Expression Of Hepatocyte Growth Factor And Its Receptor C-met In Human Pituitary Adenomas

Pituitary adenomas are common tumors in patients from Department of Neurosurgery. Progressive tumor growth or intratumoral hemorrhage can compress surrounding structures and cause clinical manifestations in patients. Compression of pituitary gland can result in disorder of hormone secretion and cause symptoms such as hyperprolactinoma, acromegaly, Cushing’s disease and hyperthyroidism; compression of optic nerve can cause changes in vision and visual field; compression or invasion of cerebral dural matter will cause symptoms like headache. Treatments of pituitary adenomas include surgery, radiotherapy and chemotherapy. Tumors may recur after surgical resection. Radiotherapy or chemotherapy should be given for tumors that may recur after surgery. Invasiveness of pituitary adenomas refers to that tumors grow beyond its capsule and invade adjacent structures such as dural matter, optic nerve and skull. Invasive pituitary adenomas make complete surgical resection impossible because of adjacent impotant structures and prone to recur after surgery.HGF is an important growth factor for tumor growth and angiogenesis. Its only known receptor c-met is a receptor tyrosine kinase. HGF/c-met pathway is important for tumor cell proliferation, migration, invasion and angiogenesis. Therapeutic approaches targeting HGF or c-met can decrease HGF and c-met expression levels and inhibit tumor growth and angiogenesis. HGF and c-met are ovexpressed in gliomas, meningiomas and schwannomas, and their expression levels correlates with patients’poor prognosis. However, HGF and c-met protein expression in pituitary adenomas has not been reported.The aim of this study is as follows:to investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.ObjectiveTo investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.MethodsImmunohistochemical staining was done to detect HGF and c-met protein expression in human pituitary adenomas. Statistical analysis was done to investigate the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness.1. Samples65samples of pituitary adenomas and patients’clinical data such as patients’age, sex, tumor phenotypes on imaging and tumor histology types were collected.2. Immunohistochemical stainingHGF and c-met protein expression, tumor angiogenesis and cell proliferation were detected by strepto-avidin-biotin complex method method using antibodies anti-HGF, anti-c-met, anti-CD34and anti-Ki-67.3. Analysis of resultsHGF and c-Met immunoreactivity was recorded as follows:-, no immunopositive cells;+,30%of tumor cells are immunopositive;++,30%-60%of tumor cells are immunopositive;+++,60%of tumor cells are immunopositive. Scores for Ki-67were recorded as the number of immunopositive cells per high-power microscope (X400). The number of immunopositive cells under5microscopes per slide with the highest cell counts was counted and the average was recorded. MVD was recorded as the number of vessels or clusters of cells immunopositive for CD34per high-power microscope (×400). Each immunostained cell or cell cluster that was clearly separated from adjacent micro vessels was considered as a single countable microvessel. MVD under5microscopes per slide with the highest vascular counts were counted and the average was recorded.4. Statistical analysisStatistical analysis of the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness were done using Spearman rank correlation analysis (SPSS Version18.0). P<0.05is considered statistically significant.ResultsHGF and c-met protein are expressed in most pituitary tumors. HGF and c-met protein expression existed in98%and92%of pituitary adenomas respectively. HGF immunoreactivity has significant correlation with MVD (Spearman’s correlation coefficient r=0.31, P=0.01) and has significant correlation with cell proliferation index Ki-67(r=0.32, P=0.01). c-met immunoreactivity has significant correlation with MVD (r=0.3, P=0.02) and has significant correlation with cell proliferation index Ki-67(r=0.38, P=0.00).ConclusionsHGF and c-met protein are expressed in most pituitary tumors, and their expression levels significantly correlate with angiogenic and proliferative markers. The results indicate that HGF and c-met protein may have important roles in angiogenesis and cell proliferation in pituitary adenomas; and offer a new direction for investigating pituitary tumor pathogenesis. HGF and c-met can be new promising chemotherapeutic targets in pituitary adenomas as previous anti-HGF or anti-c-met approaches can inhibit tumor growth in other tumors.