title: Characterization of aneuploid populations with trisomy 7 and 20 derived from diploid human colonic epithelial cells.
abstract: Chromosomal instability leading to aneuploidy occurs in most sporadic colorectal cancers (CRCs) and is believed to be an early driving force in disease progression. Despite this observation, the cellular advantages conferred by these cytogenetic alterations are poorly understood. Here, we provide evidence that serum-free passage of originally diploid, immortalized human colonic epithelial cells (HCECs) gave rise to the acquisition of trisomy 7 (+7), an aneuploidy detected in more than 40% of colorectal adenomas. These cells remain diploid under long-term growth in 2% serum conditions. Analysis by GTG banding and fluorescent in situ hybridization detected no rare preexisting +7 cell in the original population, suggesting a conversion of diploid cells to an aneuploid state. The acquisition of +7 also precedes loss or truncation of the adenomatosis polyposis coli gene as both diploid and +7 cells express full-length, functional protein. Coculturing of fluorescent-labeled cells demonstrate that +7 HCECs have a growth advantage over diploid cells in serum-free conditions. Defects in cell migration and aberrant regulation of the epidermal growth factor receptor, located on chromosome 7p, are also detected in +7 HCECs. Interestingly, knockdown of TP53 and expression of K-Ras(V12) in +7 HCECs resulted in the emergence of trisomy 20, another nonrandom aneuploidy observed in ∼85% of CRC. In summary, we describe isogenic colonic epithelial cells that represent cytogenetic changes occurring frequently in sporadic CRC. The emergence and characterization of trisomy 7 and 20 demonstrate that these HCECs may serve as unique human cell-based models to examine the effects of chromosomal instability in CRC progression.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ly
authors.forename: Ugur
authors.initials: U
authors.lastname: Eskiocak
authors.forename: Sang B
authors.initials: SB
authors.lastname: Kim
authors.forename: Andres I
authors.initials: AI
authors.lastname: Roig
authors.forename: Suzie K
authors.initials: SK
authors.lastname: Hight
authors.forename: Dypti R
authors.initials: DR
authors.lastname: Lulla
authors.forename: Ying S
authors.initials: YS
authors.lastname: Zou
authors.forename: Kimberly
authors.initials: K
authors.lastname: Batten
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000782:Aneuploidy; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D018929:Cell Culture Techniques / Q000379:methods; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D043171:Chromosomal Instability; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D020732:Cytogenetic Analysis; D004171:Diploidy; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D009030:Mosaicism; D013997:Time Factors; D014314:Trisomy / Q000235:genetics / Q000473:pathology*
chemical_list: D016895:Culture Media, Serum-Free