肝腸鈣粘蛋白CDH17：?jiǎn)慰?、雙抗、CAR T“多管齊下”，胃腸道癌GIC重磅靶點(diǎn)！
日期：2023-03-27 14:58:09
近年來(lái)，胃腸道癌（Gastrointestinal carcinoma, GIC）的靶向治療逐漸成為研究的熱點(diǎn)，越來(lái)越多的靶點(diǎn)被發(fā)現(xiàn)，如EGFR、HER-2、PD-1、CTLA-4、VEGF、DDR1、LAG-3、MUC1、TIGIT、CLDN18.2等。新型靶向治療藥物還在不斷涌現(xiàn)，美國(guó)制藥巨頭勃林格殷格翰Boehringer Ingelheim近期開(kāi)發(fā)了一款創(chuàng)新型基于CDH17的雙特異性抗體CDH17/TRAILR2/（BI 905711），已處于I/II期臨床階段，用于胃癌、胰腺癌、食管癌、膽管癌等胃腸道癌。BI 905711可同時(shí)結(jié)合腫瘤細(xì)胞表面的CDH17和死亡受體TRAILR2，誘導(dǎo)腫瘤細(xì)胞凋亡，對(duì)表達(dá)CDH17的正常細(xì)胞無(wú)損傷。
此外，香港生物制藥公司Arbele的CDH17單抗（ARB102）和雙特異性抗體CDH17/CD3（ARB202），正處于臨床前研究階段，用于治療胰腺癌、膽管癌等實(shí)體瘤。另有研究報(bào)道，一款針對(duì)CDH17的VHH1-CAR T細(xì)胞治療，可特異性根除表達(dá)CDH17的神經(jīng)內(nèi)分泌腫瘤NET、胃癌、胰腺癌以及結(jié)直腸癌細(xì)胞。因此，CDH17作為鈣黏蛋白超家族的新成員，成為開(kāi)發(fā)更安全的實(shí)體瘤免疫療法的重磅靶點(diǎn)，尤其是胃腸道癌！
1. 什么是鈣黏蛋白超家族？
鈣黏蛋白（Cadherins）是一類介導(dǎo)鈣依賴型細(xì)胞間黏附的粘附分子超家族。家族成員眾多，根據(jù)結(jié)構(gòu)不同可分為經(jīng)典鈣黏蛋白（如E-鈣黏蛋白和N-鈣黏蛋白）、橋粒鈣黏蛋白、原鈣黏蛋白、七次跨膜鈣黏蛋白和FAT樣鈣黏蛋白等。它們的主要功能是介導(dǎo)細(xì)胞間Ca2+依賴的同型或異型黏附，而且涉及多種信號(hào)傳導(dǎo)包括Wnt/β-連環(huán)蛋白（β-catenin）、PI3K/Akt、Rho GTPase和NF-κB等通路，從而調(diào)控相互黏附細(xì)胞間的行為 [1-3]。
近年有許多研究表明，鈣黏蛋白的敲低或過(guò)表與多種疾病有關(guān)，如哮喘 [4]、慢性牙周炎 [5]，動(dòng)脈粥樣硬化 [6]、糖尿病 [7]等。在一些腫瘤的侵襲和轉(zhuǎn)移過(guò)程中，某些黏附分子介導(dǎo)的細(xì)胞黏附力降低在腫瘤細(xì)胞生物學(xué)行為中發(fā)揮著關(guān)鍵作用。例如，E-cadherin在多種腫瘤中被認(rèn)為是抑癌基因，而N-Cadherin作為腫瘤侵襲的啟動(dòng)子，被視為腫瘤細(xì)胞獲得侵襲性的必要條件 [8-10]。因此，鈣黏蛋白或可作為藥物靶點(diǎn)，成為治療過(guò)敏、自身免疫病及腫瘤的一種新的手段。
2. 什么是CDH17？
2.1 CDH17的結(jié)構(gòu)
肝腸鈣黏蛋白（liver- intestine cadherin, Cadherin-17，又名CDH17；HPT-1；LI-Cadherin）是近年來(lái)新發(fā)現(xiàn)的一種鈣黏蛋白，其最早于1994年由Dietmar等通過(guò)分子克隆技術(shù)從鼠肝細(xì)胞cDNA文庫(kù)中分析得到的，由于在小鼠僅表達(dá)于肝臟和小腸，故命名為肝腸鈣黏蛋白 [11]。人CDH17基因定位于染色體8q22. 1，其結(jié)構(gòu)與鈣黏蛋白家族成員具有同源性，但CDH17又有以下獨(dú)特的結(jié)構(gòu)：①CDH17的胞外部分含有7個(gè)鈣黏蛋白重復(fù)區(qū)域，而經(jīng)典鈣黏蛋白和橋粒鈣黏蛋白為5個(gè)；②在CDH17氨基末端的細(xì)胞黏附識(shí)別區(qū)內(nèi)，決定細(xì)胞黏附特性的HAV序列由AAL序列代替；③CDH17細(xì)胞質(zhì)尾僅含有20個(gè)氨基酸殘基，經(jīng)典鈣黏蛋白有150-160個(gè)。因此，CDH17被劃分為經(jīng)典鈣黏蛋白的變異體 （圖1） [12-14]。
圖1. CDH17的結(jié)構(gòu) [14]
2.2 CDH17的表達(dá)及功能
CDH17主要表達(dá)于胚胎、成人腸上皮細(xì)胞和部分胰腺導(dǎo)管上皮細(xì)胞，在健康人群肝細(xì)胞、食管上皮細(xì)胞及胃黏膜中幾乎不表達(dá) [15-18]。CDH17在細(xì)胞黏附過(guò)程中充當(dāng)了與鈣黏蛋白同樣重要的角色，CDH17可直接與細(xì)胞支架連接，發(fā)揮其細(xì)胞黏附作用，而經(jīng)典的鈣黏蛋白必須與鏈蛋白結(jié)合形成復(fù)合體才能發(fā)揮其黏附功能 [19-20]。在一些病理情況下，CDH17可表達(dá)于其它組織。目前研究發(fā)現(xiàn)，CDH17在胃癌、結(jié)直腸癌、肝癌、胰腺癌和膽管癌等多種腫瘤組織中均有不同程度的表達(dá)，CDH17的高水平表達(dá)與患者預(yù)后和風(fēng)險(xiǎn)評(píng)估密切相關(guān) [21-23]。
3. CDH17在腫瘤中的作用機(jī)制
CDH17作為鈣黏蛋白超家族中的獨(dú)特一員，在多種疾病中均發(fā)現(xiàn)CDH17的異常表達(dá)。研究揭示CDH17的功能紊亂與腫瘤細(xì)胞的外周浸潤(rùn)及轉(zhuǎn)移關(guān)系密切，對(duì)腫瘤的復(fù)發(fā)及患者的生存率均有影響。然而，目前對(duì)于CDH17與腫瘤相關(guān)作用機(jī)制尚未闡明。
在胃癌中，CDH17高表達(dá)可使E-cadherin/catenin復(fù)合物失去穩(wěn)定而解離 [23]。研究已證實(shí)β-catenin和E-cadherin/catenin復(fù)合物通過(guò)Wnt信號(hào)傳導(dǎo)途徑參與胃癌的發(fā)生發(fā)展 [24-25]。此外，CDH17表達(dá)上調(diào)可影響GSK3的活性，抑制β-catenin-AXIN-APC-GSK3復(fù)合物的形成，穩(wěn)定β-catenin表達(dá)水平，可使其與轉(zhuǎn)錄因子LEF/TCF結(jié)合，誘導(dǎo)Cyclin D1的產(chǎn)生，從而促進(jìn)細(xì)胞增殖，抑制細(xì)胞凋亡（圖2） [26]。有研究認(rèn)為β-半乳糖苷結(jié)合蛋白Galectin-3在胃癌侵襲過(guò)程中的異常表達(dá)對(duì)CDH17起調(diào)控作用，但具體調(diào)控機(jī)制有待進(jìn)一步研究 [27-28]。
圖1. CDH17誘導(dǎo)Cyclin D1的產(chǎn)生 [26]
此外，利用慢病毒介導(dǎo)的microRNA干擾技術(shù)發(fā)現(xiàn)，抑制CDH17表達(dá)后，MMP-2和MMP-9的活性明顯降低，說(shuō)明CDH17表達(dá)上調(diào)可增強(qiáng)MMP-2和MMP-9的活性，導(dǎo)致細(xì)胞外基質(zhì)的降解和重塑，利于腫瘤細(xì)胞的轉(zhuǎn)移 [17]。另有報(bào)道，CDH17通過(guò)整合Ras/Raf/MEK/ERK信號(hào)通路，在胃癌細(xì)胞的增殖和腫瘤的生長(zhǎng)中發(fā)揮重要作用（圖3） [29]。在肝癌中，敲低CDH17表達(dá)，導(dǎo)致Wnt/β-catenin信號(hào)通路失活，腫瘤生長(zhǎng)受到抑制，因此推測(cè)靶向CDH17可滅活Wnt信號(hào)通路并激活抑癌基因，促進(jìn)腫瘤細(xì)胞的凋亡 [30]。
圖3. CDH17介導(dǎo)Ras/Raf/MEK/ERK信號(hào)通路 [29]
4. CDH17在癌癥治療中的作用
CDH17作為新型鈣黏蛋白，在細(xì)胞粘附、細(xì)胞識(shí)別、組織器官的發(fā)育和形態(tài)的維持等方面發(fā)揮重要作用。細(xì)胞間的粘附及運(yùn)動(dòng)能力的失調(diào)是腫瘤發(fā)生發(fā)展的重要機(jī)制之一。近年來(lái)有關(guān)于CDH17與腫瘤關(guān)系的靶向研究越來(lái)越多，主要見(jiàn)于胃癌、肝癌、結(jié)腸癌及胰腺癌等胃腸道惡性腫瘤。
4.1 CDH17和胃癌
CDH17最早被發(fā)現(xiàn)在胃癌中過(guò)度表達(dá)。臨床研究中，對(duì)71例胃癌患者的癌組織和正常胃組織進(jìn)行半定量PCR、免疫組化及Western blot分析發(fā)現(xiàn)CDH17的表達(dá)水平與胃癌的組織學(xué)類型、腫瘤侵襲和淋巴結(jié)轉(zhuǎn)移均呈正相關(guān)。在CDH17過(guò)表達(dá)的BGC-823細(xì)胞株中，胃腺癌的增殖、侵襲及遷移能力增強(qiáng)。RNA干擾CDH17表達(dá)，發(fā)現(xiàn)下調(diào)CDH17能夠抑制MKN-45胃癌細(xì)胞的增殖、粘附和侵襲能力，同時(shí)NF-κB信號(hào)轉(zhuǎn)導(dǎo)通路被抑制、其下游蛋白（VEGF-C和MMP-9）減少 [31-33]。
4.2 CDH17和肝癌
研究表明CDH17與肝癌發(fā)生也有一定的關(guān)系。采用RT-PCR方法對(duì)57例肝癌組織及正常肝組織進(jìn)行分析，結(jié)果顯示CDH17在肝癌組織中的陽(yáng)性表達(dá)率顯著高于正常肝組織，說(shuō)明CDH17與肝癌的發(fā)生有關(guān)，提示CDH17可能作為早期診斷肝癌的腫瘤標(biāo)志物 [34]。對(duì)34例肝內(nèi)膽管癌研究發(fā)現(xiàn)CDH17表達(dá)與腫瘤的分化程度和血管侵犯有關(guān)，敲除CDH17，發(fā)現(xiàn)CDH17表達(dá)下調(diào)，促進(jìn)血管生成有關(guān)的MTF-1和胎盤生長(zhǎng)因子PLGF的表達(dá)，進(jìn)而誘導(dǎo)腫瘤血管生成 [11, 35]。另有研究發(fā)現(xiàn)CDH17的剪接異構(gòu)體和基因多態(tài)性增加正常人群肝癌的發(fā)生風(fēng)險(xiǎn) [26]。
4.3 CDH17和結(jié)腸癌
一項(xiàng)對(duì)45例結(jié)腸癌標(biāo)本的研究發(fā)現(xiàn)，CDH17的表達(dá)下調(diào)與結(jié)腸癌的進(jìn)展及淋巴結(jié)轉(zhuǎn)移有顯著關(guān)系。下調(diào)結(jié)腸癌細(xì)胞中CDH17基因的表達(dá)水平，可以抑制結(jié)腸癌細(xì)胞的侵襲和轉(zhuǎn)移過(guò)程。對(duì)原發(fā)部位的結(jié)腸癌組織和其轉(zhuǎn)移部位的癌組織中CDH17表達(dá)進(jìn)行比較，發(fā)現(xiàn)二者之間的表達(dá)一致。因此，CDH17有望成為結(jié)腸癌轉(zhuǎn)移檢測(cè)的標(biāo)志物 [22, 36]。
4.4 CDH17和食管癌
有研究分析食管癌組織中CDH17的表達(dá)情況與食管癌患者臨床特征的關(guān)系，發(fā)現(xiàn)在分化良好的食管癌組織中有較高的CDH17免疫反應(yīng)，而低分化的食管腺癌組織中CDH17的表達(dá)水平較低或表達(dá)不明顯，證明食管腺癌的CDH17免疫反應(yīng)與患者的臨床特征具有一定的關(guān)系 [37]。在食管鱗狀細(xì)胞癌ESCC中，CDH17 CpG 島甲基化狀態(tài)增強(qiáng)，CDH17表達(dá)水平降低，CDH17 CpG 島的甲基化狀態(tài)與CDH17的表達(dá)呈負(fù)相關(guān) [38-39]。因此，CDH17可成為食管癌治療的新靶點(diǎn)。
4.5 CDH17和胰腺癌
一項(xiàng)對(duì)胰腺導(dǎo)管癌患者CDH17表達(dá)情況的研究發(fā)現(xiàn)，高分化癌中CDH17表達(dá)高于低分化癌者，Kaplan-Meier曲線分析表明CDH17高表達(dá)與患者預(yù)后生存有關(guān) [40]。低CDH17表達(dá)與腫瘤去分化相關(guān)，由于相關(guān)研究甚少，因而CDH17與胰腺癌臨床病理特征及預(yù)后之間的關(guān)系還有待進(jìn)一步探討。
4.6 CDH17和其它癌癥
對(duì)CDH17與卵巢上皮癌關(guān)系的研究發(fā)現(xiàn)，CDH17在低分化、高分期的腫瘤中高表達(dá) [41]。單變量分析表明，CDH17高表達(dá)與預(yù)后不良有關(guān)。在導(dǎo)管內(nèi)乳頭狀粘液性腫瘤（IPMN）中，CDH17誘導(dǎo)IPMN的腸型分化及癌變，隨著IPMN級(jí)別的增高，CDH17與之呈正相關(guān) [42]?？偠灾懤m(xù)的研究提示CDH17可能成為胃癌、肝癌和結(jié)直腸癌等惡性腫瘤診斷和預(yù)后的標(biāo)志物，監(jiān)測(cè)腫瘤的進(jìn)展及復(fù)發(fā)。
5. CDH17的臨床研究前景
目前已有多款基于CDH17的臨床藥物在研（表1），主要用于胃腸道腫瘤治療。其中，3款為雙特異性抗體：ARB-202（CDH17 x CD3），ARB-001.T（CDH17 x CD3），BI-905711（CDH17 x DR5/TRAIL-R2）；1款CAR-T藥物CHM-2101；2款單抗。晚期消化道惡性腫瘤的治療，往往是以化療為基礎(chǔ)的單藥或聯(lián)合治療方案，雖然化療藥物及聯(lián)合治療策略迭代更新，但療效始終未能獲得突破性進(jìn)展。腫瘤靶向免疫治療提供了全新高效、安全、低毒的治療策略，有望改變目前困境?，F(xiàn)有研究成果已表明，靶向干擾CDH17可以抑制腫瘤生長(zhǎng)。因此，CDH17作為新發(fā)現(xiàn)的肝腸鈣黏蛋白，正成為胃腸道腫瘤靶向治療的熱門靶點(diǎn)！
| 藥物 | 靶點(diǎn) | 作用機(jī)制 | 藥物類型 | 在研適應(yīng)癥 | 在研機(jī)構(gòu) | 最高研發(fā)狀態(tài) |
|---|---|---|---|---|---|---|
| ARB-202 | CDH17；CD3 | 免疫調(diào)節(jié)劑； CDH17調(diào)節(jié)劑；CD3調(diào)節(jié)劑 |
雙特異性抗體 | 膽管癌； 結(jié)直腸癌； 胃腸道腫瘤；胃癌；膽道腫瘤；胰腺癌；肝癌；胰腺腺泡癌 |
Arbele | 臨床1期 |
| BI-905711 | DR5；CDH17 | DR5激動(dòng)劑； CDH17調(diào)節(jié)劑 |
雙特異性抗體 | 彌漫性大B細(xì)胞淋巴瘤； 胃癌； 膽管癌；胃腸道腫瘤；胰腺癌；食管癌；膽管癌 |
C.H. Boehringer Sohn AG & Co. KG；勃林格殷格翰（中國(guó)）投資有限公司 Boehringer Ingelheim (China) Investment Co., Ltd.；勃林格殷格翰 Boehringer Ingelheim GmbH |
臨床1期 |
| Anti-CDH17 mAbs (ProAlt) | CDH17 | CDH17調(diào)節(jié)劑 | 單克隆抗體 | 轉(zhuǎn)移性結(jié)直腸癌；轉(zhuǎn)移性黑色素瘤 | 普羅克拉拉生物科學(xué)股份有限公司 Proclara Biosciences, Inc. |
臨床前 |
| ARB-001.M | CDH17 | CDH17拮抗劑 | 雙特異性抗體 | 胃腸道腫瘤 | Arbele | 臨床前 |
| ARB-001.T | CD3；CDH17 | CDH17調(diào)節(jié)劑 | 雙特異性抗體 | 結(jié)直腸癌；肝癌； 胃癌 |
Arbele | 臨床前 |
| ARB-201 | CDH17 | CDH17拮抗劑；CD3抑制劑 | 雙特異性抗體 | 結(jié)直腸癌 | Arbele | 臨床前 |
| CHM-2101 | CDH17 | CDH17調(diào)節(jié)劑；基因轉(zhuǎn)移 | CAR-T | 結(jié)直腸癌； 胃腸道腫瘤； 神經(jīng)內(nèi)分泌腫瘤 |
/ | 臨床前 |
| CHM-2301 | CDH17 | CDH17調(diào)節(jié)劑 | CAR-NK | 實(shí)體瘤 | / | 臨床前 |
| Anti-CDH17-based antibody drug conjugates(ProAlt) | CDH17 | CDH17調(diào)節(jié)劑 | ADC；單克隆抗體 | 結(jié)直腸癌 | Protein Alternatives SL | 藥物發(fā)現(xiàn) |
表1：CDH17的臨床藥物在研
為鼎力協(xié)助各藥企針對(duì)CDH17在胃腸道腫瘤等其它腫瘤在臨床中的研究，CUSABIO推出CDH17活性蛋白產(chǎn)品，（Code：CSB-MP613267HU），助力您在CDH17機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
CDH17 Protein&Human CDH17 Stable Cell Line
參考文獻(xiàn)：
[1] Hulpiau, Paco, Ismail Sahin Gul, and Frans Van Roy. "Evolution of cadherins and associated catenins. "The Cadherin Superfamily: Key Regulators of Animal Development and Physiology (2016): 13-37.
[2] Ma, Yi-Shih, et al. "Bisdemethoxycurcumin suppresses human osteosarcoma U-2 OS cell migration and invasion via affecting the PI3K/Akt/ NF-κB, PI3K/Akt/GSK3β and MAPK signaling pathways in vitro." Oncology Reports 48.6 (2022): 1-10.
[3] Yu, Weina, et al. "Cadherin signaling in cancer: its functions and role as a therapeutic target." Frontiers in oncology 9 (2019): 989.
[4] Türkeli, Ahmet, et al. "Anti-VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E -cadherin/β-catenin signaling axis in experimental asthma models." Experimental and Therapeutic Medicine 22.1 (2021): 1 -9.
[5] Ramesh, P. K. Immunolocalization of Gingival E-Cadherin Expression in Smokers and Non-Smokers with Chronic Periodontitis. diss. KSR Institute of Dental Science and Research, Tiruchengode, 2020.
[6] Harki, Olfa, et al. "Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta." International Journal of Molecular Sciences 23.13 (2022): 7012.
[7] Koziolek, Michael, et al. "Urine E-cadherin: a marker for early detection of kidney injury in diabetic patients." journal of clinical medicine 9.3 (2020 ): 639.
[8] Loh, Chin-Yap, et al. "The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges." Cells 8.10 (2019): 1118.
[9] Yu, Chong, et al. "The lncRNA ZNF667-AS1 Inhibits Propagation, Invasion, and Angiogenesis of Gastric Cancer by Silencing the Expression of N-Cadherin and VEGFA." Journal of Oncology 2022 (2022).
[10] Zhang, Jinyao, et al. "Clinical significance of ALDH1A1 expression and its association with E-cadherin and N-cadherin in resected large cell neuroendocrine carcinoma." Translational Oncology 19 (2022): 101379.
[11] Takamura, Masaaki, et al. "Involvement of liver-intestine cadherin in cancer progression." medical molecular morphology 46 (2013): 1-7.
[12] Ordóñez, Nelson G. "Cadherin 17 is a novel diagnostic marker for adenocarcinomas of the digestive system." Advances in anatomic pathology 21.2 (2014): 131-137.
[13] Gray, Michelle E., and Marcos Sotomayor. "Crystal structure of the nonclassical cadherin-17 N-terminus and implications for its adhesive binding mechanism." Acta Crystallographica Section F: Structural Biology Communications 77.3 (2021): 85-94.
[14] Caporuscio, Christian, et al. "Immunoaffinity enrichment LC-MS/MS quantitation of CDH17 in tissues." Bioanalysis 12.20 (2020): 1439- 1447.
[15] Horsfield, Julia, et al. "Cadherin-17 is required to maintain pronephric duct integrity during zebrafish development." Mechanisms of development 115.1-2 (2002): 15-26.
[16] Huang, Li-Ping, et al. "Up-regulation of cadherin 17 and down-regulation of homeodomain protein CDX2 correlate with tumor progression and unfavorable prognosis in epithelial ovarian cancer." International Journal of Gynecologic Cancer 22.7 (2012).
[17] Jiang, Xiao-jie, et al. "CDH17 alters MMP-2 expression via canonical NF-κB signalling in human gastric cancer." Gene 682 (2019): 92-100.
[18] Liu, Xinjian, et al. "Disruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death." Cancer Letters 454 (2019): 204-214.
[19] Xia, Peng, et al. "Surface-Engineered Extracellular Vesicles with CDH17 Nanobodies to Efficiently Deliver Imaging Probes and Chemo -Photothermal Drugs for Gastric Cancer Theragnostic." Advanced Functional Materials (2022): 2209393.
[20] Xia, Peng, et al. "Surface-Engineered Extracellular Vesicles with CDH17 Nanobodies to Efficiently Deliver Imaging Probes and Chemo -Photothermal Drugs for Gastric Cancer Theragnostic." Advanced Functional Materials (2022): 2209393.
[21] Feng, Zijie, et al. "Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues." Nature Cancer 3.5 (2022): 581-594.
[22] Pei, Xiao Meng, et al. "The diagnostic significance of CDH17-positive circulating tumor cells in patients with colorectal cancer." Expert Review of Molecular Diagnostics just-accepted (2023).
[23] Wu, Cunen, et al. "Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer." International journal of oncology 48.6 (2016): 2236-
[22] 6.
[24] Kaszak, Ilona, et al. "Role of cadherins in cancer-a review." international journal of molecular sciences 21.20 (2020): 7624.
[25] Wang, Qianwen, et al. "MICAL2 contributes to gastric cancer cell migration via Cdc42-dependent activation of E-cadherin/β-catenin signaling pathway ." Cell Communication and Signaling 20.1 (2022): 136.
[26] Lee, Nikki P., et al. "Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma. "Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1806.2 (2010): 138-145.
[27] Huang, Hsiang-Wei, et al. "Association between inflammation and function of cell adhesion molecules influence on gastrointestinal cancer development." Cells 10.1 (2021): 67.
[28] Maher, John, and David M. Davies. "CAR-Based Immunotherapy of Solid Tumours-A Survey of the Emerging Targets. "Cancers 15.4 (2023): 1171.
[29] Lin, Zhaohu, et al. "Targeting cadherin-17 inactivates Ras/Raf/MEK/ERK signaling and inhibits cell proliferation in gastric cancer." PLoS One 9.1 ( 2014): e85296.
[30] Wang, Yonggang, et al. "Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenicity of hepatocellular carcinoma." ploS one 8.9 ( 2013): e72386.
[31] Motoshita, Junichi, et al. "Molecular characteristics of differentiated-type gastric carcinoma with distinct mucin phenotype: LI -cadherin is associated with intestinal phenotype." Pathology international 56.4 (2006): 200-205.
[32] Wang, Jin, et al. "Cadherin-17 induces tumorigenesis and lymphatic metastasis in gastric cancer through activation of NFκB signaling pathway." Cancer biology & therapy 14.3 (2013): 262-270.
[33] Qiu, Hai-bo, et al. "Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling." ploS one 8.3 (2013): e56959.
[34] Su, Min-Cheng, et al. "Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system." Modern Pathology 21.11 (2008): 1379- 1386.
[35] Takamura, Masaaki, et al. "Loss of liver-intestine cadherin in human intrahepatic cholangiocarcinoma promotes angiogenesis by up-regulating metal- responsive transcription factor-1 and placental growth factor." International journal of oncology 36.1 (2010): 245-254.
[36] Harding, J. J., et al. "371P A phase Ia/b, open-label, multicentre study of the TRAILR2 agonist BI 905711 in patients (pts) with advanced gastrointestinal (GI) cancers." Annals of Oncology 33 (2022): S706.
[37] Panarelli, Nicole C., et al. "Tissue-specific cadherin CDH17 is a useful marker of gastrointestinal adenocarcinomas with higher sensitivity than CDX2 ." American journal of clinical pathology 138.2 (2012): 211-222.
[38] Shenoy, U. Sangeetha, et al. "Molecular implications of HOX genes targeting multiple signaling pathways in cancer." Cell biology and toxicology (2022) : 1-30. : 1-30.
[39] Ignatova, Ekaterina Olegovna, et al. "Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma." World Journal of Gastrointestinal Oncology 14.3 (2022): 628.
[40] Liu, Xinjian, et al. "Disruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death." Cancer Letters 454 (2019): 204-214.
[41] Huang, Li-Ping, et al. "Up-regulation of cadherin 17 and down-regulation of homeodomain protein CDX2 correlate with tumor progression and unfavorable prognosis in epithelial ovarian cancer." International Journal of Gynecologic Cancer 22.7 (2012).
[42] Karimi, S. S., T. Valyi-Nagy, and M. F. Gonzalez. "TTF-1 Immunoexpression in Primary Rectal Adenocarcinoma with Brain Metastasis. "American Journal of Clinical Pathology 156.Supplement_1 (2021): S63-S63.
