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摘要:
TGF-β信号通路影响肿瘤的多种生物学过程，包括肿瘤增殖、侵袭、转移、血管生成和免疫逃逸。目前已有多种靶向该通路的药物处在临床试验阶段，这些药物涉及TGF-β的生成、活化和信号转导三方面。基于当前的证据，TGF-β单药对晚期实体瘤的治疗效果有限。联合治疗在临床试验中展现出具有应用前景的结果，如联合PD-1抗体、联合放化疗等。新的联合治疗方式也在临床研究中崭露头角，如TGF-βBRⅡ修饰的CAR-T治疗等。本文系统梳理了靶向TGF-β的治疗策略，以期为靶向TGF-β的药物研发提供依据和思路。
Abstract:The TGF-β signaling pathway affects various biological processes of cancers, including proliferation, invasion, metastasis, angiogenesis, and immune escape. Currently, multiple drugs targeting this pathway are in clinical trial stage, which involve three aspects of TGF-β, namely, production, activation, and signal transduction. Based on current evidence, the therapeutic effect of TGF-β monotherapy on advanced solid tumors is limited. Combination therapies that show promising results include combination with PD-1 antibodies, and combination with radiotherapy and chemotherapy. New combination therapies, such as CAR-T therapy modified with TGF-βRⅡ, are also emerging in clinical research. This article systematically reviews the therapeutic strategies targeting TGF-β to provide research basis and ideas for the development of drugs targeting the TGF-β pathway.
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Key words:
- TGF-β /
- Cancer /
- Therapeutic strategies /
- Tumor immune environment
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0 引言
结直肠癌是全球第三大最常见的恶性肿瘤，也是癌症相关死亡的第二大原因[1]，给卫生保健系统带来了沉重的负担。结直肠息肉是正常结直肠黏膜表面的突出物，组织学上可分为腺瘤性和非腺瘤性息肉，而“正常黏膜-腺瘤-癌”路径被认为是结直肠癌的主要演变过程，涉及组织细胞内驱动突变的逐渐累积，最终发生癌变[2-3]。结直肠腺瘤性息肉进展为结直肠癌的发病率和死亡率显著增加，因此，通过结肠镜检查对腺瘤性息肉进行早期筛查并行内镜下切除可有效降低结直肠癌的发生风险。中老年人围手术期并发症发生率及死亡率增加，术后恢复期长，对生活质量影响大[3-4]，在早期发现和早期治疗结直肠腺瘤性息肉方面需更为重视。本文以我院就诊的中老年结直肠息肉患者为研究对象，评估不同病理类型息肉的临床和内镜特征，分析社会人口学、生活饮食习惯、临床病史、内镜特点等指标对腺瘤性息肉的影响，最终确定结直肠腺瘤性息肉的危险因素，以对高危人群进行充分的监测，为提高结直肠癌的早期筛查及诊疗水平提供依据。
1 资料与方法
1.1 研究人群
数据来源于2023年4月至2024年6月在首都医科大学附属北京友谊医院消化内镜中心行结肠镜检查及内镜下治疗的中老年患者，对以上患者进行相关问卷调查、实验室和结肠镜检查及息肉病理数据收集。本研究已经本院伦理委员会审核批准（2022-P2-401-01），所有患者均签署知情同意书。纳入标准：（1）年龄>45岁；（2）均自愿行结肠镜检查，且经病理检查确诊；（3）临床资料均完整无缺项。排除标准：（1）既往行下消化道外科手术；（2）妊娠患者；（3）正在参加其他临床研究，会影响本研究的搜集指标者。
1.2 数据收集
结肠镜检查前患者配合医生认真完成调查问卷的填写，内容包括患者姓名、年龄、性别、生活饮食习惯、慢性病史、简易精神状态评价量表（Mini-mental state examination, MMSE）等。身高和体重在内镜检查前规范测量，体重指数（Body mass index, BMI）由体重（kg）除以身高（m）的平方得出。高血压由患者自我报告的高血压病史确定。甘油三酯、血糖等空腹血液生化指标由医院检验科分析得出。益生菌是指食品中的活的有益微生物，包括双歧杆菌、乳杆菌、酪酸梭菌、布拉酵母菌、肠球菌、地衣芽孢杆菌和蜡样芽孢杆菌等。
所有患者均由经验丰富的消化内科医生使用电子结肠镜进行检查。患者在检查前一天分次口服聚乙二醇电解质散溶液以行肠道准备，检查时协助患者保持左侧卧位、双膝屈曲。结肠镜检查时准确记录息肉的数量、部位、形态、大小等信息，镜下取活检或根据患者实际情况选择合理治疗方案切除息肉，包括圈套器摘除、内镜下黏膜切除术、内镜黏膜下剥离术等。将息肉组织标本进行合理固定后送往病理科行病理检查，由经验丰富的病理科医生进行诊断。根据病理特点，炎性息肉、增生性息肉被定义为非腺瘤性息肉，而锯齿状腺瘤、管状腺瘤、管状绒毛状腺瘤、绒毛状腺瘤被定义为腺瘤性息肉。
1.3 统计学方法
数据采用R软件（4.2.2版）进行分析。正态分布的连续变量用均值和标准差表示，非正态分布的连续变量用中位数和四分位间距表示，计数资料数据用数量和百分比表示。多独立样本的组间比较时，分类变量采用卡方检验，正态分布的连续变量需采用方差分析，非正态分布的连续变量需采用Kruskal-Wallis检验。通过单因素及多因素Logistic回归分析对年龄、性别、BMI、生活饮食习惯、实验室数据、结肠镜病理检查结果等因素计算比值比（Odds ratio, OR）和95%CI。双侧P<0.05表示差异有统计学意义。
2 结果
2.1 结直肠息肉临床病理特征分析
共有1 527例45岁以上的结直肠息肉患者被纳入分析。经病理确诊，其中炎性息肉264例（17.3%），增生性息肉262例（17.2%），锯齿状腺瘤39例（2.6%），管状腺瘤926例（60.6%），管状绒毛状腺瘤33例（2.2%），绒毛状腺瘤3例（0.2%）。各病理分组下的临床和病理特征见表1，其中年龄、BMI、吸烟史、饮酒史、益生菌服用习惯、MMSE评分、息肉部位、息肉形态、息肉长径在各组间的差异均有统计学意义（均P<0.05）。
表 1 不同病理类型的结直肠息肉患者的基线特征Table 1 Baseline characteristics of patients with colorectal polyps of different pathological typesTotal Inflammatory
polypsHyperplastic
polypsSerrated
adenomasTubular
adenomasTubular villous
adenomasVillous
adenomasP Number 1 527 264 262 39 926 33 3 Gender(n(%)) 0.141 Male 826(54.1) 127(48.1) 142(54.2) 24(61.5) 518(55.9) 14(42.4) 1(33.3) Female 701(45.9) 137(51.9) 120(45.8) 15(38.5) 408(44.1) 19(57.6) 2(66.7) Age, mean(SD) 69.85(5.23) 69.29(4.49) 69.28(5.65) 69.44(4.45) 70.15(5.35) 71.03(4.58) 71.00(0.00) 0.047 BMI, mean(SD)(kg/m2) 24.44(3.34) 24.19(3.41) 24.33(3.06) 23.54(3.05) 24.68(3.38) 21.87(2.61) 24.03(1.86) <0.001 Smoking history(n(%)) 0.001 No 1117 (73.1)217(82.2) 202(77.1) 28(71.8) 643(69.4) 25(75.8) 2(66.7) Yes 410(26.9) 47(17.8) 60(22.9) 11(28.2) 283(30.6) 8(24.2) 1(33.3) Drinking history(n(%)) <0.001 No 1086 (71.1)216(81.8) 195(74.4) 29(74.4) 621(67.1) 23(69.7) 2(66.7) Yes 441(28.9) 48(18.2) 67(25.6) 10(25.6) 305(32.9) 10(30.3) 1(33.3) Hypertension(n(%)) 0.277 No 797(52.2) 143(54.2) 152(58.0) 19(48.7) 466(50.3) 15(45.5) 2(66.7) Yes 730(47.8) 121(45.8) 110(42.0) 20(51.3) 460(49.7) 18(54.5) 1(33.3) Triglyceride, mean(SD)
(mmol/L)1.44(0.76) 1.47(0.78) 1.47(0.79) 1.31(0.67) 1.44(0.75) 1.24(0.59) 1.69(0.40) 0.469 Fasting blood glucose,
mean(SD)(mmol/L)5.67(1.33) 5.64(1.46) 5.85(1.19) 6.01(1.50) 5.62(1.31) 5.47(1.43) 5.66(0.16) 0.081 Eat cereal(n(%)) 0.835 ≥4 times per week 572(37.5) 95(36.0) 96(36.6) 17(43.6) 350(37.8) 12(36.4) 2(66.7) <4 times per week 955(62.5) 169(64.0) 166(63.4) 22(56.4) 576(62.2) 21(63.6) 1(33.3) Eat fresh vegetables (n(%)) 0.686 ≥4 times per week 1412 (92.5)250(94.7) 240(91.6) 35(89.7) 853(92.1) 31(93.9) 3(100.0) <4 times per week 115(7.5) 14(5.3) 22(8.4) 4(10.3) 73(7.9) 2(6.1) 0(0.0) Eat fresh fruits(n(%)) 0.72 ≥4 times per week 1223 (80.1)213(80.7) 215(82.1) 32(82.1) 736(79.5) 24(72.7) 3(100.0) <4 times per week 304(19.9) 51(19.3) 47(17.9) 7(17.9) 190(20.5) 9(27.3) 0(0.0) Eat probiotics(n(%)) 0.027 ≥4 times per week 1363 (89.3)242(91.7) 223(85.1) 36(92.3) 834(90.1) 26(78.8) 2(66.7) <4 times per week 164(10.7) 22(8.3) 39(14.9) 3(7.7) 92(9.9) 7(21.2) 1(33.3) MMSE score, mean(SD) 28.76(2.21) 28.96(1.60) 28.99(1.61) 28.33(2.04) 28.70(2.38) 27.67(4.45) 28.00(1.00) 0.008 Polyp location(n(%)) <0.001 Ileocecal region 98(6.4) 21(8.0) 11(4.2) 7(17.9) 55(5.9) 3(9.1) 1(33.3) Ascending colon 279(18.3) 52(19.7) 29(11.1) 12(30.8) 179(19.3) 7(21.2) 0(0.0) Transverse colon 429(28.1) 62(23.5) 50(19.1) 9(23.1) 301(32.5) 7(21.2) 0(0.0) Descending colon 214(14.0) 39(14.8) 26(9.9) 5(12.8) 141(15.2) 3(9.1) 0(0.0) Sigmoid colon 321(21.0) 46(17.4) 91(34.7) 2(5.1) 172(18.6) 9(27.3) 1(33.3) Rectum 186(12.2) 44(16.7) 55(21.0) 4(10.3) 78(8.4) 4(12.1) 1(33.3) Polyp shape(n(%)) <0.001 Pedicled polyp 141(9.2) 20(7.6) 19(7.3) 2(5.1) 91(9.8) 9(27.3) 0(0.0) Sessile polyp 544(35.6) 59(22.3) 77(29.4) 16(41.0) 377(40.7) 14(42.4) 1(33.3) Flat polyp 790(51.7) 173(65.5) 162(61.8) 13(33.3) 433(46.8) 7(21.2) 2(66.7) Laterally
developmental polyp52(3.4) 12(4.5) 4(1.5) 8(20.5) 25(2.7) 3(9.1) 0(0.0) Polyp diameter,
mean(SD)(mm)7.54(6.80) 7.25(8.44) 5.24(2.68) 12.49(10.47) 7.87(6.41) 13.43(11.41) 4.67(2.89) <0.001 2.2 腺瘤性息肉的危险因素分析
在Logistic回归模型中，性别、年龄、BMI、吸烟史、饮酒史、高血压史、空腹甘油三酯水平、空腹血糖水平、饮食习惯、MMSE评分、息肉的病理特点均纳入分析范围。单变量回归分析显示，年龄更大、吸烟史、饮酒史、高血压病史及息肉长径是腺瘤性息肉的危险因素，而高MMSE评分（更良好的认知水平）、息肉部位为直肠及息肉形态为平坦型为保护性因素。经多变量模型调整后，结果显示：年龄更大（OR: 1.024，95%CI: 1.001~1.048，P=0.044）、BMI水平更高（OR: 1.046，95%CI: 1.008~1.087，P=0.020）和有吸烟史（OR: 1.493，95%CI: 1.035~2.158，P=0.032）的患者的结直肠息肉为腺瘤的风险显著升高，而高MMSE评分所代表的具有更好认知功能的患者结直肠息肉为非腺瘤性的可能性更大（OR: 0.929，95% CI: 0.871~0.984，P=0.017）。在息肉病理特征方面，病变部位在直肠（OR: 0.396，95%CI: 0.229~0.677，P=0.001）、平坦型（OR: 0.531，95%CI: 0.342~0.810，P=0.004）或侧向发育型（OR: 0.306，95%CI: 0.135~0.698，P=0.005）的息肉更多为非腺瘤性息肉，随着息肉大小的增加，病理为腺瘤性息肉的可能性显著增加（OR: 1.063，95%CI: 1.035~1.095，P<0.001），见表2。
表 2 腺瘤组和非腺瘤组单因素和多因素Logistic回归分析Table 2 Univariate and multivariate logistic regression analyses of adenoma and non-adenoma groupsVariables Univariable model Multivariable model OR 95%CI P OR 95%CI P Gander (Female) 0.834 0.675-1.031 0.094 1.168 0.892-1.530 0.258 Age 1.032 1.011-1.053 0.002 1.024 1.001-1.048 0.044 BMI 1.026 0.994-1.060 0.118 1.046 1.008-1.087 0.020 Smoking history 1.700 1.325-2.193 <0.001 1.493 1.035-2.158 0.032 Drinking history 1.726 1.354-2.212 <0.001 1.264 0.881-1.815 0.204 Hypertension 1.269 1.027-1.570 0.028 0.896 0.700-1.145 0.379 Triglyceride (mmol/L) 0.929 0.811-1.067 0.294 0.875 0.746-1.028 0.101 Fasting blood glucose (mmol/L) 0.936 0.866-1.012 0.096 0.944 0.867-1.029 0.182 Eat cereal (<4 times per week) 0.928 0.745-1.154 0.502 0.888 0.695-1.132 0.339 Eat fresh vegetables (<4 times per week) 1.166 0.781-1.774 0.461 1.653 1.003-2.769 0.052 Eat fresh fruits (<4 times per week) 1.132 0.868-1.483 0.365 0.887 0.634-1.245 0.485 Eat probiotics (<4 times per week) 0.874 0.627-1.229 0.433 0.800 0.555-1.160 0.234 MMSE score 0.922 0.865-0.975 0.008 0.929 0.871-0.984 0.017 Polyp location (Ascending colon) 1.185 0.717-1.935 0.501 1.216 0.721-2.027 0.457 Polyp location (Transverse colon) 1.372 0.847-2.191 0.191 1.368 0.828-2.231 0.214 Polyp location (Descending colon) 1.111 0.661-1.849 0.686 1.194 0.693-2.039 0.518 Polyp location (Sigmoid colon) 0.651 0.401-1.042 0.078 0.686 0.412-1.126 0.141 Polyp location (Rectum) 0.426 0.253-0.706 0.001 0.396 0.229-0.677 0.001 Polyp shape (Sessile polyp) 1.147 0.750-1.729 0.519 1.141 0.725-1.772 0.562 Polyp shape (Flat polyp) 0.519 0.346-0.765 0.001 0.531 0.342-0.810 0.004 Polyp shape (Laterally spreading polyp) 0.860 0.434-1.753 0.671 0.306 0.135-0.698 0.005 Polyp diameter 1.063 1.040-1.090 <0.001 1.063 1.035-1.095 <0.001 3 讨论
结直肠癌是世界发病率和死亡率最高的消化系统恶性肿瘤[1]，腺瘤性息肉被认为是大多数结直肠癌的前驱病变[5]，早期识别腺瘤性息肉并行内镜下治疗是预防结直肠癌的重要措施。本研究分析了中老年结直肠腺瘤性和非腺瘤性息肉患者的人口统计学、生活习惯、临床病史、实验室检查、内镜特征等信息。结果表明，年龄更大、体重指数更高、吸烟、息肉大小是腺瘤性息肉的独立危险因素，而患者认知功能更好、病变部位在直肠和平坦型或侧向发育型形态的息肉病理更可能为非腺瘤性。
本研究未发现腺瘤与非腺瘤患者间的性别差异。年龄是结直肠腺瘤发生的重要危险因素，结直肠息肉和结直肠癌的发病率一般随年龄增长而增加[6]。对无症状人群进行的结肠镜筛查研究表明，50岁人群的腺瘤患病率为25%~30%[7]。尸检研究发现，70岁人群的这一比例高达50%[8]，而20多岁或30岁人群的这一比例只有1%~4%[9]。结肠镜检查是检测结直肠息肉和结直肠癌最有效的方式，基于多项研究结果，美国癌症协会指南建议根据患者的偏好从45岁开始进行结肠镜筛查，以早期发现结直肠癌和结直肠腺瘤息肉[10]。因此，我们将研究人群的年龄限制在45岁及以上的中老年人，结果表明，与先前的结果一致，年龄越大的结直肠息肉患者越容易发生腺瘤的病理改变。
既往多项研究报道，肥胖与结直肠腺瘤的发生和复发密切相关[11-12]，而减重可以有效降低腺瘤发生风险[13]。本研究结果也表明，代表超重和肥胖的高BMI水平会增加腺瘤发生的风险。这其中的机制尚不明确，可能与肥胖伴随的胰岛素抵抗通过胰岛素和胰岛素样生长因子轴导致有丝分裂和抗凋亡信号转导异常相关。此外，肥胖也反映了一种慢性低度炎性反应状态，从而增加息肉癌变的风险[14]。
吸烟是导致结直肠癌的公认的主要风险因素。此前多项研究发现，吸烟与腺瘤性息肉以及晚期肿瘤如浸润性结直肠癌之间存在密切关联[12]，这与我们的研究结果类似。每日吸烟数量、吸烟时间与结直肠息肉的风险存在剂量-反应关系[15]。烟草中含有多种致癌物质，先前的研究揭示了一些吸烟与结直肠腺瘤发生的潜在机制，如相关基因的甲基化减少[16]、致癌物代谢酶的基因变异[17]、DNA修复基因EXO1和ATM的多态性[18]、错配修复酶的突变[19]、XPC的多态性[20]等。一项荟萃分析表示，酒精与结直肠腺瘤的风险增加有关，这种关联似乎在欧洲的研究中更为显著[21]。本研究并没有显示酒精对结直肠腺瘤发生的影响，这可能与不同地区研究人群的基因和生活方式差异相关。
本研究结果表明，MMSE代表的认知功能状态与是否为腺瘤性息肉有显著相关性，而因果关系尚不明确，既往暂无分析认知功能与结直肠腺瘤发生的相关性研究。但已有多项研究表示，结直肠癌、炎性反应性肠病等与认知功能和精神疾病有密切关联，微生物群-肠-脑轴可能在其中起重要作用，肠道微生物群组成失调和肠道屏障功能异常可能参与了重要的病理机制[22]。这一点，未来还需要大样本量的随机对照试验来证实。
除人群特征外，息肉特征也会影响腺瘤发生的风险。既往有多项研究报道息肉的大小为结直肠息肉恶性肿瘤的独立预测因子[23-24]。直径为1厘米的腺瘤发生腺癌的风险为1%，直径为1~2厘米的腺瘤为10%，而直径大于2厘米的腺瘤发生腺癌的风险为50%[25]。本研究结果表明，息肉大小也为腺瘤病理的独立危险因素。因此，对于直径较大的息肉更应警惕，尽早行内镜下切除以避免发生癌变。本研究中，息肉为平坦型和侧向发育型时较带蒂息肉病理为腺瘤的风险更低，发展为结直肠癌的可能性更小，这与既往的研究结果一致[26]。但近年来，有学者认为扁平息肉可能通过特殊的机制发生进展期肿瘤性病变[27]，因此扁平状息肉的潜在恶变可能也需警惕。本研究结果提示位于直肠的息肉多为非腺瘤性息肉。既往研究认为右半结肠腺瘤发生率更高，结直肠癌的发生位置也逐渐向右侧转移[28]，这可能与肠内容物在右半结肠中停留时间较长，使致癌物质和炎性反应介质长时间刺激而发展成腺瘤性息肉相关[29-30]，但本研究未发现腺瘤性息肉在结肠各节段发生率的差异。
本研究也存在一些局限性。首先，研究是单中心横断面研究，样本量有限，纳入分析的变量不够全面，可能会遗漏重要的指标。其次，患者的吸烟史、饮酒史、饮食习惯和高血压病史等数据来自自我报告的问卷调查，可能会造成回忆偏倚，从而对结果产生潜在影响。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：张剑、吕滨月：撰写及修改论文赵 晓：确定论文主题和撰写思路、修改论文 -
表 1 靶向TGF-β药物的特点和临床研究
Table 1 Features and clinical trials of drugs targeting TGF-β
Class Targets Representative
drugsRepresentative clinical trials Features Activation GARP Livmoniplimab Urothelial carcinoma (ORR 18%), Phase 1[15] Selective inhibition of TGF-β1 produced
by GARP positive TregsLTGF-β SRK-181 Renal cell carcinoma (ORR 20%),
Head and neck squamous cell
carcinoma (ORR 33%), Phase 1[17]Targeting latent TGF-β to inhibit
the activation of TGF-βSignal
transductionTGF-β Fresolimumab Breast cancer (ORR 0), Phase 2[18] Selectively or non-selectively neutralizing
TGF-β moleculesNIS793 Solid tumor (OOR 2.5%), Phase 1[19] SAR439359 Solid tumor (OOR 8%), Phase 1[20] TGFβRⅠ Galunisertib Rectum cancer (pCR 32%), Phase 2[25]
Liver cancer (median OS 18.8 months), Phase1[21]Blocking intracellular TGFβRI signaling
through small molecule inhibitorsVactosertib Colon rectum cancer (ORR 15.2%), Phase1[29] TGFβRⅡ IMC-TR1 Solid tumor, severe adverse events, Phase 1[30] Blocking the signal transduction of
transmembrane TGFβRⅡ using antibodiesBispecific
antibodyPD-L1/
TGF-βM7824 Solid tumor, limited efficacy, Phase 3[36] Simultaneously targeting PD-L1 and
TGF-βSHR-1701 Unresectable NSCLC (pCR 26%), Phase 2[37] Cell therapy TGFβRⅡ CAR-T Liver cancer (ORR 50%), Phase 1[40] Specifically regulating the TGFβ signaling
of CAR-T or TCR-T cellsTCR-T NCT06218914 (ongoing), Phase 1[42] Notes: NSCLC: non-small-cell lung cancer; ORR: objective response rate; pCR: Pathological complete response. 
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