奚蕾,沈偉生,曹向明(東南大學(xué)醫(yī)學(xué)院附屬江陰醫(yī)院, 江陰 214400)

·論 著·

非小細(xì)胞肺癌患者化療前后血清腫瘤標(biāo)志物、HIF-1α、VEGF的變化及相關(guān)性研究

奚蕾,沈偉生,曹向明
(東南大學(xué)醫(yī)學(xué)院附屬江陰醫(yī)院, 江陰 214400)

目的 探討非小細(xì)胞肺癌(NSCLC)患者化療前后血清腫瘤標(biāo)志物、缺氧誘導(dǎo)因子-1α(HIF-1α)、血管內(nèi)皮生長(zhǎng)因子(VEGF)的變化及其相關(guān)性。方法 選擇本院收治的40例NSCLC患者為觀察組,來(lái)本院體檢的40名健康正常人為對(duì)照組。檢測(cè)兩組血清中HIF-1α、VEGF水平;檢測(cè)觀察組血清中癌胚抗原(CEA)、神經(jīng)元特異性烯醇化酶(NSE)、鱗狀上皮細(xì)胞癌抗原(SCC)水平。評(píng)價(jià)觀察組的臨床療效和生存質(zhì)量改善情況。結(jié)果 觀察組臨床總有效率為30%,治療后NSCLC患者生存質(zhì)量改善率為32.5%。對(duì)照組血清HIF-1α、VEGF水平均明顯低于觀察組,經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)。觀察組治療后血清HIF-1α、VEGF水平明顯高于治療前,經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)。觀察組治療后血清CEA、NSE、SCC水平均顯著低于治療前,經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)。觀察組患者血清HIF-1α水平與VEGF水平呈顯著正相關(guān)(P<0.01)；與CEA、NSE、SCC水平均呈顯著負(fù)相關(guān)(P<0.01)。結(jié)論 NSCLC患者化療后血清HIF-1α、VEGF水平明顯升高,血液學(xué)腫瘤標(biāo)志物相關(guān)指標(biāo)明顯下降,且以上指標(biāo)存在顯著相關(guān)性。

化療；非小細(xì)胞肺癌；血管內(nèi)皮生長(zhǎng)因子；缺氧誘導(dǎo)因子-1α；腫瘤標(biāo)志物

目前腫瘤相關(guān)死因中,肺癌高居首位,以非小細(xì)胞肺癌(NSCLC)為主,占80%。NSCLC是一種實(shí)體腫瘤,可無(wú)限增殖和失控性生長(zhǎng),其最常見(jiàn)的現(xiàn)象是缺氧,由此所致的微環(huán)境是腫瘤發(fā)生發(fā)展的關(guān)鍵因素之一,不僅增加了腫瘤細(xì)胞對(duì)放療和化療的耐受性,還提高了腫瘤細(xì)胞的侵襲性和遠(yuǎn)處轉(zhuǎn)移能力[1,2]。腫瘤的生長(zhǎng)和轉(zhuǎn)移主要依賴(lài)腫瘤內(nèi)形成的新生血管,而參與腫瘤血管生成的血管生成因子中,作用最強(qiáng)的是血管內(nèi)皮生長(zhǎng)因子(VEGF)；起核心調(diào)控作用的是缺氧誘導(dǎo)因子-l α(HIF-1α),調(diào)節(jié)包括血清腫瘤標(biāo)志物和VEGF在內(nèi)的多種靶基因表達(dá)[3,4]。本研究主要探討了化療前后NSCLC患者血清腫瘤標(biāo)志物、VEGF、HIF-1α的變化和相關(guān)性,現(xiàn)報(bào)道如下。

1 資料與方法

1.1 臨床資料

選擇2010年7月～2012年8月本院收治的NSCLC患者40例為觀察組,所有NSCLC患者治療前均經(jīng)病理或細(xì)胞學(xué)明確診斷。其中男15例,女25例；年齡45～78歲,平均(67.2±5.0)歲；其中鱗癌24例,腺癌16例。另選擇同期來(lái)本院體檢的40名健康正常人為對(duì)照組,其中男16例,女24例,年齡48～77歲,平均(66.2±5.5)歲。兩組年齡、性別等一般資料比較,差異無(wú)統(tǒng)計(jì)學(xué)意義,具有可比性(P>0.05)。

1.2 化療方法

觀察組給予吉西他濱聯(lián)合順鉑的化療方案：吉西他濱1 000 mg/m2,靜脈滴注30～60 min,d1,8,15；順鉑100 mg/m2,靜脈滴注30～60 min,d1,每28 d重復(fù)。化療期間給予常規(guī)水化和止吐治療。每周期內(nèi)白細(xì)胞降低至(1.0～2.0)×109/L和/或血小板降低至(50～75)×109/L時(shí),將吉西他濱劑量減少25%。除惡心、嘔吐外,不良反應(yīng)未達(dá)到WHOⅢ級(jí)以上者不減少用藥劑量。

1.3 檢測(cè)方法及觀察指標(biāo)

對(duì)照組在體檢當(dāng)天,觀察組在化療前1～2 d、化療治療后2周期清晨,空腹采集肘靜脈血5 mL,5 000 r/min 離心10 min后分離血清,-20 ℃冰箱冷凍保存。ELISA法檢測(cè)血清中HIF-1α、VEGF水平。全自動(dòng)生化分析儀檢測(cè)觀察組血清中癌胚抗原(CEA)、神經(jīng)元特異性烯醇化酶(NSE)、鱗狀上皮細(xì)胞癌抗原(SCC)等相關(guān)腫瘤標(biāo)志物水平。

1.4 療效評(píng)定標(biāo)準(zhǔn)

完全緩解(CR)：腫瘤完全消失4 w以上；部分緩解(PR)：腫瘤縮小>50%；穩(wěn)定(NC)：腫瘤縮小<50%；進(jìn)展(PD)：腫瘤增大>25%或出現(xiàn)新病灶。總有效率=[(CR+PR)/總例數(shù)]×100%。生存質(zhì)量按照Karnofsky體力狀況評(píng)分標(biāo)準(zhǔn)(KPS)：治療后KPS增加≥10者為改善；減少≥10者為降低；介于二者之間為穩(wěn)定。

1.5 統(tǒng)計(jì)學(xué)方法

2 結(jié)果

2.1 觀察組臨床療效

觀察組40例患者,CR 0例,PR 12例,NC 15例,PD 13例,臨床總有效率為30%(12/40)。NSCLC患者治療后KPS評(píng)分有不同程度改善,改善率為32.5%(13/40)。

2.2 各組化療前后血清HIF-1α、VEGF水平變化

對(duì)照組血清HIF-1α、VEGF水平分別為(37.1±4.3)ng/L、(596.5±60.4)pg/mL,均明顯低于觀察組(治療前和治療后),經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)。觀察組治療后血清HIF-1α、VEGF水平明顯高于治療前,經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)(見(jiàn)表1)。

與對(duì)照組比較,**P<0.01；與治療前比較,##P<0.01

2.3 觀察組化療前后血清腫瘤標(biāo)志物水平變化情況

觀察組化療治療前檢測(cè)的血清腫瘤標(biāo)志物CEA、NSE、SCC水平分別為(40.3±4.1)、(33.8±4.6)、(38.5±4.6)；化療治療后CEA、NSE、SCC水平分別為(28.4±3.4)、(19.6±2.4)、(22.7±2.6)。觀察組治療后血清CEA、NSE、SCC水平均顯著低于治療前,經(jīng)比較差異有顯著統(tǒng)計(jì)學(xué)意義(P<0.01)(見(jiàn)表2)。

表2 觀察組血清腫瘤標(biāo)志物水平變化情況

與治療前比較,**P<0.01

2.4 化療前后觀察組血清HIF-1α與VEGF、腫瘤標(biāo)志物水平表達(dá)的相關(guān)性

NSCLC患者血清HIF-1α水平與VEGF呈顯著正相關(guān)(P<0.01)；與CEA、NSE、SCC水平均呈顯著負(fù)相關(guān)(P<0.01)(見(jiàn)表3)。

表3 化療前后觀察組血清HIF-1α與VEGF、腫瘤標(biāo)志物水平表達(dá)的相關(guān)性

3 討論

肺癌為病死率較高的惡性腫瘤,其發(fā)生部位起源于肺部支氣管黏膜上皮。近年來(lái),隨著生活環(huán)境的改變,城市工業(yè)化發(fā)展的加速,肺癌的發(fā)病率呈逐年上升趨勢(shì),日益受到學(xué)者們的關(guān)注[5,6]。研究[7]表明,癌細(xì)胞所處的環(huán)境與癌細(xì)胞的增殖、擴(kuò)散密切相關(guān),缺氧環(huán)境能導(dǎo)致癌細(xì)胞對(duì)藥物的耐受性增加。另有研究[8]證實(shí),腫瘤發(fā)生部位的新血管生成與癌細(xì)胞的擴(kuò)散遷移密切相關(guān),VEGF為參與血管新生的重要因子,在腫瘤細(xì)胞遷移擴(kuò)散的過(guò)程中發(fā)揮重要作用,HIF-1α則在血管生成的過(guò)程中起到整體調(diào)控的作用。大量研究[9-11]報(bào)道,肺癌患者的血清VEGF水平明顯高于健康對(duì)照組,且VEGF水平與肺癌TNM分期增加成正比,而不同性別、分化程度和病理類(lèi)型的NSCLC患者之間血清VEGF水平差異無(wú)統(tǒng)計(jì)學(xué)意義。由于在肺癌的發(fā)生、發(fā)展和轉(zhuǎn)移過(guò)程中VEGF具有重要作用,因此,肺癌患者血清中的VEGF水平變化可作為評(píng)估肺癌的早期診斷、療效和預(yù)后的重要指標(biāo)[12]。

HIF是一種轉(zhuǎn)錄因子,在缺氧環(huán)境下廣泛存在于人體和哺乳動(dòng)物中,具有維持氧穩(wěn)態(tài)的重要生理功能。HIF主要成分為氧調(diào)節(jié)亞單位HIF-1α和結(jié)構(gòu)亞單位HIF-1β的異二聚體[13],HIF-1α亞基具有調(diào)節(jié)HIF-1活性功能,下游靶基因有100多種,與其結(jié)合后均可促進(jìn)腫瘤的生長(zhǎng)和轉(zhuǎn)移。研究[14,15]表明,HIF-1α參與了血管形成、惡性腫瘤進(jìn)展、遷移等過(guò)程,HIF-1α的表達(dá)水平可有效評(píng)估惡性腫瘤預(yù)后。研究[16,17]表明,NSCLC患者組織中HIF-1α的高表達(dá)水平與有無(wú)遠(yuǎn)處轉(zhuǎn)移和臨床分期等有關(guān),而在遠(yuǎn)離腫瘤組織15～20 cm處的正常肺組織中無(wú)表達(dá),提示在NSCLC的發(fā)生發(fā)展、遠(yuǎn)處轉(zhuǎn)移和局部浸潤(rùn)中HIF-1α起著重要的作用。本研究結(jié)果顯示,NSCLC患者血清中HIF-1α、VEGF水平均明顯高于正常人群,且經(jīng)過(guò)化療后二者水平明顯增加,這與其他學(xué)者的研究相一致。

由于癌基因及其產(chǎn)物的異常表達(dá),腫瘤組織和細(xì)胞產(chǎn)生的抗原和生物活性物質(zhì)就是血液學(xué)腫瘤標(biāo)志物,其在肺癌早發(fā)現(xiàn)和早診斷方面具有重要研究?jī)r(jià)值。肺癌常用標(biāo)志物有CEA、VEGF、SCC和NSE,與腫瘤負(fù)荷緊密聯(lián)系,在癌癥晚期水平升高。有研究[18,19]表明,SCC水平在Ⅲ、Ⅳ期顯著高于在I、Ⅱ期,提示SCC水平與肺癌TNM分期成正比,而CEA、NSE等的升高與SCC呈正相關(guān)。本研究中,NSCLC患者化療后血清CEA、NSE、SCC水平均顯著低于治療前,且血清HIF-1α水平與VEGF、CEA、NSE、SCC水平均呈顯著正相關(guān)。

綜上所述,在預(yù)測(cè)腫瘤的發(fā)生發(fā)展、轉(zhuǎn)移和預(yù)后方面,HIF-1α、VEGF及腫瘤標(biāo)志物具有重要意義和相關(guān)性。聯(lián)合檢測(cè)NSCLC患者治療前后血清HIF-1α 、VEGF及腫瘤標(biāo)志物含量可反映腫瘤血管生成程度,對(duì)臨床判斷化療反應(yīng)、機(jī)體腫瘤負(fù)荷、預(yù)后及腫瘤生長(zhǎng)轉(zhuǎn)移有積極的指導(dǎo)作用。

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Changes and Relevance Analysis of Serum Tumor Markers, HIF-1α and VEGF Before and After Chemotherapy in Patients with Non-small Cell Lung Cancer

XILei,SHENWei-sheng,CAOXiang-ming

(JiangyinHospitalAffiliatedtoMedicalSchoolofSoutheastUniversity,Jiangyin214400,China)

Objective To explore the changes and relevance analysis of serum tumor markers, hypoxia inducible factor-1α(HIF-1α) and vascular endothelial growth factor (VEGF) before and after chemotherapy in patients with non-small cell lung cancer (NSCLC). Methods A total of 40 NSCLC patients were selected as observation group while another 40 healthy people taking physical examination in our hospital served as control group. Serum HIF-1α and VEGF levels were detected, serum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCC) levels in observation group were examined, and clinical efficacy and quality of life (QOL) in observation group were evaluated before and after treatments. Results The total clinical efficacy of observation group was 30%, and the improvement rate of QOL was 32.5%. Serum HIF-1α and VEGF levels were evidently lower in control group than in observation group (P<0.01) and were apparently higher after treatment than before (P<0.01). Serum CEA, NSE and SCC levels in observation were markedly lower after treatment than before treatment (P<0.01). Serum HIF-1α was in positive relation with VEGF level (P<0.01), and in reverse correlation with CEA, NSE and SCC levels (P<0.01). Conclusion After chemotherapy, serum HIF-1α and VEGF levels increase whereas haematological tumor markers decrease obviously in NSCLC patients. These parameters are in significant association.

Chemotherapy; Non-Small Cell Lung Cancer; Vascular Endothelial Growth Factor; Hypoxia Inducible Factor-1α; Tumor Marker

中國(guó)高校醫(yī)學(xué)期刊臨床專(zhuān)項(xiàng)資金(NO:11321679)

http://www.cnki.net/kcms/detail/51.1705.R.20140424.0407.007.html

10.3969/j.issn.1674-2257.2014.02.008

R734.2

A