Lung Cancer Models
Erica L. Jackson and Carla F. Bender Kim and Tyler Jacks
Howard Hughes Medical Institute
Massachusetts Institute of Technology
Welcome to the MMHCC Lung Cancer Site. As you enter the site you will find an introductory section
providing background information on lung cancer and a general overview of current methods for
diagnosis and treatment, molecular alterations occuring in lung cancer, and existing murine models
of lung cancer. The introductory section will be followed by several sections providing more in
depth discussion of the topics listed below.In order to keep the content current, our lab members plan to update the material on an annual basis. We also hope that readers who note any lacking or inaccurate material will send suggestions to emice@pop.nci.nih.gov, as is noted at the bottom of the website.
Links to lung cancer meetings—please inform us of your additions!
Modeling Human Lung Cancer in Mice:4th International Mouse Lung Tumorigenesis Symposium; October 23 - 26, 2003; Funded in part by the National Cancer Institute and the National Cancer Institute/Mouse Models for Human Cancer Consortium
https://webarchive.library.unt.edu/eot2008/20090131084530/http://www.jax.org/courses/cancer03.html
Introduction
Lung cancer is the leading cause of cancer deaths worldwide, with 169,500 new cases and 157,400
deaths predicted for 2001 in the United States alone (32). The majority of lung
cancer cases are related to tobacco use with approximately 10% of lung tumors arising in
non-smokers (7). However, the incidence of lung cancer deaths that are not
associated with smoking or other environmental factors is increasing at a higher rate
than in any other group (54).
Lung cancer patients suffer a high case:fatality ratio with a 5 year survival rate of ~14%.
For treatment purposes lung cancer is divided into two histopathologic classes, small cell
lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which differ in their responses to
therapy. Approximately 80% of lung cancer cases are classified as NSCLC, while SCLC accounts
for ~18% (80). The two classes of lung cancer are characterized by distinct patterns
of oncogene activation, tumor suppressor gene mutation and chromosomal alterations, which may
explain their different biologies. Little progress has been made in the treatment of lung cancer
over the past 30 years. Since 1970 to the present, the 5 year survival rate has only increased
from 7 to 14%.
The development of murine models of lung cancer may aid in our understanding of lung tumor biology
and facilitate the development and testing of novel therapeutic approaches and methods for early
diagnosis. To this end, mouse models should mimic the genetic alterations found in human lung
tumors, the histological characteristics of human tumors or both. To date, several approaches
have been taken in the development of murine lung cancer including chemically induced tumors,
transgenic strains expressing relevant oncogenes, and strains in which important tumor suppressor
genes have been knocked out. More recently, mice carrying latent and conditional alleles of
oncogenes and tumor suppressor genes known to be mutated in human lung cancer have been developed.
These models more accurately mimic the human situation in which genetic mutation occurs in a
subset of cells within adult somatic tissues.
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Diagnosis and Treatment
Chest x-ray and sputum cytology are regularly used to detect lung cancer in symptomatic
patients. Recent data suggest that low radiation dose spiral CT is capable of detecting early
abnormalities in lungs of high risk individuals, but it remains to be seen whether this screening
method will result in a reduction in lung cancer mortality (56). The ultimate diagnosis
of both SCLC and NSCLC is based on fiber-optic bronchoscopy and histologic analysis of sputum or
biopsy samples. The National Cancer Institute is currently undertaking a $200 million, eight-year
screening trial, the National Lung Screening Trial, to re-evaluate whether low dose spiral
computed tomography (CT) can effectively raise survival rates for patients with a high risk
for lung cancer by allowing early detection. Previous studies conducted in the 1970s
concluded that chest X-rays did not significantly raise survival, likely due to a high
frequency of false positives. However, the new study includes the vastly improved
technology of spiral CT, which is more sensitive than chest X-rays, reduces radiation
exposure and may be performed in less than 30 seconds. This website will be updated
as soon as the new study conclusions are available. More details about the trial and
screening for lung cancer are available at www.cancer.org, https://webarchive.library.unt.edu/eot2008/20090131084530/http://cancer.gov/NLST, and
https://webarchive.library.unt.edu/eot2008/20090131084530/http://prg.nci.nih.gov/lung/finalreport.html.
SCLCs are neuroendocrine (NE) tumors of highly aggressive nature.
Often the cancer has metastasized to distant organs by the time of diagnosis. The size
of the primary lesion and extent of metastasis dictate the treatment regimen. Due to its
propensity for metastasis, SCLC is rarely treated by surgical resection (30).
Combination chemotherapy regimens that include a platinum agent are the standard of care for most
SCLCs, with the PE regimen (cisplatin and etoposide) being the most commonly used in the US.
Although most SCLCs are initially highly responsive to therapy, typically the primary tumor or
metastasis becomes resistant to chemotherapy and >90% of patients succumb to the disease.
For more information on treatment options for SCLC please see:
Small Cell Lung Cancer (PDQ®): Treatment (www.cancer.gov)
NSCLCs can be further subclassified into squamous cell carcinoma, adenocarcinoma and
large cell carcinoma, with adenocarcinoma being the most common (histology for each subclass
will be shown). However, for treatment purposes NSCLC is considered a uniform group of
aggressive cancers, and again treatment options are based on the stage of disease at the
time of diagnosis. Surgery and radiotherapy are used to treat early-stage disease. For
patients with unresectable metastatic disease, platinum based combination chemotherapy
is again the treatment of choice. Recent randomized trials demonstrate that as long as the
therapy contains a platinum compound (cisplatin or carboplatin) and a modern agent active
against NSCLC (paclitaxel, docetaxel, gemcitabine or vinorelbine) the survival benefits are
the same (16). The addition of concurrent radiotherapy to the PE regimen may also
provide some additional survival benefits. However, most patients become resistant to therapy,
relapse and die from the disease. For more information regarding treatment options for NSCLC
see:
Small Cell Lung Cancer (PDQ®): Treatment Option Overview (www.cancer.gov)
For both SCLC and NSCLC patients the performance status of the individual is considered
when choosing a course of treatment. Platinum compounds have poor toxicity profiles and may not
be suitable for all patients. Due to the the high rate of relapse and toxic side affects under
the standard therapies, many new therapeutic strategies are being developed. Advances in the
understanding of the molecular events underlying the development of lung cancer have enabled
researchers to develop
rationally targeted therapies.
These biologic agents specifically target proteins used by cancer cells to promote inappropriate
growth and survival. Such agents include selective protein kinase inhibitors, a variety of
antisense oligonucletides, and antibodies all used to inhibit the expression or function of
growth factor receptors, signal transduction proteins or anti-apoptotic mediators.
The efficacy of such agents is still being evaluated but targeted therapeutics may provide
treatment options with increased efficacy and decreased toxicity. Genetically modified murine
lung cancer models may provide a useful reagent for pre-clinical testing of therapeutics directed
against the specific molecular lesions driving tumorigenesis in these mice.
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Molecular Characterization of Human Lung Cancer Overview
(For a more detailed description see the
Human Lung Cancer Molecular Alterations section )
Lung cancer arises as the result of numerous genetic lesions often caused by exposure to
cigarette smoke or other environmental carcinogens. It is thought that 10 or more genetic or
epigenetic abnormalities must occur before a lung tumor becomes clinically evident (63).
Genetic alterations can occur at the chromosomal level including large gains and deletions, at
the nucleotide level, or through epigenetic changes such as DNA methylation. The changes that
occur result in the activation of oncogenes and other growth promoting genes, and in the
inactivation of tumor suppressor genes. NSCLC and SCLC exhibit distinct but overlapping
patterns of genetic alterations.
Oncogene/Growth promoters
The protein products of oncogenes are involved in processes that stimulate cellular proliferation
or survival. During tumorigenesis oncogene activation can occur through point mutations
resulting in constitutively active proteins, through gene amplification and through
over expression. In addition, the acquisition of growth promoting autocrine loops, in
which individual tumor cells express both growth factors and their cognate receptor.
Several oncogenes and growth promoting factors are known to be altered in NSCLC including K-ras,
Erb-B1 (EGFR), Erb-B2 (HER-2/neu), myc, raf, bcl-1, bcl-2 and cyclin D1 (reviewed in (95), (97)).
SCLCs are characterized by activation or overexpression of myc, raf, myb, Erb-B1, Bcl-2, fms,
rlf and by Kit/SCF and GRP/GRP receptor co-expression (reviewed in (95), (81)).
Tumor Suppressor Genes (TSGs)
The protein products of tumor suppressor genes are involved in the inhibition of cell
growth or survival. Several TSGs have been found to be deleted or mutationally inactivated in
lung cancer. In addition, several chromosomal regions are specifically deleted in tumors,
suggesting the presence of unidentified TSGs in these locations. LOH of p53 is frequent in
both SCLC and NSCLC. RB mutations are common in SCLC; they are less frequent in NSCLC.
However, mutations of p16INK4, a regulator of RB function, are found in many NSCLCs (81).
In addition, deletions of several regions of chromosome 3p, 4q, 8p, 9q, Xp, Xq are found in
both SCLC and NSCLC. Several regions, including 6q, 9p and 19p are frequently lost in NSCLC,
while deletions of 5q, 10q and 22q are unique to SCLC (28). Many additional regions
of allelic loss are found at lower frequencies in lung tumors. Candidate TSGs have been
proposed for some regions, but in others the underlying TSGs remain to be discovered.
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Overview of Existing Mouse Models
(For a more in depth discussion see the
Murine Models of Lung Cancer section)
Murine lung cancer models provide opportunities to characterize the serial stages of
tumor progression and to investigate the molecular alterations associated with them. In addition
mouse models allow for the testing of novel chemopreventives, therapeutics and screening methods.
The original models include spontaneous and carcinogen induced tumors in sensitive mouse strains
such as A/J and SWR (JAX MTB Tumor Frequency Grid). A broad range of chemicals can induce the development of
adenomas/adenocarcinomas in susceptible strains including tobacco smoke (106),
urethane, metals and individual constituents of tobacco smoke such as polyaromatic hydrocarbons
and nitrosamines (Reviewed in Stoner 1988 (86) and Tuveson 1999 (97)). These murine adenocarcinomas contain certain
molecular alterations observed in human lung carcinomas including K-ras mutations (~90%) and
LOH of chromosomal regions containing the murine p16Ink4a gene. Of note, the only exisiting
murine models of squamous cell carcinoma were created either by direct application of carcinogen
through intratracheal instillation or by rigorous topical application of carcinogen.
Based on an understanding of the molecular alterations that occur in both murine and human
lung tumors, several transgenic mouse NSCLC models have been created.
More recently mice carrying latent or conditional alleles of oncogenes and tumor
suppressor genes have been created in order to more closely model the human situation in which
tumorigenesis is initiated through somatic mutations occuring in adult tissues. Alleles of tumor
suppressor genes flanked by loxP sites (floxed alleles) are expressed normally in the germline
configuration, but after expression of Cre recombinase in the cell, all or a critical portion of
the gene is deleted, leading to its inactivation. Furthermore, several inducible mouse lung
adenocarcinoma models have been created using the doxycycline regulatable tet-operator system,
which provides a unique opportunity to study the genes required for tumor maintenance and thus
may help to identify potential therapeutic targets.
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