Pengchin Chen, Ph.D.

Dissertation research performed under the direction of Bernard E. Weissman

ABSTRACT
    The formation and progression of human tumors involves genetic alterations resulting in the disruption of balances that regulate normal cellular growth and development. Activation of oncogenes and/or inactivation of tumor suppressor genes contribute to formation of tumors. While data on conveyance of hereditary tumors and cytogenetics as well as loss of heterozygosity analyses on tumor materials also support the existence of tumor suppressor genes, only somatic cell hybridization studies provide functional evidence on the suppression of tumorigenicity. Observations that specific chromosome deletions correlate with distinct groups of cancer suggest that similar types of tumors may share common defective tumor suppressor genes. In support of this sentiment, previous studies showed that four human carcinoma cell lines belonged to the same complementation group for tumorigenic potential.  In this dissertation, I have expanded the complementation study by somatic cell fusions to six human soft tissue sarcoma cell lines. The data showed that hybrid cells between a peripheral neuroepithelioma (PNET) cell line and normal human fibroblasts were non-tumorigenic. However, hybrid cells between the PNET cell line and five other soft tissue sarcoma cell lines remained highly tumorigenic suggesting at least one common genetic defect in the control of tumorigenic potential in these cells. Examinations of biochemical and molecular polymorphic markers in matched pairs of tumorigenic and non-tumorigenic hybrid cells between a PNET cell line and a normal human fibroblast show that loss of the short arm of the fibroblast-derived chromosome 17 correlated with the conversion from non-tumorigenic to tumorigenic cells. The aberrant expression of the p53 protein in all of the soft tissue sarcoma cell lines except HuT14 suggested the possible involvement of p53 as the common tumor suppressor gene. However, hybrid cells between a PNET cell line and a neuroblastoma cell line expressing a wild-type p53 gene retained tumorigenic potential implying a second tumor suppressor gene on chromosome 17. Microcell hybridization data indicates that individual PNET cell lines responded differently to microcell-mediated introduction of normal chromosomes and the effects of each chromosome are depended on the individual cell lines.