Phenotypic transitions within the category of human cell lung cancer (SCLC) and, potentially, between SCLC and forms of non- SCLC lung cancer, may play a vital role in tumor progression events in patients with these tumors. These cellular events also provide clues to the histogenic link between SCLC and non-SCLC lung tumors. Specifically, loss of neuroendocrine properties in SCLC cells and/or acquisition of features of large cell undifferentiated lung cancer correlates with emergence of some characteristics of treatment resistance. SCLC cells with such transitions (""""""""variant"""""""" SCLC cells) often have amplified and highly expressed myc family genes. The current proposal is based on initial data that insertion of the v-Ha-ras gene into """"""""variant"""""""" SCLC cells pushes the phenotype towards large cell carcinoma while other SCLC phenotypes either have no changes or differentiate more towards endocrine cells. The work will explore: (a) the role of complementation between myc and ras oncogenes in the progression of """"""""variant"""""""" SCLC to non-SCLC phenotypes by co-introduction of myc and ras genes into SCLC cells and by use of antisense RNA to the c-myc gene; (b) what gene expression events, such as those for known growth factors, may be induced by ras genes to change SCLC towards the non- SCLC phenotype; (c) how ras gene mutations map with respect to the different cell phenotypes constituting human lung carcinomaas; and (d) what signal transduction events are activated by ras genes in SCLC cells and how they differ among lung carcinoma cell types with different phenotypic responses. The results should help clarify molecular events underlying tumor progression and histogenesis events in lung cancer and increase understanding of the role of ras genes in normal and neoplastic cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048081-03
Application #
3192048
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1988-07-15
Project End
1991-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ravi, R K; Thiagalingam, A; Weber, E et al. (1999) Raf-1 causes growth suppression and alteration of neuroendocrine markers in DMS53 human small-cell lung cancer cells. Am J Respir Cell Mol Biol 20:543-9
Ravi, R K; McMahon, M; Yangang, Z et al. (1999) Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. J Cell Biochem 72:458-69
Weber, E; Ravi, R K; Knudsen, E S et al. (1999) Retinoic acid-mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27Kip1 expression. Int J Cancer 80:935-43
Ravi, R K; Weber, E; McMahon, M et al. (1998) Activated Raf-1 causes growth arrest in human small cell lung cancer cells. J Clin Invest 101:153-9
Ravi, R K; Scott, F M; Cuttitta, F et al. (1998) Induction of gastrin releasing peptide by all-trans retinoic acid in small cell lung cancer cells. Oncol Rep 5:497-501
Barr, L F; Campbell, S E; Baylin, S B (1997) Protein kinase C-beta 2 inhibits cycling and decreases c-myc-induced apoptosis in small cell lung cancer cells. Cell Growth Differ 8:381-92
Ou, X; Campau, S; Slusher, R et al. (1996) Mechanism of all-trans-retinoic acid-mediated L-myc gene regulation in small cell lung cancer. Oncogene 13:1893-9
Barr, L F; Campbell, S E; Penno, M B et al. (1996) Cell-substratum interactions mediate oncogene-induced phenotype of lung cancer cells. Cell Growth Differ 7:1149-56
Kalemkerian, G P; Slusher, R; Ramalingam, S et al. (1995) Growth inhibition and induction of apoptosis by fenretinide in small-cell lung cancer cell lines. J Natl Cancer Inst 87:1674-80
Kalemkerian, G P; Jasti, R K; Celano, P et al. (1994) All-trans-retinoic acid alters myc gene expression and inhibits in vitro progression in small cell lung cancer. Cell Growth Differ 5:55-60

Showing the most recent 10 out of 15 publications