Relationship Of Adrenomedullin Expression With Microvessel Density And Prognosis In Carcinoma Of Endometrium

Endometrial cancer is also called as corpus carcinoma,which is a series ofmalignant epithelium tumors that primarily stem from endometrium.Amongthe total , most of it is adenocarcinoma endometria that stems fromendometrial glandular organ.Endometrial cancer is one of three commonmalignant tumors in the female genital tract,counts 7% or so in the femalecarcinomas , and 20 % ~30 % in malignant tumors in female genitaltract.Endometrial cancer is frequent in the old women,and counts 70%~75% in the post-menopause women, 15%~20% in the menopausal women,and only 5%~10% in 40-year-old below women.The domestic reportsshowed it usually occurred at the age of 50～60 years old and the mean age is55 years old or so.When most patients were diagnosed,their pathologicalchanges were localized in the uterus,so their prognosis was well.But duringrecent 20 years because duration of life becomes longer and longer,elderwomen become more and more,that is said the number of patients at thehigh-incidence age of endometrial cancer is increased,adding up to usingexogenous estrogen extensively,especially without progestogen-resistance.Without progestogen-resistance endometrial hyperplasia will happen andatypical hyperplasia will result in cancerization,thus in the world the morbidityof endometrial cancer shows ascending tendency.In some Europe and Americacountries the morbidity of endometrial cancer has been at the first place offemale genital tract malignant tumor.During the period of recent 10~20 years,the morbidity of endometrial cancer maintained twice of the one of themiddle of 70's.So evaluating effective pretherapy and post-treatment for thepatients with endometrial cancer , judging various factors related withprognosis,selecting suitable individualized treatment are needed badly for thediagnosis and therapy of endometrial cancer.Adrenomedullin (ADM) is a multifunctional peptide that derives from thehuman adrenal tumor (pheochromocytoma) in 1993 by Kiamura et al, and itis most in adrenal medulla,so called as adrenomedullin.With the furtherstudies of the structure and action of ADM,more and more experiments haveshowed ADM played an important role in human physiological andpathological conditions.ADM is composed of 52 amino acids,its structuralfeature is similar to calcitonin gene-related peptide(CGRP),and has 24% ofhomology with CGRP,so it belongs to CGRP family.ADM is expressed byvarious kinds of tissues in the body, among of total its concentration is higherin adrenal medulla,anterior lobe,brain,kidney and heart.The origin of ADMis extensive,and some experiments confirmed that vascular endothelial cell,vascular smooth muscle cell,mechanocyte,heart smooth muscle cell andtumor cell all could synthesize and secrete ADM.Recently it was consideredmain cleaning places perhaps are lung and kidney.ADM receptors are mainlyspecial ADM receptor,CGRP receptors,oGPCR and so on.ADM23～52 isendogenous blocking agent,which may block up ADM to bind with specialADM receptor,and that effect may be blocked up by CGRP blockingpharmacon CGRP8～37. ADM receptor phenotype depends on not only properstructure of receptor and also the regulation of RAMPs.Hay Smith reportedthe function of ADM receptor was related with the adjustment of the receptorprotein of signal pathway,in addition,serum ADM-binding protein in bloodcould lessen the bioactivity of ADM.ADM plays an important role in the respective stage of tumor generationand development by paracrine/autocrine.Its mechanisms perhaps include:①Angiopoiesis:ADM as an angiogenesis factor can prevent vascular endothelialcell from apoptosis and promote neovascularization via cAMP deopendentprotein kinase cascade and intracellular Ca2+ migration.②Dilate bloodvessel:ADM connects with CGRP receptor in vascular endothelial cell or itsspecial receptor to loose and dilate blood vessel via cAMP-NO pathway.Andit can increase the touch of blood vessel and tumor,and that can benefit thetumor to obtain nutrition and oxygen,and increase the probability of tumorhematogenous metastasis.③Promote mitotic division and speed up tumorgrowth:Withers DJ reported ADM might promote fibroblast mitotic divisionof Swiss3T3 rat via cAMP-dependent pathway,and it hinted that ADM/ADMreceptor autocrine system was potential mechanism to stimulate tumoraccrementition.④Suppress apoptosis:ADM as an apoptosis survival factorsuppresses apoptosis via cAMP pathway.Shichiri M et al showed ADMsuppressed rat arteriae aorta endotheliocyte apoptosis via up-regulating Maxbasic-spir-cyclo-spir-leucine zipper protein.Hague et al founded that ADMexpression in endometrial cancer cell line sensitive to steroid up-regulated Bclexpression,thereby prevented cancer cell from apoptosis in the anoxiacondition.⑤Inhibit immune reaction:ADM has inhibitory action formacrophage.Recent experiments verified that complement factor H,whichwas a kind of plasma protein able to connect with ADM,might adjusteffective concentration and biological activity of ADM and be related withelimination of ADM.Complement factor H is mainly generated by liver,mononuclear macrophage,mechanocyte,endothelial cell and horizontal cellcan also synthesize it.Complement factor H is an important regulatory factorof complement system, which enhances the survival ability of tumor cellsthrough inhibiting complement-mediated cathepsis.The analysis of functionalcathepsis showed:anti-complement factor H antibody could enhance theability of kill and wound of several kinds of tumor cell line.The action ofcomplement factor H can be augmented by ADM dose dependent.PioR et alconfirmed complement factor H could promote ADM mediated MCF-7growth.Immunohistochemistry method showed ADM and its specific bindingsites were distributed in human myometrium and endometrium.In humanpost-menopause endometrium,ADM immunostaining action exists only inbase material.Through immunohistochemistry method,it showed that ADMcould induce cAMP in the endometrium cell and promote cell growth.Theseresults showed ADM might be autocrine regulatory factor in humanendometrium cell and be involved in endometrial angiogenesis.Mic hishita etal found in epithelial cells of endometrial cancer ADM mRNA expressedhighly , and ADM expression in the two tissues was not statisticallysignificant.At present it is considered angiopoiesis is significantly effectivefor tumor progression.During the period of avascularity the tumor grows veryslowly,infiltration and metastasis can not take place as well.As soon as newvessels are generated in the tumor tissues,the tumors grow quickly,and beginto infiltrate and metastasize.Besides the accrementition,apoptosis and cellphaenotype of tumor cells and body immune state all played an important rolein tumor growth.Thus we wanted to study the effect of ADM expression andthe dependability of ADM and microvessel density(MVD)in endometrialcancer so as to study the effect of ADM on the generation and progression ofendometrial cancer and on the significant relation of ADM and angiogenesis.Our experiment took immunohistochemistry method to detect ADMexpression in endometrial cancer and approach the relationship of ADM withhistological type , pathological grade , operational-pathological stage andlymphoid metastasis of endometrial cancer and to analyze if ADM is relatedwith MVD or not.The result showed the positive correlation was found betweenADM expression and microvessel density in normal endometrium andendometrial cancer(P<0.025).In endometrial cancer the positive rate of ADMexpression was 35.7%,and the one of normal endomembrane was 30.4%,ADM expression of the two groups had no significant difference (P>0.05);ADM expression had no significant difference from histological type andoperational-pathological stage(P>0.05);inversely had significant differencefrom pathological grade and lymphoid metastasis(P<0.05).There were someforeign reports about ADM:Michishita et al discovered ADM also expressed agreat deal in the endothelial cell of normal uterus and endometrial cancer,andhad not statistically significant;Hague et al found ADM was expressed in bothnormal myometrium and leiomyoma uteri,and was located in intimal epithelialcell,vascular endothelial cell and vascular smooth muscle cell,ADM wasexpressed generously in the base material of macrophage;Li et al showed ADMmRNA was expressed a great deal in infiltrating squamous carcinoma of thecervix and mainly located in the cytoplasm of cancer cell,but in early invasivecarcinoma,the expression of ADM mRNA in stroma cell around cancer cell washigher than in cancer cell.The result showed in endometrial cancer ADM expression had positivecorrelation with pathological grade and lymphoid metastasis,that inferred ADMwas one of marks for invading progress of endometrial cancer and could reflectprognosis . In normal endometrium and endometrial cancer the positivecorrelation was found between ADM expression and MVD.That showed ADMmight be a main factor of promoting angiogenesis in the endometrium and playan important role in the generation,development and metastasis of endometrialcancer.Our experiment confirmed the dependability of ADM expression andMVD,and was related closely with pathological grade and lymphoid metastasisin endometrial cancer.Thus we expected ADM might become a new molecule target in the aspectsof early diagnosis,therapy method and prognosis assess of endometrialcancer.ADM antibody or antagon might conduce to the therapy and prognosisassess of endometrial cancer.