ROLE OF TUMOR SUPPRESSOR GENES AND ONCOGENS IN CHEMICAL CARCINOGENESIS

人类和动物的癌症发展是一个多步骤的过程 涉及多个基因。 我们已经证明， 叙利亚仓鼠胚胎细胞（SHE）在培养中的转化， 这是一个多步骤的过程， 和肿瘤抑制基因的失活。 正常，早期 传代SHE细胞未被任何一种 单独的v-Ha-ras或v-myc癌基因;然而， SHE细胞通过两种癌基因的结合导致 致瘤性转化 为了确定是否有额外的 ras + myc诱导的肿瘤发生细胞遗传学改变， 对肿瘤进行分析。 非随机 染色体丢失（15号染色体单体）， ras/myc肿瘤。 这种染色体丢失的生物学作用 在ras/myc肿瘤细胞和正常细胞之间的杂交中进行了研究 SHE细胞。 ras/myc肿瘤细胞的致瘤性为 与正常细胞杂交后被抑制; 在以后的传代中，致瘤性的表达与 15号染色体的丢失表明这条染色体起着 抑制肿瘤发生的作用。 这些杂交细胞 肿瘤发生抑制后仍表达ras和myc 致癌基因 致癌物诱发的肿瘤的早期变化 SHE细胞的进展是诱导永生。 致癌物诱导的永生细胞在早期传代仍然保留 抑制细胞杂交体中致瘤性的能力。 这种能力 随着永生细胞系和亚克隆的传代， 在抑制致瘤性能力方面是异质的。 的 永生细胞系对肿瘤转化敏感性 通过用v-Ha-ras癌基因或肿瘤DNA进行DNA转染 与肿瘤抑制能力呈负相关， 细胞混合体中的细胞。 这些观察结果表明， 叙利亚仓鼠胚胎细胞的肿瘤转化 至少包括三个步骤：（1）诱导永生;（2） 转化基因或癌基因的激活和（3）转化基因或癌基因的缺失或 肿瘤抑制基因的失活。

Cancer development in humans and animals is a multistep process involving multiple genes. We have shown that the neoplastic transformation of Syrian hamster embryo cells (SHE) in culture is a multistep process involving both activation of proto-oncogenes and inactivation of a tumor suppressor gene. Normal, early passage SHE cells were not neoplastically transformed by either the v-Ha-ras or v-myc oncogenes alone; however, transfection of SHE cells by the two oncogenes in combination resulted in tumorigenic conversion. In order to determine whether additional changes occurred in the ras plus myc induced tumors, cytogenetic analyses of the tumors were performed. A nonrandom chromosome loss (monosomy of chromosome 15) was observed in the ras/myc tumors. The biological role of this chromosome loss was studied in hybrids between ras/myc tumor cells and normal SHE cells. Tumorigenicity of the ras/myc tumor cells was suppressed following hybridization with normal cells; re- expression of tumorigenicity at later passages correlated with the loss of chromosome 15 suggesting that this chromosome plays a role in suppressing tumorigenicity. The hybrid cells which were suppressed for tumorigenicity still expressed the ras and myc oncogenes. An early change in carcinogen-induced neoplastic progression of SHE cells was induction of immortality. Carcinogen-induced immortal cells at early passages still retained the ability to suppress tumorigenicity in cell hybrids. This ability decreased with passaging of immortal cell lines and subclones are heterogenous in their ability to suppress tumorigenicity. The susceptibility of immortal cell lines to neoplastic transformation by DNA transfection with v-Ha-ras oncogene or tumor DNA inversely correlated with the tumor suppressive ability of the cells in cell hybrids. Taken together these observations indicate that neoplastic transformation of Syrian hamster embryo cells involves at least three steps: (1) induction of immortality; (2) activation of transforming gene or oncogene and (3) loss of or inactivation of a tumor suppressor gene.