The metastasis of malignant neoplasms is a significant clinical problem. The death of many patients with cancer is directly or indirectly due to metastases, rather than to the primary neoplasm, which may sometimes even be occult. The current understanding of the pathogenesis of metastatic disease process has evolved from extensive studies, most of which utilized transplantable rodent tumors. Tumors cell heterogeneity has been shown to be an inherent characteristic of many malignant neoplasms and clinically significant metastases occur when specially endowed sub-populations of neoplastic cells successfully complete a complex cascade of events. Although the emergence of """"""""revertants"""""""" (sub-populations of neoplastic cells that have lost the capacity to metastasize) has been observed, a thorough examination of the process by which this occurs has not been done. In addition, the study of the processes of metastases of human neoplasms has not been possible until recently. The long term objectives of this project are to study some of the complex biologic processes associated with the metastasis of human neoplasms. To this end an unique model system will be used - that of a human lung carcinoma cell line that spontaneously metastasizes in athymic mice.
The specific aims will include 1) selection for """"""""revertants"""""""" using endothelial cell monolayers, soft agar cloning and monoclonal antibodies; 2) characterization of the derived revertants and of the metastatic variants using direct biochemical methods as well as monoclonal antibodies. A systematic analysis of the occurrence of reversion to a less malignant phenotype has hitherto been unexplored. The proposed study has been designed to analyse the mechanisms of this reversion in order to eventually elucidate the mechanisms of the malignant disease process. When such mechanisms are understood, therapeutic modalities may then be designed that will encourage this process of reversion of neoplasm thus aborting the inoxerable progression to metastases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043716-02
Application #
3186014
Study Section
Experimental Immunology Study Section (EI)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Callander, N S; Varki, N; Rao, L V (1992) Immunohistochemical identification of tissue factor in solid tumors. Cancer 70:1194-201
Varki, N M; Han, H; Hamsayeh, J et al. (1992) Clones of a spontaneously metastatic human lung carcinoma cell line differ in their in vitro and in vivo phenotypic characteristics. Tumour Biol 13:237-47
Omary, M B; de Grandpre, L; Varki, N M et al. (1992) A tyrosine sulfated human glycoprotein with an unusual cell distribution. Mol Immunol 29:9-19
McKenzie, B A; Barrieux, A; Varki, N M (1991) A novel detection system for submicroscopic human metastases in athymic mice. Cancer Commun 3:15-9
Varki, N M; Estes, L A; Tseng, A et al. (1990) Spontaneously metastasizing variants of a human lung carcinoma cell line: monoclonal antibody characterization. Tumour Biol 11:327-38
Varki, N M; Viswanathan, B; Vu, T (1990) Endothelial cells enhance spontaneous metastasis of human lung carcinoma cells in athymic mice. Cancer Lett 51:251-7
Varki, N M; Tseng, A; Vu, T P et al. (1990) Cloned low metastatic variants from human lung carcinoma metastases. Anticancer Res 10:637-43