title: Mandatory chromosomal segment balance in aneuploid tumor cells.
abstract: BACKGROUND
  Euploid chromosome balance is vitally important for normal development, but is profoundly changed in many tumors. Is each tumor dependent on its own structurally and numerically changed chromosome complement that has evolved during its development and progression? We have previously shown that normal chromosome 3 transfer into the KH39 renal cell carcinoma line and into the Hone1 nasopharyngeal carcinoma line inhibited their tumorigenicity. The aim of the present study was to distinguish between a qualitative and a quantitative model of this suppression. According to the former, a damaged or deleted tumor suppressor gene would be restored by the transfer of a normal chromosome. If so, suppression would be released only when the corresponding sequences of the exogenous normal chromosome are lost or inactivated. According to the alternative quantitative model, the tumor cell would not tolerate an increased dosage of the relevant gene or segment. If so, either a normal cell derived, or, a tumor derived endogenous segment could be lost.
  
  
  METHODS
  Fluorescence in Situ Hybridization based methods, as well as analysis of polymorphic microsatellite markers were used to follow chromosome 3 constitution changes in monochromosomal hybrids.
  
  
  RESULTS
  In both tumor lines with introduced supernumerary chromosomes 3, the copy number of 3p21 or the entire 3p tended to fall back to the original level during both in vitro and in vivo growth. An exogenous, normal cell derived, or an endogenous, tumor derived, chromosome segment was lost with similar probability. Identification of the lost versus retained segments showed that the intolerance for increased copy number was particularly strong for 3p14-p21, and weaker for other 3p regions. Gains in copy number were, on the other hand, well tolerated in the long arm and particularly the 3q26-q27 region.
  
  
  CONCLUSIONS
  The inability of the cell to tolerate an experimentally imposed gain in 3p14-p21 in contrast to the well tolerated gain in 3q26-q27 is consistent with the fact that the former is often deleted in human tumors, whereas the latter is frequently amplified. The findings emphasize the importance of even minor changes in copy number in seemingly unbalanced aneuploid tumors.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Box 280, 171 77 Stockholm, Sweden. Maria.Kost-Alimova@mtc.ki.se
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Eva
authors.initials: E
authors.lastname: Darai-Ramqvist
authors.forename: Wing Lung
authors.initials: WL
authors.lastname: Yau
authors.forename: Agneta
authors.initials: A
authors.lastname: Sandlund
authors.forename: Ludmila
authors.initials: L
authors.lastname: Fedorova
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Irina
authors.initials: I
authors.lastname: Kholodnyuk
authors.forename: Yue
authors.initials: Y
authors.lastname: Cheng
authors.forename: Maria
authors.initials: M
authors.lastname: Li Lung
authors.forename: Eric
authors.initials: E
authors.lastname: Stanbridge
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Stefan
authors.initials: S
authors.lastname: Imreh
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D051379:Mice; D016513:Mice, SCID; D018895:Microsatellite Repeats / Q000235:genetics; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods