Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

Table 2

Transgenic, conditional transgenic and carcinogen-inducible models for lung cancer (intratracheal instillation of Ad-Cre virus is required; TAg: simian virus T antigen; CCSP: clara cell secretory protein; SP-C: alveolar type II surfactant protein C; CaBP9K: rat calbindin-D9K; CC10: clara cell 10 kDa secretory protein; CGRP: calcitonin gene-related peptide; rtTA-reverse tetracycline transactivator protein; LSL: lox-stop-lox; hASH1: human achaete-scute homolog 1; EGFR: epidermal growth factor receptor; FGF: fibroblast growth factor).

Model type	Model	Background	Histology	Advantages	Disadvantages	References
Conditional
Oncogenes	LSL K-Ras G12D^*; K-Ras4b G12D^*; K-Ras V12^*	C57BL/6; C57BL/6; C57BL/6	Adenocarcinoma; Adenocarcinoma; Adenocarcinoma	(i) Limited number of cells can be targeted; (ii) Ideal for studying early lung tumor development	(i) Limited metastasis; (ii) (One mutation not sufficient to produce higher grade malignancy); (iii) Gene expression signature slightly different for human K-Ras	[44]; [45]; [46]
	Lkb1: LSL K-Ras^G12D	C57BL/6	Adenocarcinoma/squamous cell carcinoma, large cell carcinoma in some cases	(i) Metastasis; (ii) Limited number of cells can be targeted	(i) Very invasive, often early death of animal	[47]
Growth factor receptors	CCSP-rtTA; Tet-07-EGFR^L858R; CCSP-rtTA; Tet-07-EGFR^DEL	FVB/N; FVB/N	Bronchioalveolar carcinoma; Bronchioalveolar carcinoma	(i) Turning on and off with tetracycline/doxycycline; (ii) Can target expression to pulmonary epithelium; (iii) Resemblance to human adenocarcinoma	(ii) Invasive metastasis within 4 weeks; (iii) More difficult to study early cancer events	[48, 49]
Tumor suppressor genes	Trp53^*; Rb-Trp53^*	C57/BL/6 or 129/Sv wild-type; Athymic BALB/c nu/nu	Adenocarcinoma; SCLC; Neuroendocrine hyperplasia, SCLC	(i) Turning expression on and off; (ii) Metastasis towards similar organs as human SCLC; (iii) Share neuroendocrine features of SCLC	(i) Very invasive, often early death of animal; (ii) More difficult to study early cancer events	[50]
Growth factors	CC10-rtTA; Tet-07-CMV-FGF7	CBA/C57Bl6	Epithelial cell hyperplasia and adenomatous hyperplasia	(i) Hyperplasia disappears when doxycycline removed	(i) Limited metastasis (fails to accurately mimic human adenocarcinoma)	[51]
Transgenic
Transcription; factors	CC10-hASH1; CC10-Tag; CC10-hASH1	FVB; FVB	Hyperplasia and bronchioloaleveolar metaplasia; Adenocarcinoma with neuroendocrine differentiation	(i) Ideal for carcinogenesis and cancer prevention studies and the role of specific oncogene in growth, differentiation, transformation	(i) Measurable in late stage; (ii) Metastasis not uniform; (iii) Response to therapy is typically poor	[52]
Viral oncogenes	SP-C-TAg; CCSP-TAg; CaBP9K-TAg	FVB/N; FVB/N; FVB/N	Adenocarcinoma; Adenocarcinoma; Adenocarcinoma	(i) Typically 100% tumor take; (ii) Ideal for carcinogenesis and cancer prevention studies	(i) Rapid onset and aggressive; (ii) Difficult to examine early events in transformation; (iii) Difficult to detect events independent of oncogene expression	[53]; [54]; [55]
Oncogenes	CGRP-H-Ras	FVB/N	Neuroendocrine hyperplasia and non-neuorendocrine adenocarcinoma	(i) Ideal for carcinogenesis and cancer prevention studies and the role of specific oncogene in growth, differentiation, and transformation	(i) Often early death of animal; (ii) Relationship between Ras isoforms roles in transformation not fully understood	[56]
	SP-C-EML4-ALK	C57BL/6J	Adenocarcinoma	(i) Aggressive presentation; (ii) Ideal for carcinogenesis and cancer prevention studies	(i) Often early death of animal; (ii) No conditional expression	[57]
	SP-C-Myc; CC10-Myc	CD2/F1 (DBA/2 × Balb/C); CD2/F1 (DBA/2 × Balb/C)	Adenocarcinoma; Bronchioloalveolar hyperplasia	(i) Aggressive presentation; (ii) Ideal for carcinogenesis and cancer prevention studies	(i) Do not often metastasize; (ii) Metastasis not uniform; (iii) Response to therapy is typically poor	[58]
	SP-C-cRaf-1; SP-C-c-Raf-1-BxB	C57BL/6 × DBA-2; C57BL/6 × DBA-2	Adenoma; Adenoma	(i) Aggressive presentation; (ii) Ideal for carcinogenesis and cancer prevention studies	(i) Do not often metastasize; (ii) Measurable in late stage; (iii) Metastasis not uniform; (iv) Response to therapy is typically poor	[59]
Growth factors	SP-C-RON	B6C3/F1 hybrid mice (C57BL/6 × C3H, Taconic)	Adenoma and adenocarcinoma	(i) Temporal-spatial expression; (ii) Ideal for carcinogenesis and cancer prevention studies	(i) Metastasis not uniform; (ii) Response to therapy is typically poor	[60]
Growth factor receptors	SP-C-IgEGF; SP-C-cMyc; SpC-IgEGF)	CD2/F1 (DBA/2 × Balb/C); CD2/F1 (DBA/2 × Balb/C)	Alveolar hyperplasia; Bronchioloalvealor Adenocarcinoma	(i) Ideal for carcinogenesis and cancer prevention studies	(i) Metastasis not uniform; (ii) Response to therapy is typically poor	[58]
Carcinogen inducible models	Inoculation Method	Background	Growth Properties	Advantages	Disadvantages	References
Urethane	Intraperitoneal	Inbred (A/J or SWR most widely used)	Adenoma	(i) More likely to accurately predict clinical efficacy of chemotherapeutic agents; (ii) Aggressive; (iii) All tumor stages can be observed	(i) Lethality; (ii) Low metastatic potential; (iii) Varying response to carcinogen; (iv) Low rate of spontaneous development; (v) Long incubation time	[61]
Benzo(a)pyrene	Intraperitoneal		Adenoma			[62, 63]
N-Nitrosobis-(2-cloroethyl) ureas	Topical	Cr:NIH(S)	Adenosquamous carcinoma			[64]
Dimethylhydrazine	Intraperitoneal	A/J	Adenoma			[62]
DiethylInitrosamine	Intraperitoneal		Adenoma
EthylInitrosourea	Intraperitoneal		Adenoma
3-Methylchholanthrene	Intraperitoneal		Adenoma