Transfer of a normal human chromosome 11 suppresses tumorigenicity of some but not all tumor cell lines

Abstract

The complete suppression of tumorigenicity of a human cervical cancer cell (HeLa) and a Wilms' tumor cell line (G401) following the introduction via microcell fusion of a single chromosome t(X;11) has been demonstrated by Stanbridge and co-workers. To determine whether other tumor cell lines are suppressed by chromosome 11, we performed chromosome transfer experiments via microcell fusion into various human tumor cell lines, including a uterine cervical carcinoma (SiHa), a rhabdomyosarcoma (A204), a uterine endometrial carcinoma (HHUA), a renal cell carcinoma (YCR-1), and a rat ENU-induced nephroblastoma (ENU-T1). We first isolated a mouse A9 cell containing a single human chromosome 11 with integrated pSV2-neo plasmid DNA. Following microcell fusion of the neo-marked chromosome 11 with the various tumors mentioned above, we isolated clones that were resistant to G418 and performed karyotypic analyses and chromosomal in situ hybridization to ensure the transfer of the marked chromosome. Whereas the parental cells of each cell line were highly tumorigenic, SiHa and A204 microcell hybrid clones at early passages were nontumorigenic in nude mice and HHUA was moderately tumorigenic. On the other hand, YCR-1 and ENU-T1 microcell hybrid clones were still highly tumorigenic following the introduction of chromosome 11. Thus, the introduction of a normal chromosome 11 suppresses the tumorigenicity of some but not all tumors, suggesting that the function of the putative suppressor gene(s) on chromosome 11 is effective only in specific tumors.

Localization of tumor suppressor activity important in nonsmall cell lung carcinoma on chromosome 11q

“…Chr 11 also demonstrates tumor suppressor activity when introduced into cell lines derived from cervical, prostate, or breast cancers or rhabdomyosarcomas (20)(21)(22)(23). Chromosome transfer methods can be combined with this type of biological assay to further refine the positions of candidate genes when donor cells are irradiated to create fragments of chromosomes before fusion.…”

Human chromosome 7 carries a putative tumor suppressor gene(s) involved in choriocarcinoma

“…The expression of genes locating on the transferred chromosome is regulated by the physiological control of chromosomal sequences. Thus, microcell-mediated chromosome transfer procedures have been used successfully to introduce speci®c chromosomes to test for the suppression of tumorigenic phenotypes of cell lines derived from various human malignancies (Stanbridge, 1988;Yamada et al, 1990;Zenklusen et al, 1994a,b,c;Oshimura et al, 1990;Saxon et al, 1986;Tanaka et al, 1991;Porteous et al, 1989;Weissman et al, 1987;Conway et al, 1992). We generated and characterized microcellhybrids containing dierent individual chromosomes.…”

The molecular genetics of cervical carcinoma

“…The initial evidence came from somatic cell genetics. The fusion of HeLa cells (with integrated HPV18) or SiHa cells (with integrated HPV16), with microcells containing human chromosome 11, resulted in the generation of cell hybrids that have lost their tumorigenic properties in nude mice, but if these hybrids lost the introduced chromosome 11 they regained their tumorigenic phenotype (Saxon et al, 1986;Koi et al, 1989;Oshimura et al, 1990). Furthermore, the progression towards immortalization of human keratinocytes transfected with either HPV16 or HPV18 was accompanied by allele losses at 11q (Steenbergen et al, 1996), and cytogenetic studies of cervical carcinomas detected that chromosome 11 is underrepresented (Southern and Herrington, 1997).…”