title: Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations.
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, KRAS(V12), 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 KRAS(V12) 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+KRAS(V12); (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.
authors: Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas 75390, USA.
authors: Mitsuo
authors: M
authors: Sato
authors: Jill E
authors: JE
authors: Larsen
authors: Woochang
authors: W
authors: Lee
authors: Han
authors: H
authors: Sun
authors: David S
authors: DS
authors: Shames
authors: Maithili P
authors: MP
authors: Dalvi
authors: Ruben D
authors: RD
authors: Ramirez
authors: Hao
authors: H
authors: Tang
authors: John Michael
authors: JM
authors: DiMaio
authors: Boning
authors: B
authors: Gao
authors: Yang
authors: Y
authors: Xie
authors: Ignacio I
authors: II
authors: Wistuba
authors: Adi F
authors: AF
authors: Gazdar
authors: Jerry W
authors: JW
authors: Shay
authors: John D
authors: JD
authors: Minna
mesh_terms: D000818:Animals; D001980:Bronchi / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D016612:Paraffin Embedding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016707:Tissue Fixation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D050505:Mutant Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins