CEACAM6：CEA家族癌胚抗原細(xì)胞粘附分子，腫瘤新標(biāo)志物或抗癌潛力靶點(diǎn)！
日期：2023-07-19 11:38:48
最近，發(fā)表在《美國(guó)呼吸與重癥監(jiān)護(hù)醫(yī)學(xué)》雜志上的一篇文章揭示，癌胚抗原細(xì)胞粘附分子6（CEACAM6）是血紅素氧酶-1（HO-1）的抑制劑，有助于肺病的發(fā)展 [1]。癌胚抗原細(xì)胞粘附分子（CEACAMs）屬于癌胚抗原CEA基因家族（Carcinoembryonic Antigen Gene Family）。近年來(lái)，CEACAMs是研究較多的一類腫瘤相關(guān)抗原。CEACAMs成員與許多細(xì)胞進(jìn)程有關(guān)，如細(xì)胞黏附、細(xì)胞增殖、血管生成以及腫瘤發(fā)生。
今年的AACR年會(huì)上，賽諾菲（Sanofi）和禮新醫(yī)藥（LaNova Medicines）就分別公布了CEACAM5 ADC和雙抗的研究進(jìn)展。同樣地，CEACAM6作為癌胚抗原基因CEA家族的一員，大量研究表明，CEACAM6也與腫瘤的發(fā)展密切相關(guān)，被認(rèn)為是多個(gè)癌癥的有效臨床生物標(biāo)志物和有前景的治療靶點(diǎn)。因此，CEACAM6有望成為CEA家族下一個(gè)備受關(guān)注的靶點(diǎn)。
1. 什么是癌胚抗原CEA基因家族？
癌胚抗原CEA基因家族（Carcinoembryonic Antigen Gene Family）分兩大類：癌胚抗原相關(guān)細(xì)胞黏附分子（CEA-related Cell Adhesion Molecule，CEACAM）與妊娠特異性糖蛋白（Pregnancy Specific-Glycoprotein，PSG）。PSG家族包括PSG1-11等成員。CEACAM家族共有至少12種CEACAM成員，包括CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8等。CEACAM家族已成為癌癥研究領(lǐng)域中備受關(guān)注的腫瘤相關(guān)抗原。例如，CEACAM1、CEACAM5、CEACAM7已成為重要的藥物靶標(biāo)，CEACAM6在大多數(shù)腫瘤中高表達(dá)，極具有癌基因功能 [1-3]。
2. 什么是CEACAM6？
2.1 CEACAM6的結(jié)構(gòu)
癌胚抗原相關(guān)細(xì)胞黏附分子6（Carcinoembryonic antigen-related cell adhesion molecule 6，CEACAM6），又稱CD66c、NCA-90，屬于免疫球蛋白細(xì)胞粘附分子CEA家族成員之一。CEACAM6通過(guò)糖基磷脂酰肌醇（glycosyl phosphatidylinositol，GPI）連接在細(xì)胞膜上，定位于19號(hào)染色體q13.2，它編碼的蛋白含344個(gè)氨基酸殘基。一般而言，CEACAMs都包含一個(gè)N端的免疫球蛋白可變區(qū)域（IgV）、一個(gè)跨膜區(qū)和一個(gè)細(xì)胞質(zhì)區(qū)域。CEACAMs通過(guò)同種親和性相互作用和/或異種親和性相互作用（如CEACAM6-CEACAM8，CEACAM5-CEACAM6）（圖1）。此外，CEACAMs還充當(dāng)T細(xì)胞、NK細(xì)胞、TLR-2、TLR-4、VEGFR1、VEGFR2、VEGFR3、EGFR、胰島素受體和GM-CSFR等多個(gè)受體的共同作用分子 [2]
圖1. CEACAMs的結(jié)構(gòu)及親和性相互作用 [3]
2.2 CEACAM6的表達(dá)和功能
CEACAM6在正常上皮細(xì)胞、血管內(nèi)皮細(xì)胞（粒細(xì)胞，T細(xì)胞、NK細(xì)胞）中低表達(dá)。相反的，CEACAM6在眾多的惡性腫瘤中表達(dá)較高，包括結(jié)腸、胃、胰腺、乳腺、女性生殖系統(tǒng)、肺等部位腫瘤。大量研究表明，CEACAM6在腫瘤的發(fā)生和發(fā)展過(guò)程中扮演了多個(gè)角色，包括促進(jìn)腫瘤細(xì)胞增殖、遷移和侵襲，抑制腫瘤細(xì)胞凋亡，促進(jìn)血管生成以及誘導(dǎo)耐藥性等方面。在整個(gè)癌胚抗原基因家族中，CEACAM6是許多侵襲性腫瘤的最具特征性的生物學(xué)標(biāo)志。因此，CEACAM6有望作為藥物靶點(diǎn)為腫瘤轉(zhuǎn)移治療帶來(lái)全新策略（圖2） [5-9] 。
圖2. CEACAM6是許多侵襲性腫瘤的最具特征性的生物學(xué)標(biāo)志 [5]
3. CEACAM6在腫瘤中的作用機(jī)制
目前為止，研究學(xué)者發(fā)現(xiàn)CEACAM6信號(hào)途徑與以下方面相關(guān)：細(xì)胞分化和三維組織機(jī)構(gòu)改變、腫瘤的侵襲與轉(zhuǎn)移、血管生成、失巢凋亡以及腫瘤抑制。最新研究顯示，CEACAM6參與PI3K/Akt信號(hào)通路，并在調(diào)節(jié)CD8+T細(xì)胞對(duì)腫瘤的免疫反應(yīng)中扮演關(guān)鍵角色 [10-12]。盡管CEACAM6在腫瘤的發(fā)展中具有重要作用，但其詳細(xì)機(jī)制，特別是上游調(diào)控因子，仍需進(jìn)一步研究。
相關(guān)研究結(jié)果提示，CEACAM6的過(guò)度表達(dá)引發(fā)了細(xì)胞外基質(zhì)（Extracellular Matrix，ECM）的改組和重建，并激活了腫瘤微環(huán)境（Tumor Microenvironment，TME）。CEACAM6信號(hào)的增加導(dǎo)致Src活性增強(qiáng)，從而促使自分泌和胰島素樣生長(zhǎng)因子IGF-1R的激活，進(jìn)而調(diào)節(jié)PI3K/Akt通路，并增加IGF-I的旁分泌刺激。IGF-I的增加會(huì)導(dǎo)致基質(zhì)金屬蛋白酶2 （MMP-2）的加工，進(jìn)而改變ECM，促進(jìn)惡性TME的形成 [10]。
CEACAM6在細(xì)胞表面聚集后，與小窩蛋白-1（Cav1）結(jié)合，磷酸化其底物FAK，增強(qiáng)Src的活性，提高細(xì)胞對(duì)失巢凋亡的抗性。此外，在TME中，TGF-β與其II型受體（TGFBR2）結(jié)合后，可以增加I型受體（TGFBR1）的異四聚狀態(tài)，并通過(guò)激活I(lǐng)型受體來(lái)磷酸化SMAD3。磷酸化的SMAD3與SMAD4形成復(fù)合物，并遷移到細(xì)胞核，與基因啟動(dòng)子結(jié)合以激活靶基因的表達(dá)，其中包括CEACAM6。此外，TGF-β還可以通過(guò)其受體，激活其它信號(hào)傳導(dǎo)途徑，以在AKT/PI3K信號(hào)傳導(dǎo)途徑之外進(jìn)行信號(hào)傳遞 （圖3）[10]。
圖3. CEACAM6在腫瘤中的作用機(jī)制 [10]
4. CEACAM6在癌癥中的作用
4.1 CEACAM6和膽管癌
膽管癌是一種惡性腫瘤，來(lái)源于肝臟內(nèi)或外的膽管上皮細(xì)胞。對(duì)肝內(nèi)膽管癌患者進(jìn)行CEACAM6表達(dá)分析發(fā)現(xiàn)，CEACAM6高表達(dá)與淋巴結(jié)轉(zhuǎn)移和腫瘤分期密切相關(guān)，且患者生存期較短。實(shí)驗(yàn)中發(fā)現(xiàn)TFK-1細(xì)胞系的CEACAM6表達(dá)高于Hucc-T1和MEC細(xì)胞系，暗示其與吉西他濱（Gemcitabine）耐藥性增加有關(guān)。
進(jìn)一步研究發(fā)現(xiàn)，CEACAM6過(guò)表達(dá)可導(dǎo)致腫瘤增殖、侵襲能力增強(qiáng)，以及吉西他濱化療耐藥性增加，而siRNA沉默CEACAM6表達(dá)則增加了癌細(xì)胞對(duì)吉西他濱化療的敏感性 [13-14, 17]。這表明CEACAM6在評(píng)估和治療侵襲性腫瘤方面具有重要價(jià)值，可能成為臨床上的藥物靶點(diǎn)！
4.2 CEACAM6和胰腺癌
胰腺導(dǎo)管腺癌（PDA）中過(guò)表達(dá)的CEACAM6與腫瘤抗失巢凋亡（Anoikis resistance）有關(guān)。Anoikis是一種在細(xì)胞脫離細(xì)胞外基質(zhì)后誘導(dǎo)的程序性細(xì)胞死亡。抗失巢凋亡（Anoikis resistance）是腫瘤轉(zhuǎn)移的關(guān)鍵機(jī)制，它指癌細(xì)胞通過(guò)調(diào)節(jié)代謝適應(yīng)無(wú)黏附環(huán)境存活，并擴(kuò)散到遠(yuǎn)處器官 [15]。
通過(guò)siRNA沉默CEACAM6可逆轉(zhuǎn)PDA的抗腫瘤失巢凋亡過(guò)程。針對(duì)CEACAM6的siRNA提高了細(xì)胞對(duì)半胱天冬酶介導(dǎo)的腫瘤失巢凋亡，并減少了AKT磷酸化的敏感性。在裸鼠的原位移植模型中，抑制CEACAM6降低了胰腺癌細(xì)胞系的轉(zhuǎn)移能力。在PDA中，若CEACAM6被激活并過(guò)表達(dá)，可能使腫瘤細(xì)胞對(duì)吉西他濱藥物產(chǎn)生抵抗，減弱治療效果 [15-18]。
4.3 CEACAM6和乳腺癌
CEACAM6在乳腺癌細(xì)胞中高表達(dá)，可有效促進(jìn)CD34陽(yáng)性的血管生成，且與疾病進(jìn)展和三苯氧胺（Tamoxifen）耐藥性相關(guān)。CEACAM6的表達(dá)也可以作為HER2陽(yáng)性乳腺癌治療效果的指標(biāo)。CEACAM6低表達(dá)提示乳腺癌對(duì)曲妥珠單抗（Trastuzumab）敏感，而過(guò)度表達(dá)則表示耐藥 [19-20]。因此，CEACAM6的表達(dá)或可用于識(shí)別乳腺癌高?；颊?，并根據(jù)其腫瘤生物學(xué)特征進(jìn)行個(gè)體化調(diào)整治療。
4.4 CEACAM6和結(jié)腸癌
CEACAM6從正常組織、結(jié)腸腺瘤到結(jié)腸癌的表達(dá)逐漸上升，尤其在結(jié)腸癌中。應(yīng)用免疫組化技術(shù)檢測(cè)結(jié)腸癌中CEACAM6的表達(dá)，其結(jié)果表明CEACAM6可以誘導(dǎo)細(xì)胞遷移，使腫瘤細(xì)胞具有侵襲性。在結(jié)腸癌分期中，CEACAM6及FOXP3的表達(dá)與CD3+、CD4+、CD8+、CD45RO+T細(xì)胞浸潤(rùn)密度相反，III、IV期結(jié)腸癌較I、II期，CEACAM6表達(dá)明顯增高。此外，CEACAM6和FOXP3的高表達(dá)具有抑制細(xì)胞毒和記憶T細(xì)胞在結(jié)腸癌組織中的浸潤(rùn)作用 [6, 21-22]。
4.5 CEACAM6和胃癌
CEACAM6能夠增加胃癌細(xì)胞的體外遷移和侵襲能力，但其單抗可以很大程度上抑制這種變化。此外，CEACAM6能夠抑制胃癌細(xì)胞的凋亡和失巢凋亡。在裸鼠體內(nèi)，與陰性對(duì)照組相比，過(guò)表達(dá)CEACAM6，C-SRC蛋白活性升高，形成明顯的肝臟、肺臟等臟器轉(zhuǎn)移灶，提示CEACAM6能通過(guò)增加原癌基因C-SRC的表達(dá)，參與胃癌的發(fā)生發(fā)展 [2, 23-24]。
4.6 CEACAM6和其它癌癥
CEACAM6在許多其他癌癥，如肺癌 [25]，甲狀腺癌 [26]，腎細(xì)胞癌 [27 ]、B淋巴細(xì)胞白血病 [28-29]、多發(fā)性骨髓瘤 [30-31]中，CEACAM6也被證明扮演了很重要的角色。采用單克隆抗體或使用RNA干擾技術(shù)阻斷CEACAM6在骨髓瘤細(xì)胞表面的表達(dá)，可以恢復(fù)T細(xì)胞對(duì)惡性漿細(xì)胞的反應(yīng) [31]。
在B細(xì)胞急性淋巴母細(xì)胞淋巴瘤中，CEACAM6通過(guò)增加caspase活性以及上調(diào)Akt細(xì)胞生存途徑來(lái)增強(qiáng)失巢凋亡作用 [29]。在肺癌細(xì)胞中，生長(zhǎng)抑制因子-5（inhibitor of growth 5，ING5）可通過(guò)增加CEACAM6表達(dá)從而促進(jìn)EMT的發(fā)生 [32]。在腎細(xì)胞癌中，CEACAM6可能是通過(guò)ERK/AKT通路，導(dǎo)致C-MYC、Survivin和MMP-9等相關(guān)功能蛋白活化起到其促癌作用 [27]。
5. CEACAM6的在研臨床藥物
來(lái)自Pharmsnap的數(shù)據(jù)顯示，已有多款靶向CEACAM6的臨床在研藥物，用于胰腺癌、乳腺癌、肺癌、結(jié)直腸癌等 （表1）。其中，Immunomedics公司的Sulesomab（硫索單抗）已批準(zhǔn)上市。事實(shí)上，以往多項(xiàng)研究表明靶向CEACAM6提供了治療腫瘤的潛力方法，例如，一項(xiàng)針對(duì)CEACAM6的抗體-藥物結(jié)合物的研究調(diào)查了抗CEACAM6-maytansinoid（DM1）免疫結(jié)合物在PDA小鼠異種移植模型中的功效 [33]。
此外，使用人源化小鼠單克隆抗體的單鏈可變片段（scFv），通過(guò)靶向CEACAM6的特定位點(diǎn)誘導(dǎo)PDA細(xì)胞凋亡，并且該效果不依賴于抗體的細(xì)胞毒性，能夠以較低的劑量與常規(guī)化療方法聯(lián)合使用，同時(shí)保持對(duì)腫瘤細(xì)胞的凋亡效果 [34-35]?？傮w而言，隨著對(duì)CEA家族成員的研究不斷深入，除了經(jīng)典的CEACAM5外，針對(duì)CEACAM6進(jìn)行靶向治療可能為實(shí)體腫瘤和血液惡性腫瘤的新型聯(lián)合療法提供新的方向！
| 藥物 | 靶點(diǎn) | 作用機(jī)制 | 在研適應(yīng)癥 | 藥物最高研發(fā)狀態(tài)（全球） | 藥物類型 | 在研機(jī)構(gòu) |
|---|---|---|---|---|---|---|
| Sulesomab （硫索單抗） | CEACAM6 | CEACAM6抑制劑 | 骨髓炎 | 批準(zhǔn)上市 | 放射標(biāo)記抗體； 診斷用放射藥物； 單克隆抗體 |
免疫醫(yī)學(xué)股份有限公司 （Immunomedics, Inc.） |
| L-DOS-47 | CEACAM6 | CEACAM6抑制劑 | 胰腺癌； 肺癌； 非小細(xì)胞肺癌 |
臨床2期 | 融合蛋白 | 赫利克斯生物藥品公司 （Helix BioPharma Corp.） |
| NEO-201 | CEACAM5 + CEACAM6 | CEACAM5拮抗劑、CEACAM6抑制劑 | 頭頸部鱗狀細(xì)胞癌； 非小細(xì)胞肺癌； 宮頸癌； 肺腺癌； 乳腺癌； 結(jié)直腸癌； 胰腺癌 |
臨床1/2期 | 單克隆抗體 | Precision Biologics, Inc. |
| EBC-129 | CEACAM6 | CEACAM6抑制劑 | 實(shí)體瘤 | 臨床1期 | ADC | 新加坡實(shí)驗(yàn)藥物研發(fā)中心 |
| PM-4008 | CD3 + CEACAM6 | CEACAM6抑制劑 | 腫瘤 | 臨床前 | 三特異性抗體 | 普米斯生物技術(shù)（珠海）有限公司 （Biotheus Inc.） |
| DNP-002 | CEACAM6 | CEACAM6抑制劑 | 實(shí)體瘤 | 臨床前 | 小分子化藥 | 狄諾納有限公司 （DiNonA, Inc.） |
| BAY-1834942(Deutsches Krebsforschungszentrum, Dkfz) | CEACAM6 | CEACAM6抑制劑 | 腫瘤 | 臨床前 | 單克隆抗體 | 拜耳股份有限公司（Bayer AG）；德國(guó)癌癥研究公共權(quán)益基金會(huì)（German Cancer Research Center） (Deutsches Krebsforschungszentrum, DKFZ) |
| ICT-109 | CEACAM5 + CEACAM6 | CEACAM5拮抗劑、CEACAM6抑制劑 | / | 藥物發(fā)現(xiàn) | 單克隆抗體 | / |
表1：CEACAM6的在研臨床藥物
為鼎力協(xié)助各藥企針對(duì)CEACAM6在腫瘤等疾病在臨床中的研究，CUSABIO推出CEACAM6活性蛋白產(chǎn)品（Code: CSB-MP005166HU），助力您在CEACAM6機(jī)制方面的研究或其潛在臨床價(jià)值的探索。（點(diǎn)擊查看CEACAM6系列產(chǎn)品：CEACAM6蛋白 ；CEACAM6抗體）
CEACAM6蛋白
The purity was greater than 95% as determined by SDS-PAGE. (Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human CEACAM6 at 2 μg/mL can bind Human CEACAM8 (CSB-MP005168HU), the EC50 is 144.7-223.8 ng/mL.
Immobilized Human CEACAM6 at 2 μg/mL can bind Anti- CEACAM5/CEACAM6 recombinant antibody (CSB-RA005165MA2HU), the EC50 is 0.9430-1.377 ng/mL.
CEACAM5/CEACAM6重組抗體
CEACAM5/CEACAM6 Recombinant Monoclonal Antibody (Code: CSB-RA005165MA2HU)
Measured by its binding ability in a functional ELISA. Immobilized Human CEACAM5 at 2μg/mL can bind Anti-CEACAM5/CEACAM6 recombinant antibody (CSB-RA005165MA2HU), the EC50 is 0.4282-1.151 ng/mL.
Measured by its binding ability in a functional ELISA. Immobilized Human CEACAM6 (CSB-MP005166HU) at 2 μg/mL can bind Anti- CEACAM5/CEACAM6 recombinant antibody, the EC50 is 0.9430-1.377 ng/mL.
參考文獻(xiàn)：
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