Carcinogenesis and cellular immortalization without persistent inactivation of p16/Rb pathway in lung cancer.

Existence of cancer stem cells (CSCs) is still hypothetical and their practical marker is not available yet in lung cancer. To verify the possible existence of CSCs and to find their markers in lung cancer, we compared the p16/Rb and telomerase status in 83 lung cancer tissues and 15 lung cancer cell lines, since inactivation of p16/Rb pathway is considered to be a prerequisite for normal somatic cells to become immortal cancer cells. We found that 7 of 14 adenocarcinoma, but not squamous cell carcinoma, tissues with high telomerase activity and 3 adenocarcinoma cell lines likely had intact p16/Rb. Such cell lines showed higher colony formation capacity in soft agar compared with inactivated ones with similar growth rate. Moreover, cisplatin-resistant cell line PC9/CDDP with intact p16/Rb, but not PC14/CDDP with its inactivation, increased the colony formation capacity compared with the parent cells. Since CSCs are considered to be resistant to conventional anticancer drugs, they could have been concentrated as long as CSCs existed. We propose that half of immortal lung adenocarcinomas are derived from innately telomerase-positive stem cells, which might be the origin of CSCs, and that high telomerase activity with intact p16/Rb could be a marker of stem cell origin.