Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations

Sato, Mitsuo, Larsen, Jill E., Lee, Woochang, Sun, Han, Shames, David S., Dalvi, Maithili P., Ramirez, Ruben D., Tang, Hao, DiMaio, John Michael, Gao, Boning, Xie, Yang, Wistuba, Ignacio I., Gazdar, Adi F., Shay, Jerry W. and Minna, John D. (2013) Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. Molecular Cancer Research, 11 6: 638-650. doi:10.1158/1541-7786.MCR-12-0634-T

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads

Author Sato, Mitsuo
Larsen, Jill E.
Lee, Woochang
Sun, Han
Shames, David S.
Dalvi, Maithili P.
Ramirez, Ruben D.
Tang, Hao
DiMaio, John Michael
Gao, Boning
Xie, Yang
Wistuba, Ignacio I.
Gazdar, Adi F.
Shay, Jerry W.
Minna, John D.
Title Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations
Journal name Molecular Cancer Research   Check publisher's open access policy
ISSN 1541-7786
Publication date 2013-06
Sub-type Article (original research)
DOI 10.1158/1541-7786.MCR-12-0634-T
Open Access Status
Volume 11
Issue 6
Start page 638
End page 650
Total pages 13
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Collection year 2014
Language eng
Formatted abstract
We used CDK4/hTERT–immortalized normal human bronchial epithelial cells (HBEC) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, and MYC) and followed the stepwise transformation of HBECs to full malignancy. This model showed that: (i) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; (ii) genetically identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; (iii) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; (iv) high levels of KRASV12 are required for full malignant transformation of HBECs, however, prior loss of p53 function is required to prevent oncogene-induced senescence; (v) overexpression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; (vi) growth of parental HBECs in serum-containing medium induces differentiation, whereas growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); (vii) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; (viii) an mRNA signature derived by comparing tumorigenic versus nontumorigenic clones was predictive of outcome in patients with lung cancer. Collectively, our findings show that this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.
Keyword Cellular-transformation
Viral oncoproteins
Induced senescence
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 34 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 38 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 04 Oct 2013, 13:47:28 EST by Jill Larsen on behalf of Medicine - Prince Charles Hospital