BioMed Research International / 2015 / Article / Tab 2

Review Article

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 typeModelBackgroundHistologyAdvantagesDisadvantagesReferences

Conditional
OncogenesLSL 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-RasG12DC57BL/6Adenocarcinoma/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 receptorsCCSP-rtTA; Tet-07-EGFRL858R
CCSP-rtTA; Tet-07-EGFRDEL
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 genesTrp53*
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 factorsCC10-rtTA; Tet-07-CMV-FGF7CBA/C57Bl6Epithelial 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 oncogenesSP-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]

OncogenesCGRP-H-RasFVB/NNeuroendocrine 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-ALKC57BL/6JAdenocarcinoma(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 factorsSP-C-RONB6C3/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 receptorsSP-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 modelsInoculation MethodBackgroundGrowth PropertiesAdvantagesDisadvantagesReferences

UrethaneIntraperitonealInbred (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)pyreneIntraperitonealAdenoma[62, 63]
N-Nitrosobis-(2-cloroethyl) ureasTopicalCr:NIH(S)Adenosquamous carcinoma[64]
DimethylhydrazineIntraperitonealA/JAdenoma [62]
DiethylInitrosamineIntraperitonealAdenoma
EthylInitrosoureaIntraperitonealAdenoma
3-MethylchholanthreneIntraperitoneal Adenoma

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