POSTER NO: 472

Carcinogenesis of renal cell lines in nude mice in a physiological context clarifying the origin of malignant rhabdoid tumor (MRT)

¹De-Li Zhang, ²Gao-Sheng Huang, ²Liu-Jin Li, ³Shang-Gao Liu, ³Lung-Fei Yen, ⁴Fu-De Fang, ¹Hao-Ran Wang, ¹Ming-Xu Xu, ¹Pei-Guo Ding, ⁴Xiao-Jing Sun, ¹Qi-Peng Zhang, ¹Ying Huang
¹School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100083, P.R.China, ²Department of Pathology at School of Pre-clinical Education, Section of Pathology at Xi-Jing Hospital, and Institute for Cancer Research at China Cancer Research Foundation, Fourth Military Medical University, Xian710032, P.R.China, ³College of Animal Medical Sciences and State Key Laboratory of Agricultural Biotechnology, China Agricultural University, Beijing 100094, P.R.China, ⁴State Key Laboratory of Medical Molecular Biology, Peking Union Medical Colloge/Chinese Academy of Medical Sciences, Beijing 100005, P.R.China

The purpose of this study lies in analyzing the relationship between karyortypic variations of animal renal epithelial cell lines leading to superhighly malignant tumor including MRT and their carcinogenesis in nude mice in a physiological context and thus in clarifying the origin of MRT at last. Malignant rhabdoid tumor (MRT) is a rare, enigmatic and highly lethal childhood cancer characterized by extreme aggressiveness and resistance to chemotherapy. As the most malignant human tumor, MRT is histologically characterized by the existence of intracytoplasmic eosinophilic inclusions composed of whorls of intermediate filaments. This is the so-called distinct 'rhabdoid' cytologic feature in common. Cytogenetic and molecular analyses have shown that the deletion of region 11.2 of the long arm of chromosome 22 (22q11.2) is a recurrent genetic characteristic of MRT, indicating that this locus may encode a tumour suppressor gene. p53 gene alterations may have an important role to play in the aggressive biological behavior and poor prognosis of this tumor, and the discovery of this candidate tumor suppressor gene for MRT, INI1 on chromosome (Ch)22q11.2, has re-established this neoplasm as a distinct entity. However, the origin of MRT, a long-standing very important problem, has been controversial in the world up to date, various cellular origins having been proposed because of the phenotypic diversity of MRT. It is known to all that clarifying a tumor origin is of great important basis for the diagnosis, treatment and prevention of the extremely malignant tumor. Furthermore, we can rarely meet MRT by chance even in human body, but we can not expect to repeat it in the same way or condition, even we can not reproduce it as a transplanted tumor in model animals, or have difficulty in well establishing a continuous tumor cell line in vitro culture. Thus, the lack of an in vivo animal model or even a good in vitro culture model for MRT has been a major stumbling block in understanding it. In this investigation, we found that as a whole cell phenomenon, the tumorigenicity of cell line is different among different-karyotypic cells, and that it is the genetic characteristics of chromosomes of cell lines that determines their tumorigenicity, but with species- specific carcinogenecity, especially the development of MRT is determined by chromosomal characteristics of renal cell lines, and that the chromosome number variation of cell lines has positive relationship with their carcinogenesis, and highly variable strains of tumor cell line can be selected quickly and successfully in nude mice by alternate cultivation in vitro and in vivo. MRT was evolved in nude mice inoculated with violently variable HeLa, BHK-21 or Vero cells, especially repeatedly evolved with BHK-21, thus kidney epithelium is an important original tissue of MRT. It jumps out of the dilemma of using tumor tissue from human body without clear origin for clarifying itself origin. Although the incidence of MRT in nude mice inoculated subcutaneously with violently variable Hela cells of NM20/X strain on passage 11, Hela cells of KB strain on passages 10-11, Vero cells of JA strain on passage 42 and BHK-21 cells reaches 100%(5/5), 100%(4/4), 100%(3/3) & 62%(26/42), respectively, yet it is needed that the inoculated biologically active cell number is huge [(2-12.75)x10,000,000 cells per nude mouse], the tumor emerges immediately, develops violently, grows very fast, and has an extremely aggressive malignancy, the tumor is rich in the blood vessel giving a full supply of blood for it, the mean value of major diameter x minor diameter of the tumor is essentially up to the standard of 30mm-20mm in 10-20 days or 2-3 weeks after the inoculation of the cells into the nude mice. Discovery of MRT Pathogeny (Chromosome karyotypes of highly variable renal cell strains), mastery of developmental conditions and growth laws, investigation and determination of clinical features, and exploration into animal models of MRT are all our unique contributions in the field.