1. Model of malignant transformation of in vitro HBECs following stepwise introduction of common lung cancer mutations.
Model of malignant transformation of in vitro HBECs following stepwise introduction of common lung cancer mutations. The experimental data presented in this article identify the following steps: step 1, CDK4 and hTERT immortalized, HBECs are nontransformed and lack of anchorage-independent growth in soft agar; step 2, in vitro transformation as defined by anchorage-independent growth in soft agar is achieved with the single manipulation of loss of p53, moderate KRASV12 expression or both, whreas expression of high levels of KRASV12 expression leads to in vitro transformation with significant cellular senescence; step 3, partial in vivo transformation with subcutaneous tumor growth in immunocompromised mice in 30% to 80% of injections is observed with the combination of p53 loss and high KRASV12; step 4, an EMT occurs following overexpression of cMYC or growth in serum-containing media; step 5, combination of cMYC overexpression and growth in serum-containing media results in complete oncogenic transformation of HBECs with tumor growth in vivo observed in more than 80% of injections in immunocompromised mice. Clonal selection of partially transformed HBECs identifies tumorigenic and nontumorigenic clones.
Mitsuo Sato et al. Mol Cancer Res 2013;11:
©2013 by American Association for Cancer Research