CEACAM8：免疫球蛋白超家族的“低調(diào)”成員，生殖腫瘤、消化腫瘤研究的潛力候選靶點(diǎn)！
日期：2024-03-08 13:16:14
2024年2月，愛思維爾（Elsevier）數(shù)據(jù)庫收錄了一篇關(guān)于CEACAM8的生信文章，該研究通過分析多發(fā)性硬化癥患者孕期的轉(zhuǎn)錄組數(shù)據(jù)，基于生物信息學(xué)分析工具GEO、STRING、KEGG等，發(fā)現(xiàn)了42個(gè)差異表達(dá)基因，其中包括CEACAM8，以及多個(gè)重要通路如IL-10、ErbB2和IL-17。這些結(jié)果表明CEACAM8可能是免疫炎癥性疾病一個(gè)重要的靶點(diǎn)研究方向 [1]。早在2010年，已有1款靶向CEACAM8的藥物用于骨髓炎。盡管，近年的研究鮮有關(guān)于CEACAM8臨床的報(bào)道，但CEACAM8作為CEA家族的“低調(diào)”一員，陸續(xù)的研究表明其有望作為眾多腫瘤的候選靶點(diǎn)，尤其是生殖和消化腫瘤研究。因此，針對(duì)CEACAM8進(jìn)一步的研究探索可能為更多的研究方向帶來參考！
1. 什么是CEACAM8？
1.1 CEACAM8的結(jié)構(gòu)
癌胚抗原相關(guān)細(xì)胞粘附分子8（CEACAM 8）是免疫球蛋白超家族的CEA家族中的一個(gè)成員，屬于GPI錨定的高度糖基化蛋白質(zhì)，又被稱為CD66b、NCA-95或CD67。CEACAM 8具有11個(gè)N-糖基化位點(diǎn)，其分子量為95kDa。一些研究提出了一種純化CEACAM8的方法，可用于進(jìn)一步研究其結(jié)構(gòu)和功能，并在蛋白質(zhì)水平證實(shí)了CEACAM8是CGM6（NCA-W272）基因的產(chǎn)物。此外，研究表明，CEACAM8可能調(diào)節(jié)CEACAM6的順式和反式相互作用，并可能與其它CEACAMs中的一種或兩種結(jié)合起調(diào)節(jié)作用。例如，表達(dá)CEACAM6和CEACAM8的粒細(xì)胞將主要形成順式CEACAM6/8異二聚體，從而抑制CEACAM6的反式交聯(lián)。然而，CEACAM8的結(jié)構(gòu)目前仍需要進(jìn)一步闡明（圖1）[2-4]。
1.2 CEACAM 8的表達(dá)和功能
CEACAM8是一種粒細(xì)胞譜系細(xì)胞特異性的活化抗原，主要在人類嗜中性粒細(xì)胞和嗜酸性粒細(xì)胞中表達(dá)。在靜息狀態(tài)的中性粒細(xì)胞中，CEACAM8主要分布在質(zhì)膜中的較少部分；然而，一旦激活，CEACAM8在質(zhì)膜上的表達(dá)會(huì)通過細(xì)胞內(nèi)的池子快速上調(diào)。CEACAM8作為癌胚抗原家族的一員，不僅參與調(diào)節(jié)細(xì)胞間的黏附，還在細(xì)胞信號(hào)傳導(dǎo)中發(fā)揮重要作用，例如，調(diào)節(jié)與病原體結(jié)合、炎癥、正常細(xì)胞的生長(zhǎng)或分化有關(guān)的免疫反應(yīng)、促進(jìn)或抑制腫瘤生長(zhǎng)、血管生成等等 [6-8]。
圖1. CEACAM8的結(jié)構(gòu) [5]
2. CEACAM8相關(guān)的信號(hào)機(jī)制
2.1 CEACAM8在腫瘤中的調(diào)節(jié)機(jī)制
CEACAM8主要參與調(diào)節(jié)中性粒細(xì)胞的粘附和激活。中性粒細(xì)胞被認(rèn)為是急性炎癥反應(yīng)中最早被募集的效應(yīng)細(xì)胞之一，招募到腫瘤環(huán)境的中性粒細(xì)胞具有少量顆粒和活性氧ROS，其功能是復(fù)雜的。中性粒細(xì)胞不同活化狀態(tài)具有相應(yīng)的作用。腫瘤細(xì)胞能夠產(chǎn)生出TGF-β，其能促進(jìn)腫瘤相關(guān)中粒細(xì)胞的極化，這種類型的中粒細(xì)胞有促進(jìn)癌癥進(jìn)展的可能，因?yàn)樗墚a(chǎn)生抑制細(xì)胞毒性淋巴細(xì)胞的生長(zhǎng)因子，如血管內(nèi)皮生長(zhǎng)因子VEGF、基質(zhì)金屬蛋白酶9（MMP9）、肝細(xì)胞生長(zhǎng)因子（HGF）等。因此，CEACAM8在中性粒細(xì)胞中的表達(dá)提示了它對(duì)腫瘤的發(fā)生和發(fā)展起著調(diào)節(jié)作用 [9-11]。
2.2 CEACAM8的其它免疫信號(hào)機(jī)制
此外，一些研究發(fā)現(xiàn)，CEACAM8在免疫調(diào)節(jié)中扮演了更廣泛的角色，不僅局限于腫瘤。例如，在調(diào)節(jié)下呼吸道細(xì)菌感染方面，可溶性重組CEACAM8-Fc能夠有效抑制表達(dá)CEACAM1的人肺上皮細(xì)胞對(duì)TLR2的免疫反應(yīng) [12]。此外，CEACAM8的過度表達(dá)與吞噬功能障礙密切相關(guān)，其中CEACAM8與CD11b比率的改變以及C5a受體C5aR1和C5L2的減少是關(guān)鍵因素。實(shí)驗(yàn)還表明，中性粒細(xì)胞麻痹程度與CEACAM8受體的表達(dá)水平直接相關(guān)，這可能為開發(fā)新的標(biāo)志物提供了線索。總體而言，這些發(fā)現(xiàn)揭示了CEACAM8在調(diào)節(jié)免疫反應(yīng)中的重要性 [13-15]。
3. CEACAM8和疾病研究
3.1 CEACAM8和乳腺癌研究
CEACAM8/CD66b被廣泛認(rèn)可作為腫瘤相關(guān)中性粒細(xì)胞（tumor associated neutrophils，TANs）的標(biāo)志物，可用于監(jiān)測(cè)腫瘤實(shí)質(zhì)中TANs的數(shù)量。研究表明，在浸潤(rùn)性乳腺癌中，CEACAM8/CD66b的表達(dá)在擴(kuò)散組中顯著高于非擴(kuò)散組，并且侵襲性亞組的生存率更低。CD66b陽性TANs與淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移密切相關(guān)。進(jìn)一步的研究結(jié)果顯示CD66b+TANs會(huì)影響免疫細(xì)胞上PD-L1的表達(dá)，二者呈正相關(guān)的關(guān)系。總之，乳腺癌中存在TANs，且與腫瘤的轉(zhuǎn)移、復(fù)發(fā)密切相關(guān)，檢測(cè)CD66b陽性TANs的密度可能成為預(yù)測(cè)乳腺癌轉(zhuǎn)移和復(fù)發(fā)的潛在指標(biāo) [16-17]。
3.2 CEACAM8和宮頸癌研究
宮預(yù)癌組織中，中粒細(xì)胞的浸潤(rùn)與患者無復(fù)發(fā)生存（RFS）密切相關(guān)，并且中粒細(xì)胞浸潤(rùn)數(shù)量的增加是宮頸癌患者復(fù)發(fā)的一個(gè)獨(dú)立危險(xiǎn)因素。如前所述，CEACAM8/CD66b是中粒細(xì)胞表明的特異性分子標(biāo)志。一項(xiàng)研究表明，在宮頸癌患者的腫瘤和鄰近基質(zhì)組織中，CEACAM8含量較高，特別是在腫瘤周圍觀察到了高密度的CEACAM8。此外，在宮頸癌中，CD66b與CD8比率（Neutrophil to Lymphocyte Ratio，NLR）升高已被確定為不良的預(yù)后因素。進(jìn)一步研究發(fā)現(xiàn)，CEACAM8與宮頸癌患者的無復(fù)發(fā)生存率相關(guān)，可以作為宮頸癌患者預(yù)后不良的潛在預(yù)測(cè)因子 [18-19]。
3.3 CEACAM8和膀胱癌研究
有關(guān)CEACAM8與膀胱癌之間的關(guān)系僅在少量最新的研究中發(fā)現(xiàn)，同樣在膀胱癌中，NLR值的變化可以預(yù)測(cè)治療效果和患者的生存期，高NLR比值，患者的癌癥特異性死亡風(fēng)險(xiǎn)顯著增高；此外，一項(xiàng)采用ELISA的方法檢測(cè)尿液中CEACAM8的含量，測(cè)定的結(jié)果顯示，在膀胱癌組CEACAM8含量高于非膀胱癌組尿液；不同病理分級(jí)的膀胱癌組尿液中CEACAM8濃度不同。研究結(jié)果提示，CEACAM8在膀胱癌的診斷、篩查及監(jiān)測(cè)中具有較高的臨床應(yīng)用價(jià)值 [20-22]。
3.4 CEACAM8和非小細(xì)胞肺癌研究
在非小細(xì)胞肺癌（NSCLC）中，研究發(fā)現(xiàn)CEACAM8與疾病特異性生存密切相關(guān)，且存在著淋巴結(jié)轉(zhuǎn)移，與預(yù)后不良有關(guān)。在肺鱗癌（SCC）中，CEACAM8密度升高預(yù)示著較好的生存率，而在肺腺癌（ADC）中，卻預(yù)示著較差的生存率。對(duì)腺癌患者發(fā)現(xiàn)，CEACAM8水平與預(yù)后不良有關(guān)。但在組織間質(zhì)中，CEACAM8與患者的預(yù)后無關(guān)。這表明CEACAM8可能對(duì)不同類型的非小細(xì)胞肺癌產(chǎn)生不同的影響，可能受到腫瘤分期和免疫活性的影響 [23-24]。
3.5 CEACAM8和消化系統(tǒng)腫瘤研究
CD66b陽性中性粒細(xì)胞是腫瘤相關(guān)中性粒細(xì)胞（tumor associated neutrophils，TANs）的標(biāo)記，TANs在腫瘤微環(huán)境中對(duì)腫瘤的發(fā)生、發(fā)展起著至關(guān)重要的作用。目前，CEACAM8在多種消化系統(tǒng)腫瘤中，包括胃癌、肝癌、食管癌、口腔癌。例如，胃癌中，CEACAM8的浸潤(rùn)增加，與胃癌的預(yù)后密切相關(guān)。高CEACAM8浸潤(rùn)與腫瘤大小、分化程度和早期TNM分期顯著相關(guān) [25-26]；TANs被發(fā)現(xiàn)通過GM-CSF-PD-L1途徑抑制T細(xì)胞的增殖和功能，促進(jìn)胃癌的進(jìn)展 [27-28]。肝癌患者中，CEACAM8在腫瘤周圍組織中的表達(dá)密度高于腫瘤內(nèi) [29]；TANs可能通過分泌BMP2和TGF-β，增加其干細(xì)胞特性 [30]。此外，TANs通過IL-7a促進(jìn)結(jié)腸癌細(xì)胞的侵襲和遷移 [31]。在食管鱗狀細(xì)胞癌患者中，腫瘤內(nèi)CEACAM8的增加與淋巴結(jié)轉(zhuǎn)移和晚期病理分期密切相關(guān) [32]。
4.CEACAM8的臨床藥物研究前景
CEACAM8作為腫瘤研究的潛在靶點(diǎn)，展現(xiàn)出了的臨床藥物研究前景。Tc 99m besilesomab是一種CEACAM8抑制劑，在骨髓炎的治療中已獲得批準(zhǔn)上市，并有望在感染、皮膚和肌肉骨骼疾病等領(lǐng)域發(fā)揮作用，由CIS Bio International SA機(jī)構(gòu)開發(fā)。現(xiàn)階段國(guó)內(nèi)外關(guān)于CEACAM8臨床藥物研究還比較少，僅1款靶向靶向CEACAM8藥物上市。其它2款的藥物，Yttrium-90 besilesomab和Besilesomab尚未有臨床信息披露，但表明了該靶點(diǎn)領(lǐng)域的積極研究和開發(fā)態(tài)勢(shì)，這為未來CEACAM8相關(guān)藥物的臨床應(yīng)用提供了新的希望。
為鼎力協(xié)助各藥企針對(duì)CEACAM8在生殖腫瘤、消化腫瘤等在臨床中的研究，華美CUSABIO推出CEACAM8（CSB-MP004954HU1）活性蛋白產(chǎn)品，助力您在對(duì)CEACAM機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
華美CUSABIO蛋白CEACAM8
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized Human CEACAM8 at 2μg/mL can bind Anti-CEACAM8 recombinant antibody (CSB-RA005168MA1HU). The EC50 is 19.38-21.68 ng/mL.
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