MOLECULAR BASIS FOR CELLULAR CHANGES IN CHEMICAL CARCINOGENESIS

叙利亚仓鼠胚胎(SHE)细胞的肿瘤发育是一个多步骤的过程 进程。然而，步骤的数量和所涉及的基因或变化 都是未知的。转染v-Ha-ras DNA和v-myc DNA的SHE细胞形成 潜伏期短的肿瘤。要确定是否激活RAS 加上myc足以致癌，我们进行了细胞遗传学 转基因后形成的肿瘤的分析。肿瘤(ras/myc-T) V-Ha-ras和v-myc联合诱导的癌基因是单克隆性的，具有 非随机染色体变化，15号染色体单体。因此，一种 额外的改变，丢失15号染色体，是必要的或有利的 V-HA-ras联合v-myc癌基因的致瘤性。要确定是否 正常的细胞因子或基因可以调节表型表达 致瘤性和/或癌基因，肿瘤和/或癌之间的细胞-细胞杂交 分离非致瘤仓鼠细胞。Ras/myc肿瘤的杂交瘤 细胞和SHE细胞无致瘤性，不能在琼脂中生长。这些 受抑制的杂交瘤细胞仍表达ras和myc癌基因。之后 在杂交细胞中出现了几代、变异体，它们重新表达了 成瘤性和锚定独立性。白粉病的核型分析 被抑制和重新表达的杂交种表现出非随机的染色体丢失 15与肿瘤致瘤性的再表达有关。她的杂交后代 细胞和化学转化的仓鼠细胞系也受到抑制 致瘤性。致癌药物对SHE细胞的致死作用 细胞作为多步骤肿瘤性转化的早期步骤。在早些时候 传代永生细胞抑制完全转化成瘤细胞的致瘤性 细胞。在以后的传代中，细胞失去了抑制 细胞杂交瘤的致瘤性，但仍未完全转化。 失去肿瘤抑制功能的细胞很容易转化为 通过转化癌基因(如ras)致瘤，而细胞 保留这一功能的人对肿瘤转化具有抵抗力。这些 结果表明，化学诱导的叙利亚人肿瘤进展 仓鼠胚胎细胞至少包括三个步骤：(1)诱导 永生；(2)转化癌基因的激活；以及(3) 具有抑瘤作用。

Neoplastic development of Syrian hamster embryo (SHE) cells is a multistep process. However, the number of steps and the genes or changes involved are unknown. SHE cells transfected with v-Ha-ras DNA plus v-myc DNA formed tumors with short latency periods. To determine whether activation of ras plus myc was sufficient for tumorigenicity, we performed cytogenetic analyses of tumors formed following transfection. Tumors (ras/myc-T) induced by v-Ha-ras plus v-myc oncogenes were monoclonal and had a nonrandom chromosome change, monosomy of chromosome 15. Thus, an additional change, loss of chromosome 15, is required or advantageous for tumorigenicity induced by v-HA-ras plus v-myc oncogenes. To determine if normal cellular factors or genes can regulate the phenotypic expression of tumorigenicity and/or oncogenes, cell-cell hybrids between neoplastic and nontumorigenic hamster cells were isolated. Hybrids between ras/myc tumor cells and SHE cells were nontumorigenic and failed to grow in agar. These suppressed hybrids still expressed the ras and myc oncogenes. After several passages, variants arose in the hybrid cells which re-expressed tumorigenicity and anchorage-independence. Karyotypic analysis of the suppressed and re-expressed hybrids showed a non-random loss of chromosome 15 associated with re-expression of tumorigenicity. Hybrids between SHE cells and chemically transformed hamster cell lines were also suppressed for tumorigenicity. Carcinogen treatment of SHE cells induced immortal cells as an early step in a multistep, neoplastic transformation. At early passages immortal cells suppressed tumorigenicity of fully transformed cells. At later passages the cells lost the ability to suppress tumorigenicity in cell hybrids but were still not completely transformed. Cells which had lost the tumor suppression function were readily converted to tumorigenicity by a transforming oncogene (eg ras) whereas cells which retained this function were resistant to neoplatic transformation. These results suggest that chemically induced neoplastic progression of Syrian hamster embryo cells involves at least three steps: (1) induction of immortality; (2) activation of a transforming oncogene; and (3) loss of a tumor suppression function.