Gjerset R A, Arya J, Volkman S, Haas M
UCSD Cancer Center, University of California, San Diego, La Jolla 92093-0063.
Mol Carcinog. 1992;5(3):190-8. doi: 10.1002/mc.2940050305.
We investigated the mechanism of radiation induction of murine thymic lymphomas by studying the characteristics of primary x-ray-induced thymic lymphoma (PXTL) cell lines and of their oncogene-induced, progressed progeny. It is widely thought that proto-oncogene alterations are associated with the induction of murine lymphomas; however, few, if any primary murine radiation-induced lymphomas possess (proto-)oncogene alterations. Independently derived cell lines grown directly (i.e., without in vivo transplantation) from thymic lymphomas of irradiated C57BL/6 mice possess the properties of immortalized pre-T cells and lack many of the characteristics of "tumor cells". PXTL cells are poorly tumorigenic upon transplantation, do not clone in methylcellulose cultures, are growth factor dependent and autocrine, and lack consistent chromosome and oncogene abnormalities. However, the thymic lymphomas are malignant and cause the death of each afflicted mouse. PXTL cells expressed two immunologically distinct forms of the tumor suppressor protein p53 that have moderately increased stability (t1/2 = 1 h) when compared with p53 of normal splenic T lymphocytes. Early PXTL cells could progress in vitro to a fully tumorigenic phenotype after infection with retroviruses encoding the c-myc and v-ras oncogenes. Progressed T-lymphoma cells acquired growth factor independence, a highly transplantable and tumorigenic phenotype, and the ability to quantitatively clone in methylcellulose cultures. Progressed lymphoma cells coordinately downregulated the expression of five T-cell differentiation markers, upregulated the expression of CD44 (Pgp-1), and harbored vastly elevated levels of two immunologically distinct forms of p53. Our results suggest that the early thymic lymphomas consist of differentiation-inhibited, immortal pre-T cells that are precursors to progressed, fully tumorigenic T-lymphoma cells.
我们通过研究原发性X射线诱导的胸腺淋巴瘤（PXTL）细胞系及其癌基因诱导的进展后代的特征，来探究辐射诱导小鼠胸腺淋巴瘤的机制。人们普遍认为原癌基因改变与小鼠淋巴瘤的诱导有关；然而，极少有原发性小鼠辐射诱导的淋巴瘤（如果有的话）具有（原）癌基因改变。从受照射的C57BL/6小鼠的胸腺淋巴瘤直接培养（即未经体内移植）而独立获得的细胞系具有永生化前T细胞的特性，并且缺乏许多“肿瘤细胞”的特征。PXTL细胞移植后致瘤性较差，在甲基纤维素培养基中不能克隆，依赖生长因子且具有自分泌性，并且缺乏一致的染色体和癌基因异常。然而，胸腺淋巴瘤是恶性的，会导致每只患病小鼠死亡。PXTL细胞表达两种免疫上不同形式的肿瘤抑制蛋白p53，与正常脾T淋巴细胞的p53相比，其稳定性适度增加（半衰期=1小时）。早期PXTL细胞在用编码c-myc和v-ras癌基因的逆转录病毒感染后，可在体外进展为完全致瘤的表型。进展的T淋巴瘤细胞获得了生长因子非依赖性、高度可移植和致瘤的表型，以及在甲基纤维素培养基中定量克隆的能力。进展的淋巴瘤细胞协同下调五种T细胞分化标志物的表达，上调CD44（Pgp-1）的表达，并含有两种免疫上不同形式的p53的大量升高水平。我们的结果表明，早期胸腺淋巴瘤由分化受抑制的永生化前T细胞组成，这些细胞是进展的、完全致瘤的T淋巴瘤细胞的前体。
