一、钙黏素
(一)食管鳞状细胞癌
食管鳞状细胞癌细胞中的E-钙黏素表达情况与食管鳞癌的临床病理变化密切相关。E-钙黏素的表达还决定了患者的预后情况。当患者的E-钙黏素表达水平减少时,其手术后出现血液复发的概率增大,并且预后较差;而如果手术前患者的E-钙黏素表达水平正常,则其预后较好。以上研究结果提示,患者体内的E-钙黏素免疫反应性下降会导致食管鳞癌细胞的转移潜能增加。因此,通过对E-钙黏素免疫反应性的评估也许可以预测食管癌血液播散和复发的情况,并且作为食管鳞癌患者术后辅助治疗的手段之一。另外,有研究者认为E-钙黏素可能会成为预测患者淋巴结微小转移的标志物,而组织病理学分析其分期仅为N0期。
(二)食管腺癌
在食管腺癌病例中通过对E-钙黏素、α-链蛋白和β-链蛋白表达情况的分析,发现这三种蛋白的表达下调与肿瘤患者的存活率下降密切相关。除此之外,E-钙黏素和β-链蛋白的表达还与患者预后有关,因此可以利用它们来评估患者的复发风险性。在一些病例中,E-钙黏素和链蛋白的复合体染色并没有显示出其表达缺失或下降,但是却提示存在从细胞膜向细胞质的重新分布。这一重新分布过程的具体机制尚不十分明确,然而该蛋白磷酸化状态的改变可能为其原因之一。目前已知β-链蛋白特定位点酪氨酸的磷酸化可以阻止E-钙黏素和α-链蛋白的结合作用,尽管此时E-钙黏素表达正常。以上研究结果表明,虽然这些蛋白表达正常,但并不一定发挥其功能。有研究者认为利用钙黏素和链蛋白复合体中的某些成分评价预后优于其他分子。考虑到该复合体的所有成分相互依赖从而来维持正常细胞间的黏附过程,因此同时检测E-钙黏素和链蛋白的表达会发挥一定作用。但是很明显,科学家们还必须对钙黏素和链蛋白复合体进行大量实验才能将其应用于临床分析,尤其是研究这些分子在细胞信号转导通路中的重要作用。
二、整合素
(一)食管鳞状细胞癌
有研究者发现在食管鳞状细胞癌中αv整合素亚单位表达较强,而在正常食管组织中却没有发现该蛋白的表达。因此,αv整合素亚单位可能可以作为细胞恶性表型的一个重要标志物。这些研究者还报道,α2和β1整合素亚单位表达下调会引起细胞黏附能力下降和迁移能力增加,而这一结果却与食管鳞状细胞癌中αv整合素亚单位表达后引起的结果一致。Takayama等也发现在食管鳞状细胞癌中β1整合素亚单位表达下调与淋巴结转移正相关。对食管鳞状细胞癌细胞系进行cDNA微阵列的分析表明,α3、α6和β4整合素在肿瘤细胞中表达上调。Sato等利用两株食管癌细胞系确定了整合素的黏附作用在食管癌的血液转移过程中具有重要作用。他们还推测肿瘤细胞是在选择素介导的细胞黏附过程起始之后才接收到内皮细胞产生的细胞因子的刺激。因此,增加细胞黏附分子(如β1整合素家族)的表达可以导致肿瘤细胞与血管壁的黏附能力增加,最终结果是肿瘤细胞迁移到血管外的组织,从而形成转移瘤。
(二)食管腺癌
科学家通过对食管腺癌的基因表达谱进行分析发现,在肿瘤组织中α3和α6整合素表达增高。而通过利用免疫组织化学技术对慢性食管炎伴腺上皮化生进行分析则发现β1整合素表达与组织形态学、存活率无明显关联,提示这些分子对这类疾病的预后价值不大。然而研究者却在87%的食管腺癌标本中检测到α6整合素mRNA水平过表达,而该因子则是层粘连蛋白的主要受体,并且参与肿瘤细胞的侵袭过程。以上结果提示α6整合素在人类食管腺癌中mRNA水平过表达,而且能够影响食管癌的恶性侵袭性。但是整合素发挥功能不能仅仅通过其是否表达来推断,表达整合素的细胞还可以通过改变其配体结合特性而不是改变其表达水平来发挥功能。
三、CD44
(一)食管鳞状细胞癌
CD44v异构体的表达上调可以作为评价多种肿瘤转移和预后的分子标志物。而在头颈部鳞癌和神经母细胞瘤中却发现有CD44v的表达下调。通过对食管鳞状细胞癌进行免疫组织化学检测,发现CD44v2在肿瘤细胞中表达下调。尽管CD44v2表达与临床病理因素无密切关系,但是CD44v2表达阳性的肿瘤患者存活率明显高于CD44v2阴性的肿瘤患者。因此,研究者提示在食管鳞状细胞癌中CD44v2的表达下调与患者预后不良相关,并且认为CD44v2可以作为决定患者是否需要辅助治疗的临床标志物。
(二)食管腺癌
研究者对慢性食管炎伴腺上皮化生中CD44s和CD44v(v4/5,v6)的免疫反应性进行分析,发现CD44s和CD44v6在慢性食管炎伴腺上皮化生的癌变过程中发挥作用。另外,CD44v6在腺癌中的表达与肿瘤的侵袭、新生血管侵袭和神经侵袭具有一定相关性,但却不影响最终结果。另有研究者在研究食管腺癌中CD44s和CD44v4表达情况时却发现,CD44v4表达增高与患者预后相关,即可以降低患者存活率。在临床诊断中最可能应用CD44的领域就是对患者体液的分析。科学家们已经检测到膀胱癌患者的尿液标本中脱落的肿瘤细胞,并且准确率较高。而通过检测患者胃内或食管腔内容物的CD44v表达水平来筛查有症状和无症状的人群具有很高应用价值。
四、免疫球蛋白超家族
(一)食管鳞状细胞癌
目前癌胚抗原(CEA)是所有黏附分子中被应用最多的分子之一,原因在于它被证明在结直肠癌的检测中发挥作用。前期研究已经表明只有在复层鳞状上皮细胞膜中才有CEA的表达,并且免疫组织化学染色可以将其作为判断这些上皮分化的标志物,即在食管癌、胃癌和结肠癌中CEA的表达与这些肿瘤的分化程度密切相关。而间质中CEA的表达在食管鳞状细胞癌的淋巴结侵袭过程中发挥一定功能。另外有研究者报道,当检测食管鳞状细胞癌患者手术后血浆中的CEA mRNA水平时发现,在肿瘤切除后不久CEA即出现阳性的患者,其总复发率与血液复发率明显高于CEA为阴性的患者,并且与结节状态和肿瘤分级有关。于是,研究人员建议对于那些术后CEA mRNA水平为阳性的患者应该使用一些有效的辅助疗法进行治疗。
Rockeet等检测了食管癌中人类主要组织相容性抗原Ⅰ型(HLA-ABC)、Ⅱ型(HLA-DR)和细胞间黏附分子-1的表达情况,结果发现在绝大多数食管鳞状细胞癌中HLA-DR和细胞间黏附分子表达缺失;但是与组织分化程度和分期无明显关联,可能与抑制浸润性淋巴细胞相关。此外,还有科学家报道食管癌,尤其是食管鳞状细胞癌中的HLA-Ⅰ型抗原和细胞间黏附分子-1的表达是降低肿瘤复发风险性的重要预测因子,然而在HLA-Ⅰ型抗原阴性的肿瘤患者中细胞间黏附分子-1的表达却往往增高肿瘤复发的风险性。淋巴结转移与HLA-Ⅰ型抗原缺失表达的相关性提示肿瘤细胞的播散可能是由于免疫系统识别这些细胞的能力减弱所引起的。
(二)食管腺癌
Rockeet等的研究显示:在20%的食管腺癌中HLA-DR主要在细胞质中弱表达,与肿瘤的分期、分级无相关性。另外,在被认为即将发生食管癌的患者细胞中HLA-DR和细胞间黏附分子-1的表达出现异常。这些分子在激活人体免疫系统的过程中发挥重要作用,但当它们表达下降时,将部分抑制免疫系统对食管鳞状细胞癌和食管腺癌的免疫应答反应,最终可能导致恶性肿瘤的进展。
五、选择素
食管鳞状细胞癌
目前尚没有科学家研究食管癌中选择素的免疫表达情况。然而在51%的食管鳞状细胞癌中可以检测到E-选择素的配体Sialyl Le(a)。研究还表明不仅在黏膜内癌中检测到Sialyl Le(a)的高表达,而且还可以在侵袭癌中检测到Sialyl Le(a)的高表达。以上结果提示Sialyl Le(a)的表达与肿瘤进展的早期密切相关。此外,有报道表明在具有远处淋巴结转移的食管鳞状细胞癌患者中其Sialyl Le(a)和Sialyl Le(a)抗原表达增高,并且容易发生血液系统复发。
(汪 洋 邵淑娟 詹启敏)
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