.9-fold higher FSHR levels than nonpapillary serous cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8-fold, 2.7-fold and 2.4-fold higher than that of serous cystadenomas, papillary serous cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR mRNA was found in peritoneal implants, which were associated with SBTs. FSHR levels among serous carcinomas decreased with an increase in carcinoma grade. Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous cystadenomas, while grade 1 carcinomas had 6.5-fold higher FSHR levels than those in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR in ovarian epithelium may play important roles in ovarian OET development. Both the receptor and ligand may act in a synergistic way to promote tumor growth. The observation that high FSHR levels are present in peritoneal implants suggests that FSH may also play a similar role in the development of peritoneal serous tumors. From this perspective, circulating FSH may be considered a driving force in the field effect theory for the development of both ovarian neoplasms and their associated peritoneal implants. However, the exact role of FSH and/or FSHR in the development of epithelial tumors arising in both the ovary and peritoneum needs further investigation.
Clinical and Translational Oncology, 2015
PURPOSE-Estrogen receptor (ER) and progesterone receptor (PR) status is prognostic and predictive in breast cancer. Because metastatic breast tumor biopsies are not routinely feasible, circulating tumor cells (CTCs) offer an alternative source of determining ER/PR tumor status. METHODS/PATIENTS-Peripheral blood was collected prospectively from 36 patients with metastatic breast cancer. CTCs were isolated using the microfluidic OncoCEE ™ platform. Detection was accomplished with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on the CK+ cells and compared to the primary and/or metastatic tumor (immunohistochemistry: IHC). RESULTS-Among the 24 CK+ CTC cases, a concordance of 68% (15/22) in ER/PR status between primary breast tumor and CTCs and 83% (10/12) between metastatic tumor and CTCs was observed. An overall concordance of 79% (19/24) was achieved when assessing CTC and metastatic tumor (primary tumor substituted if metastatic breast biopsy not available). A test sensitivity of 72% and specificity of 100% was identified when comparing CTCs to tumor tissue. Of the 7 discordant cases between CTCs and primary tumor tissue, 2 were concordant with the metastatic biopsy. CONCLUSIONS-CTC ER/PR status using the OncoCEE ™ platform is feasible, with high concordance in ER/PR status between tumor tissue (IHC) and CTCs (ICC). The prognostic and predictive significance of CTC ER/PR protein expression needs further evaluation in larger trials.