**1. Introduction**

Lung cancer is the leading cause of cancer deaths in the world, which is a cause for more solid tumor-related deaths than all other carcinomas combined. More than 170,000 new cas‐ es are diagnosed each year in the United States alone, of whom ~160,000 will eventually die, accounting for nearly 30% of all cancer deaths (Siegel *et al.*, 2012). The annual incidence for lung cancer per 100,000 population is highest among African Americans (76.1), followed by whites (69.7), American Indians/Alaska Natives (48.4), and Asian/Pacific Islanders (38.4). Hispanic people have much lower lung cancer incidence (37.3) than non-Hispanics (71.9) (CDC, 2010). These results identify the racial/ethnic populations and geographic regions that would benefit from enhanced efforts in lung cancer prevention, specifically by reducing cig‐ arette smoking and exposure to environmental carcinogens.

Lung lobectomy provides the best chance for patients with early-stage disease to be cured. African American patients with early-stage lung cancer have lower five-year survival rates than whites, which has been attributed to lower rates of resection in former patients (Wisni‐ vesky *et al*., 2005). Several potential factors underlying racial differences in receiving surgical therapy include differences in pulmonary function, access to care, beliefs about tumor spread at the time of operation, and the possibility of cure without surgery. Of these, access to care is considered to be the most important factor underlying racial disparities.

The most outstanding modifiable risk factor for lung cancer is cigarette smoking (Swierzew‐ ski III, 2011). Other risk factors include asbestos exposure, radon, occupational chemicals, radiation, and alcohol. People who smoke tend to drink more alcohols and consume more non-narcotic pain relievers than non-smokers, thus reducing the intoxicating effects of alco‐ hol, promoting the progression from moderate to heavy drinking. Alcoholism is also associ‐

© 2013 Inoue et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ated with significant immune suppression - therefore, a history of drinking may increase a person's susceptibility to lung cancer.

dogenous lung cancer in mice that harbor specific mutations will undoubtedly provide a further insight into the mutation-specific effects on lung tumor initiation/development. Moreover, a high degree of pathophysiological similarity between mouse lung tumors and human lung carcinomas will make it possible to use these mouse models in pre-clinical tests for novel anticancer drug screening. Various intervention strategies against specific muta‐ tion can then be tested to evaluate both specificity and efficacy in mouse lung tumors at ev‐ ery developing stage. The number of genetically engineered mouse models for lung cancer is ever expanding. Continuous attempt to manipulate the mouse genome has enabled us to adjust compound mouse models of lung cancer in a way that they start to reproduce the

Genetically Engineered Mouse Models for Human Lung Cancer

http://dx.doi.org/10.5772/53721

31

While susceptibility and incidence of spontaneous lung tumors vary among well-established mouse strains, endogenous mouse lung tumors share many similarities with human lung cancers. This was clearly demonstrated in early studies where defined chemical carcinogens were used to induce lung tumors in mice (Wakamatsu *et al*., 2007). The incidence of sponta‐ neous and induced lung tumors were very high (61%) in A/J and SWR strains, but very low (6%) in resistant strains such as C57BL/6 and DBA (Wakamatsu *et al*., 2007). Contrary to hu‐ man lung cancer with its complex molecular genetics and four distinct tumor types (adeno‐ carcinoma, squamous cell carcinoma, large-cell carcinoma, and small-cell carcinoma) that easily metastasize, spontaneous and chemically-induced lung lesions in mice often result in pulmonary adenomas and more infrequent adenocarcinomas. Mouse lung adenocarcinomas are usually 5mm or more in diameter; however, they are categorized into carcinomas when nuclear atypia or signs of local invasion/metastasis is found in tumors less than 5mm. Mouse lung tumor development shows initial hyperplastic foci in bronchioles and alveoli, which then become benign adenomas and eventually adenocarcinomas (Shimkin *et al*., 1975). The tumor latency depends on mouse strain and carcinogen administration protocols. Most potent carcinogens are found in cigarettes, such as polycyclic aromatic hydrocarbons, tobacco-specific nitrosamine, and benzopyrene (BaP) (Pfeifer *et al*., 2002). It has been espe‐ cially difficult to reproduce well-characterized pre-malignant lesions found in human air‐ way epithelium in mice (Sato *et al*., 2007). Nevertheless, major histopathological features remain the same between the two species and molecular characterization of spontaneous and carcinogen-induced murine lung tumors revealed a high degree of similarity as com‐ pared to their human counterparts (Malkinson, 2001). A common early event is the occur‐ rence of activating *K-ras* mutations in hyperplastic lesions. Besides overexpression of c-*Myc*, inactivation of well-known tumor suppressor genes, such as *p53*, *fhit*, *Apc*, *Rb, Mcc*, *p16Ink4a* and/or *Arf* occur in both mice and human lung cancers; only a small percentage of lung ade‐

more complex human lung cancer in a higher degree.

nomas progress into AdCAs (Malkinson, 2001).

**2. The first generation mouse models for lung cancer**

The first generation transgenic models for lung cancer were created by ectopic transgene ex‐ pression under control of lung-specific promoters. Thus transgenic expression was constitu‐ tive. Transgene expression was mainly found in specific subsets of lung epithelial cells. Lung *surfactant protein C* (*SPC*) promoter was used for constitutive gene expression in type II

Lung cancer has a high morbidity because it is difficult to detect early and is frequently re‐ sistant to available chemotherapy and radiotherapy. The overall 5-year survival rate for all types of lung cancer is around 15 % at most, and it is even worse in SCLC (~5 %) although SCLC is more sensitive to chemo/radiation therapy than NSCLC (Meuwissen & Berns, 2005; Schiller, 2001; Worden & Kalemkerian, 2000). Non-smokers who develop lung cancer may experience delays in diagnosis due to the fact that many early symptoms of lung cancer mimic those of non-specific respiratory infections (Menon, 2012). Thus, a physician may misdiagnose the malignant disease for asthma or other respiratory illnesses. Another reason for delayed diagnosis of lung cancer is that there is no sensitive and specific biomarker, such as prostate-specific antigen in prostate cancer (Brambilla *et al.*, 2003). Thus several biomark‐ ers will have to be used together for early diagnosis of lung cancer at present, which include mutant Ras, mutant p53, and methylation of a variety of genes using bronchial biospies or bronchoalveolar lavage (Brambilla *et al.*, 2003).

Certain combinations of clinical signs and symptoms – e.g. endocrine, neurologic, immuno‐ logic, and hematologic - are associated with lung cancer as a manifestation of the secretion of cytokines/hormones by tumor cells or as an associated immunologic response (Yeung *et al.*, 2011). These paraneoplastic syndromes occur commonly in patients with SCLC. Since the syndromes can be the first clinical manifestation of malignant disease, increased awareness of these syndromes associated with lung cancer is critical to the earlier diagnosis of malig‐ nancies, thereby improving the overall prognosis of patients.

Lung cancer has been categorized into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Moran, 2006) and small-cell lung cancer (SCLC) (Schiller, 2001), the latter of which show neuroendocrine features and thus are different from the former. Ap‐ proximately 80 % of lung cancers are NSCLC, and they are subcategorized into adenocarci‐ nomas (AdCA), squamous cell (SqCLC), bronchioalveolar, and large-cell carcinomas (LCLC) (Travis, 2002). SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic alterations found in both tumor types (Zochbauer-Muller *et al*., 2002). The *K-Ras* gene is mutated in 20~30 % of NSCLC while its mutation is rare in SCLC; *Rb* inactivation is found in ~90 % of SCLC while *p16INK4a* is inac‐ tivated by gene deletion and/or promoter hypermethylation in ~50 % of NSCLC (Fong *et al*., 2003; Meuwissen & Berns, 2005). Responsiveness of tumor cells to chemotherapy and/or ra‐ diation therapy significantly varies between NSCLC and SCLC, and thus, has a dramatic ef‐ fect on the prognosis of patients.

Progress in whole genome approaches to detect genetic alterations found in human lung cancer has resulted in the identification of a growing number of genes. Genome-wide associ‐ ation studies, whether they are based on single-nucleotide polymorphism array or in gene copy number assays, have identified mutations in lung cancer-related genes. Identification of these lung cancer-related genes will provide great potential as therapeutic targets for lung cancer intervention. Target validation should be done through intervention studies of specif‐ ic genetic alterations in human lung cancer cell lines. Since *in vitro* cell culture studies cannot fully mimic more complex *in vivo* onset/development of lung carcinogenesis, developing en‐ dogenous lung cancer in mice that harbor specific mutations will undoubtedly provide a further insight into the mutation-specific effects on lung tumor initiation/development. Moreover, a high degree of pathophysiological similarity between mouse lung tumors and human lung carcinomas will make it possible to use these mouse models in pre-clinical tests for novel anticancer drug screening. Various intervention strategies against specific muta‐ tion can then be tested to evaluate both specificity and efficacy in mouse lung tumors at ev‐ ery developing stage. The number of genetically engineered mouse models for lung cancer is ever expanding. Continuous attempt to manipulate the mouse genome has enabled us to adjust compound mouse models of lung cancer in a way that they start to reproduce the more complex human lung cancer in a higher degree.

ated with significant immune suppression - therefore, a history of drinking may increase a

Lung cancer has a high morbidity because it is difficult to detect early and is frequently re‐ sistant to available chemotherapy and radiotherapy. The overall 5-year survival rate for all types of lung cancer is around 15 % at most, and it is even worse in SCLC (~5 %) although SCLC is more sensitive to chemo/radiation therapy than NSCLC (Meuwissen & Berns, 2005; Schiller, 2001; Worden & Kalemkerian, 2000). Non-smokers who develop lung cancer may experience delays in diagnosis due to the fact that many early symptoms of lung cancer mimic those of non-specific respiratory infections (Menon, 2012). Thus, a physician may misdiagnose the malignant disease for asthma or other respiratory illnesses. Another reason for delayed diagnosis of lung cancer is that there is no sensitive and specific biomarker, such as prostate-specific antigen in prostate cancer (Brambilla *et al.*, 2003). Thus several biomark‐ ers will have to be used together for early diagnosis of lung cancer at present, which include mutant Ras, mutant p53, and methylation of a variety of genes using bronchial biospies or

Certain combinations of clinical signs and symptoms – e.g. endocrine, neurologic, immuno‐ logic, and hematologic - are associated with lung cancer as a manifestation of the secretion of cytokines/hormones by tumor cells or as an associated immunologic response (Yeung *et al.*, 2011). These paraneoplastic syndromes occur commonly in patients with SCLC. Since the syndromes can be the first clinical manifestation of malignant disease, increased awareness of these syndromes associated with lung cancer is critical to the earlier diagnosis of malig‐

Lung cancer has been categorized into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Moran, 2006) and small-cell lung cancer (SCLC) (Schiller, 2001), the latter of which show neuroendocrine features and thus are different from the former. Ap‐ proximately 80 % of lung cancers are NSCLC, and they are subcategorized into adenocarci‐ nomas (AdCA), squamous cell (SqCLC), bronchioalveolar, and large-cell carcinomas (LCLC) (Travis, 2002). SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic alterations found in both tumor types (Zochbauer-Muller *et al*., 2002). The *K-Ras* gene is mutated in 20~30 % of NSCLC while its mutation is rare in SCLC; *Rb* inactivation is found in ~90 % of SCLC while *p16INK4a* is inac‐ tivated by gene deletion and/or promoter hypermethylation in ~50 % of NSCLC (Fong *et al*., 2003; Meuwissen & Berns, 2005). Responsiveness of tumor cells to chemotherapy and/or ra‐ diation therapy significantly varies between NSCLC and SCLC, and thus, has a dramatic ef‐

Progress in whole genome approaches to detect genetic alterations found in human lung cancer has resulted in the identification of a growing number of genes. Genome-wide associ‐ ation studies, whether they are based on single-nucleotide polymorphism array or in gene copy number assays, have identified mutations in lung cancer-related genes. Identification of these lung cancer-related genes will provide great potential as therapeutic targets for lung cancer intervention. Target validation should be done through intervention studies of specif‐ ic genetic alterations in human lung cancer cell lines. Since *in vitro* cell culture studies cannot fully mimic more complex *in vivo* onset/development of lung carcinogenesis, developing en‐

person's susceptibility to lung cancer.

30 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

bronchoalveolar lavage (Brambilla *et al.*, 2003).

fect on the prognosis of patients.

nancies, thereby improving the overall prognosis of patients.

While susceptibility and incidence of spontaneous lung tumors vary among well-established mouse strains, endogenous mouse lung tumors share many similarities with human lung cancers. This was clearly demonstrated in early studies where defined chemical carcinogens were used to induce lung tumors in mice (Wakamatsu *et al*., 2007). The incidence of sponta‐ neous and induced lung tumors were very high (61%) in A/J and SWR strains, but very low (6%) in resistant strains such as C57BL/6 and DBA (Wakamatsu *et al*., 2007). Contrary to hu‐ man lung cancer with its complex molecular genetics and four distinct tumor types (adeno‐ carcinoma, squamous cell carcinoma, large-cell carcinoma, and small-cell carcinoma) that easily metastasize, spontaneous and chemically-induced lung lesions in mice often result in pulmonary adenomas and more infrequent adenocarcinomas. Mouse lung adenocarcinomas are usually 5mm or more in diameter; however, they are categorized into carcinomas when nuclear atypia or signs of local invasion/metastasis is found in tumors less than 5mm. Mouse lung tumor development shows initial hyperplastic foci in bronchioles and alveoli, which then become benign adenomas and eventually adenocarcinomas (Shimkin *et al*., 1975). The tumor latency depends on mouse strain and carcinogen administration protocols. Most potent carcinogens are found in cigarettes, such as polycyclic aromatic hydrocarbons, tobacco-specific nitrosamine, and benzopyrene (BaP) (Pfeifer *et al*., 2002). It has been espe‐ cially difficult to reproduce well-characterized pre-malignant lesions found in human air‐ way epithelium in mice (Sato *et al*., 2007). Nevertheless, major histopathological features remain the same between the two species and molecular characterization of spontaneous and carcinogen-induced murine lung tumors revealed a high degree of similarity as com‐ pared to their human counterparts (Malkinson, 2001). A common early event is the occur‐ rence of activating *K-ras* mutations in hyperplastic lesions. Besides overexpression of c-*Myc*, inactivation of well-known tumor suppressor genes, such as *p53*, *fhit*, *Apc*, *Rb, Mcc*, *p16Ink4a* and/or *Arf* occur in both mice and human lung cancers; only a small percentage of lung ade‐ nomas progress into AdCAs (Malkinson, 2001).
