Research progress on relationship between receptor tyrosine kinase-like orphan receptor 1 and signaling pathway of tumor cells
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摘要:
受体酪氨酸激酶样孤儿受体1(ROR1)属于受体酪氨酸激酶(RTKs)大家族的一种表面跨膜蛋白, 在调控骨骼与神经的发育, 细胞迁移与细胞极性中有重要作用。ROR1在正常组织中表达低或不表达, 在肿瘤组织中高表达。研究发现ROR1能与配体螯合来调节Wnt等多种细胞信号通路, 从而在多种疾病尤其是恶性肿瘤中发挥重要的作用, 逐渐成为恶性肿瘤的治疗靶标。本文就ROR1在恶性肿瘤中与细胞信号通路相互作用及靶向ROR1肿瘤免疫治疗的研究进展进行综述, 为肿瘤临床治疗策略的制订提供参考。
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关键词:
- 受体酪氨酸激酶样孤儿受体1 /
- 恶性肿瘤 /
- 细胞内信号通路 /
- 肿瘤免疫治疗
Abstract:Receptor tyrosine kinase-like orphan receptor 1 (ROR1) belongs to the transmembrane protein family of receptor tyrosine kinases (RTKs), and plays an important role in regulating the development of bones and nerves as well as cell migration and cell polarity. ROR1 is expressed at low or no levels in normal tissues, but is highly expressed in tumor tissues. Researches have found that ROR1 can regulate various cell signaling pathways such as Wnt through chelating with ligand, thereby playing an important role in multiple diseases, especially malignant tumors, and gradually become a therapeutic target for malignant tumors. This paper reviewed the interactions between ROR1 and cell signaling pathways in malignant tumors, the researches on targeted ROR1 tumor immunotherapy in order to provide references for clinical therapeutic strategies for tumors.
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由输卵管因素导致的不孕占不孕症患者总数的28%~42%, 盆腔炎是最常见的输卵管损伤因素，长期炎症未得到及时有效治疗最终导致输卵管积水和/或输卵管梗阻[1]。多数盆腔炎患者无明显临床症状，经常会在子宫输卵管造影检查时被发现患有输卵管炎[2-3]。输卵管因素不孕症可通过药物保守治疗或者手术治疗恢复输卵管功能，达到自然受孕的目的，也可直接采用体外受精-胚胎移植(IVF-ET)方式助孕[4-5]。目前研究[6]认为，输卵管积水会降低IVF-ET的妊娠率，助孕前行输卵管积水预处理可以达到积极有效的治疗效果。本研究对3组输卵管因素患者IVF-ET结局进行分析，探讨输卵管因素对IVF-ET的影响，以期为临床提供参考依据。
1. 资料与方法
1.1 一般资料
回顾性分析2013年1月—2020年1月江苏省徐州市中心医院生殖医学中心收治的首次接受IVF-ET的419例(419个周期)女性患者的临床资料。纳入标准: 年龄18~40岁，首次接受新鲜周期胚胎移植患者; 基础性激素中卵泡刺激素(FSH) < 10 IU/mL者; 获卵数>5个者; 子宫输卵管造影明确诊断为输卵管积水、输卵管梗阻或输卵管通而不畅者。排除标准: 一侧或双侧卵巢有卵巢手术、化疗、放疗史或其他卵巢疾病治疗史者; 多囊卵巢综合征者; 子宫内膜异位症者; 子宫内膜炎者; 子宫腺肌病者; 男方睾丸或附睾穿刺取精后卵胞浆内单精子显微注射(ICSI)治疗者。
根据输卵管不同情况将患者分为输卵管炎组(213例, A组)、输卵管积水组(81例, B组)和输卵管梗阻组(125例, C组)。输卵管积水表现为子宫输卵管造影中显示输卵管扭曲、狭窄和扩张交替出现，盆腔弥散欠佳; 输卵管梗阻是子宫输卵管造影中出现输卵管的突然狭窄、切割样改变及远端输卵管显影中断; 输卵管积水表现为输卵管全程显影并见伞端增粗扩张，盆腔内无造影剂弥散。单侧或双侧非梗阻性输卵管炎症归为A组，单侧或双侧输卵管积水者归为B组，单侧或双侧输卵管梗阻者归为C组。A组和C组均不包扩输卵管积水患者。
1.2 方法
① 促性腺激素释放激素激动剂(GnRH-a)长方案: 3组患者均自月经第3天口服短效避孕药(OC), 月经第21天起给予GnRH-a(达菲林，法国), 0.1 mg/d, 3 d后减量至0.05 mg/d。14 d后，根据年龄、体质量指数(BMI)和早卵泡期超声监测到的窦卵泡数，给予重组人促卵泡激素(rFSH, 果纳芬，默克雪兰诺，德国)150~225 U/d启动，随后促排剂量根据超声监测卵泡发育和血清雌二醇(E2)水平进行调整。当至少有2~3个卵泡平均直径大于18 mm时，应用重组人绒毛膜促性腺激素0.25 mg(艾泽，默克雪兰诺，德国)进行扳机, 36~38 h后行经阴道超声引导下取卵。②胚胎质量评判: 取卵后行常规IVF或ICSI治疗。受精后16~18 h, 倒置显微镜下确认受精情况; 受精后44~46 h, 观察受精卵卵裂情况; 受精后66~68 h, 根据伊斯坦布尔共识对胚胎情况分为4级(本中心评估标准略有改变): 1级，均匀和规则的卵裂球，碎片率 < 5%; 2级，稍不均匀或不规则的卵裂球，碎片率5%~15%; 3级，明显不均匀卵裂球，碎片率>15%~25%; 4级，严重不均匀的卵裂球，碎片率>25%。D3高评分胚胎被定义为1~2级, 7~9个卵裂球。一般认为，1~3级胚胎、碎片率 < 25%、卵裂球≥6个为可移植胚胎。③胚胎移植及后续治疗: 根据女性年龄，子宫内膜厚度，患者有无腹胀等不适症状，可用胚胎的数量和质量以及患者夫妇双方的意愿，在取卵后第3天移植2枚胚胎，移植当天采用黄体酮针60 mg进行黄体支持, 14 d后定量检测血清人绒毛膜促性腺激素(β-HCG)水平以确定妊娠情况，移植28~35 d行经阴道超声检查确定是否为临床妊娠。
1.3 体外受精结局鉴定标准
正常受精率=正常受精时卵细胞内出现两个原核(2PN)及受精后16~18 h可见双极体未见原核(2PB)卵子数/IVF加精卵子数×100%。卵裂率=D2卵裂胚胎数/正常受精卵子数×100%。D3高评分胚胎率=高评分胚胎数/D2卵裂胚胎数×100%。种植率=孕囊数/移植胚胎数(当胎囊数大于移植胚胎数时，移植胚胎数即植入胚胎数)×100%。活产率=活产周期/胚胎移植周期×100%。异位妊娠率=宫外孕周期数/临床妊娠周期总数×100%。临床妊娠率=临床妊娠数/移植周期数×100%。
1.4 统计学处理
采用SPSS 19.0进行统计学分析。计量资料采用均值±标准差表示，分类数据采用频率和百分比表示，采用卡方检验或Fisher精确检验比较类别变量，采用单因素方差分析(ANOVA)比较连续变量。3组样本量的事后效能检验值大于80%。P < 0.05为差异有统计学意义。
2. 结果
2.1 一般资料比较
3组年龄、基础激素水平、BMI、不孕年限、抗缪勒氏管激素(AMH)等一般情况比较，差异无统计学意义(P>0.05)。见表 1。
表 1 3组基线资料情况比较(x±s)指标 A组(n=213) B组(n=81) C组(n=125) 年龄/岁 30.7±5.3 31.4±4.5 31.5±4.8 BMI/(kg/m2) 22.6±4.1 22.3±3.9 22.2±4.0 不孕年限/年 4.0±1.5 3.8±2.0 3.7±2.3 FSH/(mIU/mL) 6.9±2.2 6.7±2.6 6.7±2.4 LH/(mIU/mL) 4.7±2.0 4.5±1.8 4.4±1.3 E2/(pg/mL) 34.6±18.2 34.4±19.0 38.8±30.6 PRL/(ng/mL) 18.1±5.5 17.6±6.7 17.7±6.3 CA125/(IU/mL) 12.5±5.8 12.6±5.5 12.8±5.7 TSH/(mIU/L) 1.5±1.1 1.8±1.2 1.8±1.6 AMH/(ng/mL) 3.4±1.8 3.6±1.4 3.6±1.7 移植胚胎数/个 1.9±0.4 1.9±0.5 1.9±0.5 移植高评分胚胎数/个 1.4±0.9 1.3±0.8 1.4±0.7 移植日内膜厚度/mm 10.5±4.0 10.2±3.4 10.2±4.1 卵巢刺激天数/d 9.9±1.5 9.9±1.6 10.2±1.6 BMI: 体质量指数; FSH: 卵泡刺激素; LH: 黄体生成素;
E2: 雌二醇激素; PRL: 催乳素; CA125: 癌抗原125;
TSH: 促甲状腺激素; AMH: 抗缪勒氏管激素。2.2 2组IVF-ET结果比较
B组和A组获卵数比较，差异无统计学意义(P>0.05); B组和A组获卵数均低于C组，但无统计学意义(P>0.05)。3组受精率、卵裂率、出生体质量比较，差异无统计学意义(P>0.05)。A组D3高评分胚胎率较B组和C组患者低，差异有统计学意义(P < 0.05)。C组种植率、临床妊娠率高于B组和A组，差异有统计学意义(P < 0.05)。B组异位妊娠发生率高于A组和C组，差异有统计学意义(P < 0.05), 但C组和A组异位妊娠发生率比较，差异无统计学意义(P>0.05)。B组和A组活产率低于C组，差异有统计学意义(P < 0.05), 但A组与B组活产率比较，差异无统计学意义(P>0.05), 见表 2、3。
表 2 3组获卵数、活产情况及出生体质量比较(x±s)[n(%)]组别 n 获卵数/个 活产情况 出生体质量/g A组 213 12.5±4.1 97(45.5)* 2 648.1±569.5 B组 81 12.2±4.0 31(38.3)* 2 748.4±588.6 C组 125 13.9±4.2 72(57.6) 2 758.6±590.3 IVF-ET: 体外受精-胚胎移植。与C组比较, *P < 0.05。 表 3 3组患者IVF-ET情况比较[n(%)]指标 A组 B组 C组 IVF加精卵子数/个 2 662 987 1 736 受精情况 2 049(77.0) 758(76.8) 1 323(76.2) 正常受精卵子数/个 2 049 758 1 323 卵裂情况 2 015(98.3) 746(98.4) 1 310(99.0) D2卵裂胚胎数/个 2 015 746 1 310 D3高评分胚胎情况 751(37.3) 322(43.2)* 562(42.9)* 移植胚胎数/个 404 154 237 种植情况 135 (33.4)# 49(31.8)# 101(42.6) 移植周期数/个 213 81 125 临床妊娠情况 121(56.8)# 41(50.6)# 87(69.6) 临床妊娠周期总数/个 121 41 87 异位妊娠情况 2(1.7)△ 5(12.2) 1(1.1)△ 与A组比较, *P < 0.05; 与C组比较, #P < 0.05;
与B组比较, △P < 0.05。3. 讨论
长期输卵管炎症可导致输卵管扭曲、伞端粘连、积水和/或输卵管梗阻[7]。宫腔镜或腹腔镜下输卵管积水的栓塞治疗与输卵管切除治疗在辅助生殖技术中具有同样的治疗效果[8]。本研究中，输卵管梗阻患者种植率、临床妊娠率和活产率显著高于输卵管积水和输卵管炎症患者，但3组受精率差异无统计学意义(P>0.05), 提示输卵管炎症、输卵管积水和输卵管梗阻对卵母细胞受精能力的影响无差异。虽然3组年龄、激素水平、BMI、不孕年限等基线资料比较，差异无统计学意义(P>0.05), 但输卵管炎症和输卵管积水患者的获卵率低于输卵管梗阻患者，提示输卵管炎症、积水可能会降低卵巢反应性，降低IVF-ET的妊娠率。
在高评分胚胎率方面，输卵管炎患者低于输卵管积水和输卵管梗阻患者，但输卵管积水组和输卵管梗阻组比较，差异无统计学意义(P>0.05), 结果提示输卵管炎对卵母细胞的质量存在负相关影响。输卵管炎与盆腔微环境中炎症介质因子的表达调节密切相关[9], 这些细胞因子以自分泌和旁分泌的形式刺激细胞增殖，扩大局部免疫反应造成卵巢的反应性降低[10-12]。因此，本研究输卵管炎组高评分胚胎率和种植率低于输卵管梗阻组，可能是由于颗粒细胞和卵泡细胞中炎性因子水平增加及炎性因子激发的某些免疫反应影响了卵母细胞质量。
本研究输卵管积水组的D3高评分胚胎率高于输卵管炎组，提示输卵管积水对卵母细胞质量的影响较小。目前输卵管积水的形成机制不明，细菌和衣原体感染是引起积水的2大主要因素，沙眼衣原体感染后常导致宿主对感染产生免疫应答反应而引起输卵管积液[13]。
早期胚胎发育对环境中各种物质能量供应及生长因子具有较高要求，输卵管积液中葡萄糖及蛋白含量降低, pH值及碳酸氢根浓度升高，钾离子、钙离子浓度降低以及输卵管积液中衣原体感染率增加均会对IVF-ET产生负向影响[14-16]。本研究结果显示，输卵管积水组的临床妊娠率和活产率低于输卵管梗阻组，但2组D3高评分胚胎方面，差异无统计学意义(P>0.05)。输卵管积水可能一方面通过炎症因子刺激子宫肌层收缩减少子宫内膜血流，另一方面通过破坏局部内膜影响宫腔内环境，降低子宫内膜的容受性影响胚胎着床，进而影响IVF-ET的治疗结局。研究表明，输卵管积水对胚胎发育过程存在剂量依赖，高浓度输卵管积液会对胚胎发育产生不利影响。输卵管积水患者输卵管上皮细胞囊性纤维化跨膜转导调控子表达增高, IVF-ET中卵泡刺激素会增加细胞内环磷酸腺苷浓度，从而激活氯离子通道蛋白，促进输卵管积水增多，而大量输卵管积液返流入宫腔会使胚胎离开宫腔的机会增多，影响胚胎着床，导致异位妊娠率增高[17-18]。IVF-ET中大量输卵管积水返流入宫腔的概率较输卵管炎和输卵管梗阻患者大，也验证了本研究中输卵管积水组异位妊娠发病率高于其他2组的结果。
综上所述，输卵管炎对IVF-ET治疗存在不良影响，与输卵管梗阻组比较，输卵管炎组患者的高评分胚胎率、种植率和临床妊娠率降低，因此在IVF-ET治疗前积极治疗输卵管炎十分必要。
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