| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell, Tumor, and Stem Cell Biology |
1 Hamon Center for Therapeutic Oncology Research and Departments of 2 Internal Medicine, 3 Pathology, 4 Cell Biology, and 5 Pharmacology, The University of Texas Southwestern Medical Center; and 6 Dallas Veterans Administration Medical Center, Dallas, Texas
Requests for reprints: John D. Minna, Hamon Center for Therapeutic Oncology Research NB8.206, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593. Phone: 214-648-4900; Fax: 214-648-4940; E-mail: John.Minna{at}UTsouthwestern.edu.
We evaluated the contribution of three genetic alterations (p53 knockdown, K-RASV12, and mutant EGFR) to lung tumorigenesis using human bronchial epithelial cells (HBEC) immortalized with telomerase and Cdk4-mediated p16 bypass. RNA interference p53 knockdown or oncogenic K-RASV12 resulted in enhanced anchorage-independent growth and increased saturation density of HBECs. The combination of p53 knockdown and K-RASV12 further enhanced the tumorigenic phenotype with increased growth in soft agar and an invasive phenotype in three-dimensional organotypic cultures but failed to cause HBECs to form tumors in nude mice. Growth of HBECs was highly dependent on epidermal growth factor (EGF) and completely inhibited by EGF receptor (EGFR) tyrosine kinase inhibitors, which induced G1 arrest. Introduction of EGFR mutations E746-A750 del and L858R progressed HBECs toward malignancy as measured by soft agar growth, including EGF-independent growth, but failed to induce tumor formation. Mutant EGFRs were associated with higher levels of phospho-Akt, phospho–signal transducers and activators of transcription 3 [but not phospho-extracellular signal-regulated kinase (ERK) 1/2], and increased expression of DUSP6/MKP-3 phosphatase (an inhibitor of phospho-ERK1/2). These results indicate that (a) the HBEC model system is a powerful new approach to assess the contribution of individual and combinations of genetic alterations to lung cancer pathogenesis; (b) a combination of four genetic alterations, including human telomerase reverse transcriptase overexpression, bypass of p16/RB and p53 pathways, and mutant K-RASV12 or mutant EGFR, is still not sufficient for HBECs to completely transform to cancer; and (c) EGFR tyrosine kinase inhibitors inhibit the growth of preneoplastic HBEC cells, suggesting their potential for chemoprevention. (Cancer Res 2006; 66(4): 2116-28)
This article has been cited by other articles:
|
|
 |
|
  K. Oda, J. Okada, L. Timmerman, P. Rodriguez-Viciana, D. Stokoe, K. Shoji, Y. Taketani, H. Kuramoto, Z. A. Knight, K. M. Shokat, et al. PIK3CA Cooperates with Other Phosphatidylinositol 3'-Kinase Pathway Mutations to Effect Oncogenic Transformation Cancer Res., October 1, 2008; 68(19): 8127 - 8136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Guha, R. Chaerkady, A. Marimuthu, A. S. Patterson, M. K. Kashyap, H. C. Harsha, M. Sato, J. S. Bader, A. E. Lash, J. D. Minna, et al. Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS PNAS, September 16, 2008; 105(37): 14112 - 14117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shivapurkar, V. Stastny, N. Okumura, L. Girard, Y. Xie, C. Prinsen, F. B. Thunnissen, I. I. Wistuba, B. Czerniak, E. Frenkel, et al. Cytoglobin, the Newest Member of the Globin Family, Functions as a Tumor Suppressor Gene Cancer Res., September 15, 2008; 68(18): 7448 - 7456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamamoto, H. Shigematsu, M. Nomura, W. W. Lockwood, M. Sato, N. Okumura, J. Soh, M. Suzuki, I. I. Wistuba, K. M. Fong, et al. PIK3CA Mutations and Copy Number Gains in Human Lung Cancers Cancer Res., September 1, 2008; 68(17): 6913 - 6921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Macias-Perez, C. Borza, X. Chen, X. Yan, R. Ibanez, G. Mernaugh, L. M. Matrisian, R. Zent, and A. Pozzi Loss of Integrin {alpha}1{beta}1 Ameliorates Kras-Induced Lung Cancer Cancer Res., August 1, 2008; 68(15): 6127 - 6135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, K. Iwanaga, K. C. Choi, M. Wislez, M. G. Raso, W. Wei, I. I. Wistuba, and J. M. Kurie Intratumoral Epiregulin Is a Marker of Advanced Disease in Non-Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells Cancer Prevention Research, August 1, 2008; 1(3): 201 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Iwanaga, Y. Yang, M. G. Raso, L. Ma, A. E. Hanna, N. Thilaganathan, S. Moghaddam, C. M. Evans, H. Li, W.-W. Cai, et al. Pten Inactivation Accelerates Oncogenic K-ras-Initiated Tumorigenesis in a Mouse Model of Lung Cancer Cancer Res., February 15, 2008; 68(4): 1119 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Chen and C. S. Nirodi The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage Clin. Cancer Res., November 15, 2007; 13(22): 6555 - 6560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Padron, M. Sato, J. W. Shay, A. F. Gazdar, J. D. Minna, and M. G. Roth Epidermal Growth Factor Receptors with Tyrosine Kinase Domain Mutations Exhibit Reduced Cbl Association, Poor Ubiquitylation, and Down-regulation but Are Efficiently Internalized Cancer Res., August 15, 2007; 67(16): 7695 - 7702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Das, B. P. Chen, M. D. Story, M. Sato, J. D. Minna, D. J. Chen, and C. S. Nirodi Somatic Mutations in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor (EGFR) Abrogate EGFR-Mediated Radioprotection in Non-Small Cell Lung Carcinoma Cancer Res., June 1, 2007; 67(11): 5267 - 5274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Vikis, M. Sato, M. James, D. Wang, Y. Wang, M. Wang, D. Jia, Y. Liu, J. E. Bailey-Wilson, C. I. Amos, et al. EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity Cancer Res., May 15, 2007; 67(10): 4665 - 4670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. V. Sequist, D. W. Bell, T. J. Lynch, and D. A. Haber Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 10, 2007; 25(5): 587 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Das, M. Sato, M. D. Story, M. Peyton, R. Graves, S. Redpath, L. Girard, A. F. Gazdar, J. W. Shay, J. D. Minna, et al. Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation Cancer Res., October 1, 2006; 66(19): 9601 - 9608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Nazarenko, G. Kristiansen, S. Fonfara, R. Guenther, C. Gieseler, W. Kemmner, R. Schafer, I. Petersen, and C. Sers H-REV107-1 Stimulates Growth in Non-Small Cell Lung Carcinomas via the Activation of Mitogenic Signaling Am. J. Pathol., October 1, 2006; 169(4): 1427 - 1439. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
