Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels

Abstract

The follicle-stimulating hormone (FSH) receptor is expressed in adult humans and animals almost exclusively in the testicular Sertoli cells and the ovarian granulosa cells; low levels are expressed in the endothelial cells of the ovary and testis. Previous studies using immunohistochemical methods detected the FSH receptor in the tumor cells of prostate adenocarcinomas. It has been suggested that the FSH receptor is expressed in proliferating tumor cells. A number of studies have found more intense proliferation of tumor cells in variety of human cancers at the tumor periphery. Expression of FSH receptor by endothelial cells may be associated with their proliferation in this specific location. If intravenously administered antibodies to the FSH receptor were able to detect tumor cells on the endothelial cell surface in a wide range of tumors, such tumor-specific endothelial receptors for FSH could be a specific target for tumor imaging and therapy. This study was designed to assess endothelial-cell expression of the FSH receptor in blood vessels of a wide range of human cancers. The FSH receptor was detected in surgical samples from 1336 patients with a wide range of tumors by use of immunohistochemical and immunoblotting techniques, involving 4 monoclonal FSH-receptor antibodies specific for different FSH-receptor epitopes, and by use of in situ hybridization techniques. Immunoelectron microscopy was used to detect the FSH receptor in mice with xenograft tumors. Surgical specimens were obtained from tumors located in the prostate, breast, lung, liver, colon, pancreas, stomach, testis, ovary, urinary bladder, and kidney. The FSH receptor was expressed by endothelial cells of tumor blood vessels in all 1336 patients among all grades including early T1 tumors. The FSH receptor was not expressed in the normal tissues located more than 10-mm outside the tumors in specimens obtained during surgery. Lymphatic vessels in tumors did not express the FSH receptor. Endothelial cells expressing the FSH receptor were found only at the periphery of the tumors in a layer with a thickness of about 10 mm that extended a few millimeters both inside and outside the tumor. After intravenous perfusion of mice bearing the xenograft tumors with anti-FSH-receptor antibodies coupled to colloidal gold, the FSH receptor was exposed on the luminal endothelial surface and could bind and internalize circulating ligands. In contrast, there was only rare binding of anti-FSH-receptor antibodies after perfusion in endothelial cells of normal organs obtained from the same animals. These findings demonstrate the selective expression of the FSH receptor on the endothelial surface of blood vessels in a wide range of tumors in the human beings. The data suggest that tumor-specific endothelial receptors for FSH could be a specific target for tumor imaging and therapy.