骨肉瘤中血管生成拟态与HIF-1α蛋白的关系及临床意义

Clinical significance of vasculogenic mimicry and its relation with hypoxia inducible factor-1α in osteosarcoma

目的检测骨肉瘤中血管生成拟态(vasculogenic mimicry,VM)和缺氧诱导因子-1α(HIF-1α)的关系及临床意义,旨在探寻影响骨肉瘤进展及预后的有效指标。方法采用CD34和PAS套染法检测108例骨肉瘤及28例骨软骨瘤中VM、微血管密度(Microvessel density,MVD)及HIF-1α表达水平差异,并分析其与骨肉瘤患者临床病理因素及5年存活率之间的关系。结果骨肉瘤组织中VM、HIF-1α过表达及MVD≥22的阳性率分别为62.96%(68/108)、57.41%(62/108)和58.33%(63/108),骨软骨瘤中分别为0%(0/28)、32.14%(9/28)和28.57%(8/28)(P<0.05);VM、HIF-1α过表达及MVD与骨肉瘤分级、远处转移及软组织浸润和Enneking分期有关(P<0.05),与患者年龄、性别、部位、肿瘤大体、组织学类型和直径无关(P>0.05);骨肉瘤中VM、HIF-1α过表达与MVD之间呈正相关(P<0.05);VM阳性、HIF-1α过表达及MVD≥22组患者5年存活率分别为8.82%(6/68)、8.06%(5/62)和3.17%(2/63);VM阴性、HIF-1α低表达及MVD<22组分别为87.5%(35/40)、78.26%(36/46)和86.67%(39/45)(P<0.05);Cox多因素分析提示VM、HIF-1α、MVD、远处转移、软组织浸润和Enneking分期是影响骨肉瘤患者预后的独立危险因素(P<0.05)。结论 VM可能是判断骨肉瘤预后的新指标,联合检测VM、HIF-1α及MVD对骨肉瘤的侵袭、转移及预后判断有重要意义。

Objective To find good markers for predicting the progression and prognoms ot osteosar- coma via investigating the existence of vasculogenic mimicry （VM） and the level of hypoxia inducible factor-la （HIF 15） and their relationship in osteosarcoma. Methods VM, HIF-1a, and microvessel density （MVD） were examined by CD34 ElivisionTM immunohistochemical and periodic acid-Shiff＇s （PAS） histo- chemical staining in 108 osteosarcoma and 28 osteochondroma paraffin embedded specimens. The relation- ship between VM, over expression of HIF-1a protein and MVD was statistically analyzed via spearman correlation analysis, and their relationship with clinicopathologic factors was analyzed by chi square test. The relationship of VM, HIF-1a expression and MVD with overall survival （OS） time and disease-free survival （DFS） time of patients with ostoesarcoma was analyzed by Cox multifactor regression and Kaplan-Meier survival analysis. Results The positive rate of VM was 62.96% （68/108） in osteosarcoma and 0% （0/28） in osteochondroma, the positive rate of HIF-1a protein over-expression was 57.41% （62/108） in osteosarcoma and 32.14%（9/28） in osteochondroma, and the rate of MVD≥22 was 58.33% （63/108） in osteosarcoma and 28.57% （8/28） in osteochondroma respectively, with significant differences （P〈0.01 for all）. There were significant differences, between positive and negative groups of VM, MVD≥22 or over-expression of HIF-I~ in pathological degree, parenchyma infiltration, distant metastasis and Ennek- ing stage （P^0.05 for all）, but not in age, gender, anatomic location, histological type and tumor diame- ter （P）0. 05 for all）. A positive relationship was found between VM and over-expression of HIF la protein （r=0.813,Pd0. 01）,betweenVMandMVD（r=0. 830,P^0. 01）,andbetweenMVD and over-expression of HIF la protein （r 0.7!）1 , P〈-＇0.01）. In osteosarcoma patients, the mean OS was 4：;. 318-b21. 869 and mean Db＇S was 22. 055 b 16. 095, respectively. I.ong rank and Kaplan Meier survival analysis indicated that the .% year survival rate osteosareoma was 8.82% （6/68） in VM positive group, 87%（35/40） in VM negative group respectively （P〈0.0]）; 8.06% （5/62）in over expression of HIF-1a and 78. 26%（36,/46） in low HIE-1a expression respectively （P〈0.01）, and 3. 17% （2/63） in MVD≥22 group and 86.67% （39/45） in N4VD〈22 group, respectively （P〈0.01 for all）. Cox mullifactor regression anal ysis indicated that Enneking stage, parenchyma infiltration, distant metastasis, VM, MVD and expression level of HIE-1a protein were independent prognosis risk factors of osteosarcoma （P〈0. 05 for all）, Conclusion VM MVI） and the expression level of HIF-1a protein are related to tumor pathological degrent parenchyma infiltration, distant metastasis, Enneking stage and prognosis of patients with osteosarcoma.VM may be a new target for predicting the prognosis of osteosarcoma. Combined detection of VM and MVD and HIF-1 a is of great significance t-or predicting the progression and prognosis of osleosarcoma.