Relationship Of Adrenomedullin Expression With Microvessel Density And Prognosis In Sarcoma Of Uterus

Sarcoma of uterus is a kind of rare malignant tumor in clinic and accountsfor 1%～3% of the female malignant tumor.It is difficult to diagnose inadvanced stages and has high recurrence rate,mortality and poor prognosis.Thestudy about its prognosis factors contributes to clinical diagnosis,therapy andmonitoring.It has been reported the potential prognosis factors are sarcomatouspathological type,clinical stage,heteromorphism and mitotic figures ofneoplastic cell,vascular metastasis and lymphatic metastasis.Adrenomedullin (ADM) is an endogenous vasoactive peptide distributedextensively.Its physiological function is involved in regulating function ofcirculation system.Recently there are many reports with regard to therelationship between ADM and malignant tumor.It is showed that ADM isexpressed in many tissues in the body and play an important role in tumordevelopment via promoting angiogenesis,stimulating cell mitotic division,suppressing apoptosis and encouraging tumor immune escape.Zhao et al hadfirstly demonstrated that ADM is a kind of novel endothelial cell growth factorto stimulate angiogenesis.At present it is identified that angiogenesis isextremely important for tumorous malignant bionomics such as tumorgeneration,invasion,metabasis and so on,moreover,the studies about the effectof ADM on tumor vessel growth become a hot spot especially.It is confirmed by immunohistochemical staining that there is specialbinding site of ADM in human myometrium and endomembrane.Wherever ingynecological benign tumors or malignant tumors,ADM is expressed in varyingdegrees.Hague et al had reported ADM expression was up-regulated in themyometrial vascular endothelial cell and myometrium of leiomyoma-bearinguteri,accordingly inferred that ADM was associated with the vascular densityand endothelial proliferation.Hata and coworkers showed the expression ofADM was obviously correlated with histological grades and prognosis in theepithelial ovarian tumors.More and more studies have hinted that ADM wasclosely related with the generation and development of the malignant tumors,and the further research on it would present molecule target for the clinicaldiagnosis and therapy of gynecological tumors.In our experiment the expression of ADM and microvessel density (MVD)were evaluated by immunohistochemical S-P technique of tumor specimensfrom 46 patients with sarcoma of uterus without preoperative radiotherapy orchemotherapy.We investigated the expression of ADM in the sarcoma of uterusand the relationship between ADM and microvessel density as well asprognosis.Our studies showed the positive correlation was found between ADMexpression and mitotic figures in uterine leiomyosarcoma (LES) andendometrical stromal sarcoma(ESS)(P<0.05).The higher the expression ofADM was, the more the mitotic figures were,and the worse the prognosiswas.It has been identified that the mitotic figure is a significant prognosis factorof the leiomyosarcoma uteri.Oehler et al studied the function of ADM on thevascular smooth muscle cell generation,and showed that ADM could sitimulatemitotic division and suppress apoptosis as a positive growth factor via proteintyrosine kinase and mitogen active protien kinase signal transductionpathway.Meanwhile ADM has been demonstrated to be a simulator of cellproliferation via autogenous regulatory mechanism for the malignant tumorousgrowth.In addition to mitotic figures,ADM would perhaps become a newprognosis factor to be utilized to determine the prognosis of the sarcoma ofuterus in clinic and to guide the therapy.In contrast,no association was found between histological typing as well asclinical grade and ADM expression in sarcoma of uterus as the report of Hata etal,which was showed that ADM expression reflected the malignant degree ofovarian cancer , but it had the negative correlation with tumorousprogression.Hata et al also reported that ADM expression had the positivecorrelation with the degree of lymphatic metastasis in ovarian epithelial cellcarcinoma.Our research showed that ADM expression of the positive lymphaticmetastasi group was higher than the negative one.But that ought to be studiedfurther because of few cases of pelvic lymphadenectomy.Moreover, the mean microvessel density count of ADM strong-expressiontumors was higher than that of ADM low-expression tumors (P<0.01).Thepositive correlation was found between ADM expression and microvesseldensity(rs=0.317,P<0.05)in sarcoma of uterus.Be reported that ADM canincrease vassular permeation via Hypoxia-inducible factor 1 (HIF-1)-dependentpath way,it also can both prevent vascular endothelial cell from apoptosis andpromote neovascularization via cAMP deopendent protein kinase cascade andintracellular Ca2+ migration.Our results was similar to that,meanwhile alsosuggested that ADM might be involved in angiopoiesis in the sarcoma ofuterus,and might demonstrate that ADM was intimately related with tumorprogression as a angiogenesis factor.In addithon,We chose 15 patients in normal controls,28 patients withuterine leiomyoma,detected ADM expression by the same method above andcompared with the one of sarcoma of uterus . As we knew uterineleiomyosarcoma might stem from sarcomatous change.Prayson et al proposedthat smooth muscle tumors of uncertain malignant potential belonged toleiomyosarcoma uteri subtype.The diagnosis of transitional leiomyoma betweenbenign and malignant tumor has been thought more and more highly of ,andnumerous studies have showed immunohistochemical feature of LES issignificantly different from one of LE.For example Poncelet et al founded theexpression of CD44v3 in the cellular leiomyoma was most higher than the onein the leiomyosarcoma uteri.So immunohistochemical method may contributeto differential diagnosis,therapy and prognosis estimation.Recent researcheshave taken ADM as the main regulator of the cancer-tumor growth to sitimulatecell mitotic division , suppress cancer apoptosis and promote tumorousgrowth.Our result showed the expression of ADM in leiomyomas or inleiomyosarcoma uteri was statistically greater than that of normal myometriumrespectively(P<0.01) , and the expression of ADM in leiomyomas wasstatistically greater than that of LES (P <0.05).That significant difference ofADM expression between LE and LES presumed ADM might be involved inthe futher development of benign and malignant tumour cells in smooth muscletumor of uterus.The result showed that ADM expression was graduallyincreased among the normal controls, LE and LES in turn,and showed higherand higher following tumorous malignant degree aggravating.It suggested thatADM perhaps gave some important play in sarcomatous change of LE and LESprogression,moreover it showed ADM might verdict the malignant potency ofthe fibromyoma uteri as a novel accessory criteria.Following the penetrating research on ADM,it's possible to take ADM as anovel molecular target of antiangiogenic and to develop new anticarcinogenicstrategies by suppressing the expression of ADM in tumorous tissue in any way(such as anti-AM antibody).Especially,for extremely malignant sarcoma ofuterus,it's of special significance to develop a kind of drug for targeted therapyaiming directly at ADM against the gynecological malignant tumors.