模式动物疾病模型在结直肠癌医学研究中的应用进展

doi:10.12300/j.issn.1674-5817.2023.076

摘要/Abstract

摘要：

结直肠癌（colorectal cancer，CRC）是全球第三大常见的恶性肿瘤，最新统计数据显示CRC发病人数占全球癌症病例总数的10%，为癌症死亡的第二大主因。CRC是一种高度异质性疾病，其发生发展是由多个基因表达突变引起功能异常或表观遗传变化所驱动，并经过不同途径发展为肿瘤。由于遗传、环境、伦理以及患者本身个体差异等复杂因素限制了CRC在人体上的研究，动物疾病模型已成为研究该疾病必不可少的工具，在预防、治疗、临床前研究和基础性研究中发挥重要作用。CRC疾病模型种类丰富，其中小鼠模型应用最为广泛，根据造模方式不同分为自发性、化学诱导、移植瘤和基因工程小鼠模型，各有其不同特点及应用前景。本文重点阐述CRC小鼠模型，同时介绍大鼠、实验猪、斑马鱼等动物模型的最新研究进展，以期为CRC动物模型的选择和应用提供参考。

关键词: 结直肠癌, 动物模型, 移植瘤模型, 化学诱导模型, 基因工程模型

Abstract:

Colorectal cancer (CRC) is the third most common malignant tumor in the world. The latest statistics show that CRC accounts for 10% of all cancer cases worldwide and is the second leading cause of cancer deaths. CRC is a highly heterogeneous disease, the development of which is driven by functional abnormalities or epigenetic changes caused by multiple gene expression mutations, and there are different pathways that lead to tumor formation. Complex factors such as genetics, environment, ethics, and individual differences of patients themselves limit the study of CRC in humans, so the disease animal models have become an indispensable tool for the study of CRC, and play an important role in prevention, treatment, preclinical research and basic research. There are various types of CRC animal models, of which mouse models are the most widely used. According to different model establishing methods, the models are divided into spontaneous, chemically induced, transplanted tumor and genetic-engineering mouse models. Different models have different characteristics and application prospects. In this study, we focus on these mouse models of CRC in detail, and introduce the latest research progress of CRC models in rats, experimental pigs and zebrafish, to provide reference for the selection and application of animal models of CRC.

Key words: Colorectal cancer, Animal model, Transplanted tumor model, Chemical induced model, Genetic-engineering model

中图分类号:

R-332

陈艳娟, 沈如凌. 模式动物疾病模型在结直肠癌医学研究中的应用进展[J]. 实验动物与比较医学, 2023, 43(5): 512-523.

Yanjuan CHEN, Ruling SHEN. Progress in the Application of Animal Disease Models in the Medical Research on Colorectal Cancer[J]. Laboratory Animal and Comparative Medicine, 2023, 43(5): 512-523.

图/表 2

参考文献 81

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肿瘤细胞系名称 Tumor cell line names	来源 Source	MSI状态 MSI status	突变基因 Mutant gene	参考文献 Reference
HCT116	人源	MSI	KRAS、PIK3CA	[40]
LIM1215	人源	-	-	-
HT29	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
SW480	人源	MSS	APC、KRAS、TP53	[40]
SW620	人源	MSS	APC、KRAS、TP53	[40]
HCT15	人源	MSI	APC^[41]、KRAS、PIK3CA、TP53	[40]
Colo320DM	人源	MSS	APC、TP53	[40]
Co115	人源	MSI	BRAF、PTEN	[40]
CaCo2	人源	MSS	APC、TP53	[40]
WiDr	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
COLO205	人源	MSS^[42]	BRAF^[43]	-
DLD-1	人源	MSI	KRAS、PIK3CA、TP53	[40]
CT26	BALB/c小鼠	MSS^[44]	KRAS^[45]	[44-45]
MC38	C57BL/6J小鼠	MSI^[44]	-	[44]

肿瘤细胞系名称 Tumor cell line names	来源 Source	MSI状态 MSI status	突变基因 Mutant gene	参考文献 Reference
HCT116	人源	MSI	KRAS、PIK3CA	[40]
LIM1215	人源	-	-	-
HT29	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
SW480	人源	MSS	APC、KRAS、TP53	[40]
SW620	人源	MSS	APC、KRAS、TP53	[40]
HCT15	人源	MSI	APC^[41]、KRAS、PIK3CA、TP53	[40]
Colo320DM	人源	MSS	APC、TP53	[40]
Co115	人源	MSI	BRAF、PTEN	[40]
CaCo2	人源	MSS	APC、TP53	[40]
WiDr	人源	MSS	APC、BRAF、PIK3CA、TP53	[40]
COLO205	人源	MSS^[42]	BRAF^[43]	-
DLD-1	人源	MSI	KRAS、PIK3CA、TP53	[40]
CT26	BALB/c小鼠	MSS^[44]	KRAS^[45]	[44-45]
MC38	C57BL/6J小鼠	MSI^[44]	-	[44]

模型分类 Model classification	诱导方式 Induction mode	动物品种品系 Species	涉及化合物及细胞系 Relates to compounds and cell lines	突变基因Mutant gene	局限性 Limitation	有无转移 Metastasis	应用范围 Application	参考文献 Reference
自发性肠道肿瘤模型	自发性	C57BL、 BALB/c-nu小鼠	-	-	发生率极低	无	老龄化研究	[16-17]
自发性肠道肿瘤模型	单纯饮食诱导	C57BL/6小鼠	-	-	诱导时间长	无	饮食对肿瘤的影响	[18]
化合物诱导模型	致癌物诱导模型	F344大鼠	PhIP、IQ	Apc	PhIP诱导未发现Kras和Tp53基因突变	无	化合物预防和风险因素识别	[81]
		F344大鼠	MNNG、MNU	Apc、Kras	引起多器官恶性肿瘤	-		[24]
		F344大鼠	DMBA	Apc、Kras	引起多器官恶性肿瘤	-		[22]
		F344大鼠、A/J小鼠	DMH、AOM	Apc、Kras	诱导时间长，极少转移	无		[27]
		F344大鼠、ICR小鼠	AOM/DSS	Apc、Kras	极少转移	无		[24, 31]
移植瘤模型	CDX模型	BALB/c、C57BL/6小鼠	C T26、MC38	-	不能准确反映人类CRC发病过程	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[33]
移植瘤模型	PDX模型	免疫缺陷小鼠、人源化小鼠	HCT116、HT29、LIM1215、SW480、SW620	-	建立周期长（2～4个月），成本高，过程中存在发生突变的可能	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[38-39]
基因工程模型	Apc突变相关模型	Apc^min小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移	研究特定基因，化合物预防，风险因素识别	[56]
		Apc^Δ716、Apc^Δ14和Apc^1638N小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移		[7, 29]
		Apc CKO/LSL-Kras小鼠	-	Apc、Kras		肝转移		[60]
		Apc^minSmad3^-/-、Apc^∆716/+Smad4^+/-小鼠	-	Apc、Smad3或者Smad4	寿命短，缺乏转移	缺乏转移		[29]
		Apc^fl/+p53^fl/+、Apc^fl/+p53^R172H/+小鼠	-	Apc、p53	缺乏转移	无		[57]
		iKAP小鼠	-	Apc、Kras、p53	寿命短	肝和肺		[61]
	其他基因突变模型	Kras^G12DTgfbr2^-/-小鼠	-	Kras、Tgfbr2	-	12%～25%的小鼠肿瘤转移到局部淋巴结、胰腺或肺		[62]
	其他基因突变模型	Vil-Cre；Braf^V637E/+；p53^{LSL-R172H/+-/-}小鼠	-	BRAF、p53	-	15%转移到淋巴结和肺部		[63]
	HNPCC	Mlh1^-/-、Msh2^-/-、Msh6^-/-小鼠	-	-	过早死于侵袭性淋巴瘤	无		[21]
	IBD-CRC	Il-10^-/-、Il-2^-/-、Muc2^-/-小鼠	-	-	较低肿瘤发生率，受肠道菌群影响	无		[64-65]
	Apc突变模型	Pirc:F344/NTac-Apcam¹¹³⁷大鼠	-	Apc	4个月自发肠道腺瘤，缺乏转移	无	化合物预防	[69-70, 63]
	Apc突变模型	KAD大鼠	-	Apc	不自发肿瘤，经过AOM/DSS联合诱导发生肿瘤	无	化合物预防	[71]
	Apc突变模型	Apc¹³¹¹猪	-	Apc	肠道肿瘤为腺瘤	无	转化医学研究	[73]

模型分类 Model classification	诱导方式 Induction mode	动物品种品系 Species	涉及化合物及细胞系 Relates to compounds and cell lines	突变基因Mutant gene	局限性 Limitation	有无转移 Metastasis	应用范围 Application	参考文献 Reference
自发性肠道肿瘤模型	自发性	C57BL、 BALB/c-nu小鼠	-	-	发生率极低	无	老龄化研究	[16-17]
自发性肠道肿瘤模型	单纯饮食诱导	C57BL/6小鼠	-	-	诱导时间长	无	饮食对肿瘤的影响	[18]
化合物诱导模型	致癌物诱导模型	F344大鼠	PhIP、IQ	Apc	PhIP诱导未发现Kras和Tp53基因突变	无	化合物预防和风险因素识别	[81]
		F344大鼠	MNNG、MNU	Apc、Kras	引起多器官恶性肿瘤	-		[24]
		F344大鼠	DMBA	Apc、Kras	引起多器官恶性肿瘤	-		[22]
		F344大鼠、A/J小鼠	DMH、AOM	Apc、Kras	诱导时间长，极少转移	无		[27]
		F344大鼠、ICR小鼠	AOM/DSS	Apc、Kras	极少转移	无		[24, 31]
移植瘤模型	CDX模型	BALB/c、C57BL/6小鼠	C T26、MC38	-	不能准确反映人类CRC发病过程	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[33]
移植瘤模型	PDX模型	免疫缺陷小鼠、人源化小鼠	HCT116、HT29、LIM1215、SW480、SW620	-	建立周期长（2～4个月），成本高，过程中存在发生突变的可能	可发生转移	发现新的肿瘤标志物，测试化合物，手术模型	[38-39]
基因工程模型	Apc突变相关模型	Apc^min小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移	研究特定基因，化合物预防，风险因素识别	[56]
		Apc^Δ716、Apc^Δ14和Apc^1638N小鼠	-	Apc	缺乏转移，肿瘤集中在小肠	缺乏转移		[7, 29]
		Apc CKO/LSL-Kras小鼠	-	Apc、Kras		肝转移		[60]
		Apc^minSmad3^-/-、Apc^∆716/+Smad4^+/-小鼠	-	Apc、Smad3或者Smad4	寿命短，缺乏转移	缺乏转移		[29]
		Apc^fl/+p53^fl/+、Apc^fl/+p53^R172H/+小鼠	-	Apc、p53	缺乏转移	无		[57]
		iKAP小鼠	-	Apc、Kras、p53	寿命短	肝和肺		[61]
	其他基因突变模型	Kras^G12DTgfbr2^-/-小鼠	-	Kras、Tgfbr2	-	12%～25%的小鼠肿瘤转移到局部淋巴结、胰腺或肺		[62]
	其他基因突变模型	Vil-Cre；Braf^V637E/+；p53^{LSL-R172H/+-/-}小鼠	-	BRAF、p53	-	15%转移到淋巴结和肺部		[63]
	HNPCC	Mlh1^-/-、Msh2^-/-、Msh6^-/-小鼠	-	-	过早死于侵袭性淋巴瘤	无		[21]
	IBD-CRC	Il-10^-/-、Il-2^-/-、Muc2^-/-小鼠	-	-	较低肿瘤发生率，受肠道菌群影响	无		[64-65]
	Apc突变模型	Pirc:F344/NTac-Apcam¹¹³⁷大鼠	-	Apc	4个月自发肠道腺瘤，缺乏转移	无	化合物预防	[69-70, 63]
	Apc突变模型	KAD大鼠	-	Apc	不自发肿瘤，经过AOM/DSS联合诱导发生肿瘤	无	化合物预防	[71]
	Apc突变模型	Apc¹³¹¹猪	-	Apc	肠道肿瘤为腺瘤	无	转化医学研究	[73]

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