Mouse models of lung cancer : understanding the molecular and cellular basis of lung tumorigenesis
Name
54808262-MIT.pdf
Description
Full printable version
Size
9.84 MB
Format
Adobe PDF
Checksum (MD5)
41cfbd1255789157ed7a6a545487876b
Author(s)
Jackson, Erica L. (Erica Lynn), 1973-
Advisor(s)
Tyler Jacks.
Date Issued
2003
Publisher
Massachusetts Institute of Technology
Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Patients are typically diagnosed with advanced disease and have a high fatality:case ratio. Despite its prevalence, the identity of the cell of origin, precursor lesions and stages of disease progression have not been well characterized for most types of lung cancer. Furthermore, there are no effective screening methods for lung cancer and standard chemotherapeutics are ineffective in treating advanced lung cancer. The work presented here describes the development and characterization of a murine lung cancer model that uses conditional expression of oncogenic K-ras to drive tumorigenesis. The conditional allele is controlled by the Cre-loxP system. Using adenovirus to deliver Cre recombinase to the lungs we have controlled the timing and multiplicity of tumor initiation. We used this model to investigate several aspects of tumor biology. Timecourse experiments revealed the histologic stages of lung tumor progression, advancing from atypical adenomatous hyperplasia to adenoma to adenocarcinoma. Studies of early lesions provided insights into the ras effector pathways required for tumor initiation, implicating the JNK and p38 pathways in this process. In addition, our studies regarding the cell of origin of lung tumors led to the identification of a novel cell type in the adult lung that resembles an embryonic lung precursor cell.
(cont.) A common feature of mouse tumor models is that they mainly resemble the early stages of tumor development. In an effort to create a model representing advanced disease, we generated K-rasG12D;p53 compound mutant mice with varyious combinations of different conditional mutant p53 alleles. The compound mutant mice develop lung tumors that recapitulate several aspects of advanced human disease including stromal desmoplasia, invasion and metastasis. Missense mutation is the most common form of p53 mutation in human tumors, suggesting that the mutant p53 protein may confer a selective advantage on the tumor cells during tumorigenesis. Our comparison of the oncogenic effects of p53R172H, p53R270H and a conditional null allele, p53Fl, revealed that the p53R270H mutation results in a dominant negative allele. Furthermore, our studies revealed an oncogenic gain-of-function effect of both p53R172H and p53R270H on the development of nasopharyngeal carcinomas.
Description
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2003.
Includes bibliographical references.
Subjects
Biology.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.
Persistent DSpace Link
