v-Ha-ras oncogene insertion: a model for tumor progression of human small cell lung cancer.
Small cell lung cancer (SCLC) manifests a range of phenotypes in culture that may be important in understanding its relationship to non-SCLCs and to tumor progression events in patients. Most SCLC-derived cell lines, termed "classic" SCLC lines, have properties similar to SCLC tumors in patients, including high expression of neuroendocrine markers and low c-myc oncogene expression. A significant number of SCLC lines characterized as "biochemical or morphologic variant" SCLC lines have decreased levels of endocrine differentiation markers associated with increased proliferative indices, amplification of the c-myc oncogene, and growth patterns and biochemical markers more typical of non-SCLCs. To delineate further the relationships between these phenotypes and the molecular events involved, we have inserted the v-Ha-ras gene in SCLC cell lines with (biochemical variant) and without (classic) an amplified c-myc gene. These two SCLC subtypes had markedly different phenotypic responses to similar levels of expression of v-Ha-ras RNA. No biochemical or morphologic changes were observed in classic SCLC cells. In contrast, in biochemical variant SCLC cells, v-Ha-ras expression induced features typical of large cell undifferentiated lung carcinoma, including adherent monolayer growth patterns, increased cloning efficiency, increased levels of non-SCLC cell markers, ultrastructural characteristics and an acquired resistance to polyamine depletion typical of large cell carcinoma, but not SCLC, in vitro. Expression of v-Ha-ras in biochemical variant SCLC cells directly demonstrates that important transitions can occur between phenotypes of human lung cancer cells and that these may play a critical role in tumor progression events in patients. The findings provide a model system to study molecular events involved in tumor progression steps within a series of related tumor types.
Mabry
M
M
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
Nakagawa
T
T
Nelkin
B D
BD
McDowell
E
E
Gesell
M
M
Eggleston
J C
JC
Casero
R A
RA
Baylin
S B
SB
D002272:Carcinoembryonic Antigen / Q000032:analysis; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D004251:DNA Transposable Elements; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D000518:Eflornithine / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009693:Nucleic Acid Hybridization
D002272:Carcinoembryonic Antigen; D004251:DNA Transposable Elements; D004273:DNA, Neoplasm; D000518:Eflornithine