v-Ha-ras oncogene insertion: a model for tumor progression of human small cell lung cancer.

Abstract

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 finding provide a model system to study molecular events involved in tumor progression steps within a series of related tumor types.

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

“…SCLC cell lines consisting of: OH1 (Gazdar et al, 1980;Mabry et al, 1988), OH3 (Carney et al, 1985;Griffin and Baylin, 1985;Mabry et al, 1988) and H82 from pleural effusions and SW2 from bone metastasis (Zimmermann et al, 1997); ATCC SCLC cell lines consisting of: H69, H128, H146, H209, CRL2195 and H446, normal lung fibroblast PIDF (Strissel et al, 2000), kidney cell line HEK293 and the breast cancer cell line ZR751. The NSCLC cell line HCC44 is DSMZ (no.…”

Modeling human lung cancer in mice: similarities and shortcomings

“…Small cell carcinoma (SCLC) represents 20% of lung cancers, arises centrally, metastasizes frequently, and is characterized by intermediate cell size, speci®c neuroendocrine nuclear features such as the lack of nucleoli, and very high mitotic and apoptotic rates. Human lung tumor specimens are often histologically heterogeneous, which suggests the presence of a common precursor cell or transitions between di erent histologic types (Roggli et al, 1985;Mabry et al, 1988). The pathway of histologic progression in lung cancer is poorly understood due to the scarcity of pre-invasive lesions for analysis, although potential candidates include squamous metaplasia and carcinoma-in-situ detected in some patients prior to or concomittant with the diagnosis of squamous cell carcinoma (Auerbach et al, 1961), and a lesion termed`atypical adenomatous hyperplasia' that is identi®ed occasionally in the lungs of smokers without lung cancer and frequently in tissue adjacent to bronchiolo-alveolar carcinoma specimens (Nakanishi, 1990).…”

Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer

“…In many cell types, ras gene overexpression or mutation is associated with neoplastic transformation or progression (5,(16)(17)(18)(19)(20)(21)(22)(23). However, previous studies in two well-defined neuroendocrine tumor cell lines, rat pheochromocytoma cell line PC 12 (6)(7)(8) (24).…”

“…However, when classic SCLC cells similarly express high levels of v-ra? ', their growth characteristics, drug sensitivity, and neuroendocrine markers were not affected (5).…”

“…We have been interested in the genetic and biochemical signals that mediate differentiation of these cell phenotypes in the SCLC lineage and recently have shown that when the viral Harvey ras oncogene (v-ras1) is expressed via retroviral infection in variant SCLC, these cells acquire features typical of large cell lung cancer cell lines including adherent growth, increased growth rate, augmented cloning efficiency, resistance to the polyamine analogue a-difluoromethylornithine, and further loss of neuroendocrine markers (5). However, when classic SCLC cells similarly express high levels of v-ra?…”