Tumors result when cells with defects in proliferation control arise that are indistinguishable from normal cells by the host's immunocytes. We are investigating the expression of the epidermal growth factor receptor (EGFR) in normal and tumor cells as well as the host's immune response to viral transforming proteins. Normal human fibroblasts progress with passage in vitro from EGF responsive (young) cells into a nonproliferating senescent state. By comparative analysis of the EGFR from young and senescent cells, we find that although it is equivalently expressed by both cell types and binds comparable levels of EGF, the autophosphorylating tyrosine kinase activity of EGFR is defective in senescent cells. This defect provides a mechanism for removal of normal cells from the proliferating pool and we are investigating how this aberration arises. The stem cells of teratocarcinoma share properties with those of the implanting embryos and like embryonic cells, can be induced to differentiate in vitro into a variety of cell types. We have found human teratocarcinoma stem cells express EGFR and their differentiated derivatives do not. Such a change results in cell populations in loco with differing requirements for cell growth control and suggests a mechanism of development based on expression of cell surface receptors and availability of growth factors. While investigating the relationship between hepatitis B virus integration, chromosome rearrangements, and abnormal growth control in human liver tumors, we found one hepatoma cell line that contains a rearrangement of the region of the chromosome that encodes EGFR, and expresses 20-fold more EGFR than other hepatoma cells. Thus, genetic rearrangements can lead to defective growth control through increased expression of a normal growth factor receptor. We find that strong protection against SV40-induced tumors in the mouse is correlated with the host's ability to mount a cytotoxic T-cell immune response to the viral transforming protein, SV40 T-antigen. SV40 transgenic mice (obtained by injecting SV40 plasmids into the zygotes) that die of progressive SV40 tumors are immunologically tolerant to SV40 T-antigen while transgenics (containing the same plasmid) that remain tumor-free are not. We hypothesize that the stage of development at which the SV40 T-antigen is expressed determines if it is immunologically recognized as foreign and rejected, or as self and tumors develop. (A)
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