CEACAM8:免疫球蛋白超家族的“低調”成員,生殖腫瘤、消化腫瘤研究的潛力候選靶點!
日期:2024-03-08 13:16:14
2024年2月,愛思維爾(Elsevier)數據庫收錄了一篇關于CEACAM8的生信文章,該研究通過分析多發性硬化癥患者孕期的轉錄組數據,基于生物信息學分析工具GEO、STRING、KEGG等,發現了42個差異表達基因,其中包括CEACAM8,以及多個重要通路如IL-10、ErbB2和IL-17。這些結果表明CEACAM8可能是免疫炎癥性疾病一個重要的靶點研究方向 [1]。早在2010年,已有1款靶向CEACAM8的藥物用于骨髓炎。盡管,近年的研究鮮有關于CEACAM8臨床的報道,但CEACAM8作為CEA家族的“低調”一員,陸續的研究表明其有望作為眾多腫瘤的候選靶點,尤其是生殖和消化腫瘤研究。因此,針對CEACAM8進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的結構
癌胚抗原相關細胞粘附分子8(CEACAM 8)是免疫球蛋白超家族的CEA家族中的一個成員,屬于GPI錨定的高度糖基化蛋白質,又被稱為CD66b、NCA-95或CD67。CEACAM 8具有11個N-糖基化位點,其分子量為95kDa。一些研究提出了一種純化CEACAM8的方法,可用于進一步研究其結構和功能,并在蛋白質水平證實了CEACAM8是CGM6(NCA-W272)基因的產物。此外,研究表明,CEACAM8可能調節CEACAM6的順式和反式相互作用,并可能與其它CEACAMs中的一種或兩種結合起調節作用。例如,表達CEACAM6和CEACAM8的粒細胞將主要形成順式CEACAM6/8異二聚體,從而抑制CEACAM6的反式交聯。然而,CEACAM8的結構目前仍需要進一步闡明(圖1)[2-4]。
1.2 CEACAM 8的表達和功能
CEACAM8是一種粒細胞譜系細胞特異性的活化抗原,主要在人類嗜中性粒細胞和嗜酸性粒細胞中表達。在靜息狀態的中性粒細胞中,CEACAM8主要分布在質膜中的較少部分;然而,一旦激活,CEACAM8在質膜上的表達會通過細胞內的池子快速上調。CEACAM8作為癌胚抗原家族的一員,不僅參與調節細胞間的黏附,還在細胞信號傳導中發揮重要作用,例如,調節與病原體結合、炎癥、正常細胞的生長或分化有關的免疫反應、促進或抑制腫瘤生長、血管生成等等 [6-8]。

圖1. CEACAM8的結構 [5]
2. CEACAM8相關的信號機制
2.1 CEACAM8在腫瘤中的調節機制
CEACAM8主要參與調節中性粒細胞的粘附和激活。中性粒細胞被認為是急性炎癥反應中最早被募集的效應細胞之一,招募到腫瘤環境的中性粒細胞具有少量顆粒和活性氧ROS,其功能是復雜的。中性粒細胞不同活化狀態具有相應的作用。腫瘤細胞能夠產生出TGF-β,其能促進腫瘤相關中粒細胞的極化,這種類型的中粒細胞有促進癌癥進展的可能,因為它能產生抑制細胞毒性淋巴細胞的生長因子,如血管內皮生長因子VEGF、基質金屬蛋白酶9(MMP9)、肝細胞生長因子(HGF)等。因此,CEACAM8在中性粒細胞中的表達提示了它對腫瘤的發生和發展起著調節作用 [9-11]。
2.2 CEACAM8的其它免疫信號機制
此外,一些研究發現,CEACAM8在免疫調節中扮演了更廣泛的角色,不僅局限于腫瘤。例如,在調節下呼吸道細菌感染方面,可溶性重組CEACAM8-Fc能夠有效抑制表達CEACAM1的人肺上皮細胞對TLR2的免疫反應 [12]。此外,CEACAM8的過度表達與吞噬功能障礙密切相關,其中CEACAM8與CD11b比率的改變以及C5a受體C5aR1和C5L2的減少是關鍵因素。實驗還表明,中性粒細胞麻痹程度與CEACAM8受體的表達水平直接相關,這可能為開發新的標志物提供了線索。總體而言,這些發現揭示了CEACAM8在調節免疫反應中的重要性 [13-15]。
3. CEACAM8和疾病研究
3.1 CEACAM8和乳腺癌研究
CEACAM8/CD66b被廣泛認可作為腫瘤相關中性粒細胞(tumor associated neutrophils,TANs)的標志物,可用于監測腫瘤實質中TANs的數量。研究表明,在浸潤性乳腺癌中,CEACAM8/CD66b的表達在擴散組中顯著高于非擴散組,并且侵襲性亞組的生存率更低。CD66b陽性TANs與淋巴結轉移、遠處轉移密切相關。進一步的研究結果顯示CD66b+TANs會影響免疫細胞上PD-L1的表達,二者呈正相關的關系。總之,乳腺癌中存在TANs,且與腫瘤的轉移、復發密切相關,檢測CD66b陽性TANs的密度可能成為預測乳腺癌轉移和復發的潛在指標 [16-17]。
3.2 CEACAM8和宮頸癌研究
宮預癌組織中,中粒細胞的浸潤與患者無復發生存(RFS)密切相關,并且中粒細胞浸潤數量的增加是宮頸癌患者復發的一個獨立危險因素。如前所述,CEACAM8/CD66b是中粒細胞表明的特異性分子標志。一項研究表明,在宮頸癌患者的腫瘤和鄰近基質組織中,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后因素。進一步研究發現,CEACAM8與宮頸癌患者的無復發生存率相關,可以作為宮頸癌患者預后不良的潛在預測因子 [18-19]。
3.3 CEACAM8和膀胱癌研究
有關CEACAM8與膀胱癌之間的關系僅在少量最新的研究中發現,同樣在膀胱癌中,NLR值的變化可以預測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險顯著增高;此外,一項采用ELISA的方法檢測尿液中CEACAM8的含量,測定的結果顯示,在膀胱癌組CEACAM8含量高于非膀胱癌組尿液;不同病理分級的膀胱癌組尿液中CEACAM8濃度不同。研究結果提示,CEACAM8在膀胱癌的診斷、篩查及監測中具有較高的臨床應用價值 [20-22]。
3.4 CEACAM8和非小細胞肺癌研究
在非小細胞肺癌(NSCLC)中,研究發現CEACAM8與疾病特異性生存密切相關,且存在著淋巴結轉移,與預后不良有關。在肺鱗癌(SCC)中,CEACAM8密度升高預示著較好的生存率,而在肺腺癌(ADC)中,卻預示著較差的生存率。對腺癌患者發現,CEACAM8水平與預后不良有關。但在組織間質中,CEACAM8與患者的預后無關。這表明CEACAM8可能對不同類型的非小細胞肺癌產生不同的影響,可能受到腫瘤分期和免疫活性的影響 [23-24]。
3.5 CEACAM8和消化系統腫瘤研究
CD66b陽性中性粒細胞是腫瘤相關中性粒細胞(tumor associated neutrophils,TANs)的標記,TANs在腫瘤微環境中對腫瘤的發生、發展起著至關重要的作用。目前,CEACAM8在多種消化系統腫瘤中,包括胃癌、肝癌、食管癌、口腔癌。例如,胃癌中,CEACAM8的浸潤增加,與胃癌的預后密切相關。高CEACAM8浸潤與腫瘤大小、分化程度和早期TNM分期顯著相關 [25-26];TANs被發現通過GM-CSF-PD-L1途徑抑制T細胞的增殖和功能,促進胃癌的進展 [27-28]。肝癌患者中,CEACAM8在腫瘤周圍組織中的表達密度高于腫瘤內 [29];TANs可能通過分泌BMP2和TGF-β,增加其干細胞特性 [30]。此外,TANs通過IL-7a促進結腸癌細胞的侵襲和遷移 [31]。在食管鱗狀細胞癌患者中,腫瘤內CEACAM8的增加與淋巴結轉移和晚期病理分期密切相關 [32]。
4.CEACAM8的臨床藥物研究前景
CEACAM8作為腫瘤研究的潛在靶點,展現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上市,并有望在感染、皮膚和肌肉骨骼疾病等領域發揮作用,由CIS Bio International SA機構開發。現階段國內外關于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,但表明了該靶點領域的積極研究和開發態勢,這為未來CEACAM8相關藥物的臨床應用提供了新的希望。
為鼎力協助各藥企針對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)活性蛋白產品,助力您在對CEACAM機制方面的研究或其潛在臨床價值的探索。
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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