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Chromosomal instability and phenotypic plasticity during the squamous–spindle carcinoma transition: association of a specific T(14;15) with malignant progression

Oncogene volume 24, pages 7608–7618 (2005)Cite this article

Abstract

In mouse epidermal carcinogenesis, the latest stage of malignant progression involves the transition from squamous cell carcinoma to a highly aggressive type of tumor with spindle morphology. In this work, we have isolated a minor epithelial cell subpopulation (CarC-R) contained in the highly malignant spindle carcinoma cell line CarC. CarC-R exhibited a drastic reduction in tumorigenicity when compared with CarC, but CarC-R-induced tumors were mainly sarcomatoid, although they subsequently reverted to the epithelial phenotype when tumor explants were recultured in vitro. Several single-cell clones with either stable epithelial or fibroblastic phenotypes were isolated from an explanted CarC-R tumor (CarC-RT). All these cell lines contained the same specific point mutation in H-Ras codon 61, but while CarC spindle cells had lost the normal H-Ras allele, it was retained in CarC-R- and CarC-RT-derived cell lines. Furthermore, CarC cells have inactivated p16INK4a and p19INK4a/ARF transcription, while CarC-R and CarC-RT clones expressed p19 mRNA and protein but not p16. Altogether, these results suggest that CarC-R represents a precursor stage to CarC in malignant progression. Spectral karyotyping analysis revealed that CarC-R was highly aneuploid and contained many chromosomal abnormalities. In contrast, CarC had a diploid or tetraploid modal chromosome number and contained a specific T(14;15) translocation in all of the analysed metaphases. The T(14;15) translocation was present in only a minority (1.9%) of CarC-R cells, but it was widely spread in CarC-RT and its derived cell clones, regardless of their epithelial or fibroblastic phenotype, indicating that T(14;15) segregates with malignancy.

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Acknowledgements

We thank Dr Ignacio Palmero for his generous gift of anti-p19 antibody and helpful suggestions during the course of this work, Maria Villa-Morales for kindly providing us with thymic DNA from mice and Maria M Yurrita for critical reading of the manuscript. This study was supported by grants from the ‘Ministerio de Educación y Ciencia’ of Spain (SAF2004-04902 to MQ, and BOS2002-00232 to JLB), ‘Fondo de Investigación Sanitaria’ (Red de Centros de Cáncer, RTICCC, CO3/10) to MQ, and by the European Union (Cost Action B19, ‘Molecular Cytogenetics of Solid Tumours’) to JCC. MP and SR-P were the recipients of fellowships from the ‘Ministerio de Educación y Ciencia’ and ‘Fundación Inocente Inocente’ of Spain, respectively.

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Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas, Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Arturo Duperier 4, Madrid, 28029, Spain

    Mar Pons, Cristina González, Carlos Gamallo & Miguel Quintanilla

  2. Cytogenetics Unit, Centro Nacional de Investigaciones Ocológicas (CNIO), Madrid, Spain

    Juan C Cigudosa & Sandra Rodríguez-Perales

  3. Department of Biology, Facultad de Ciencias, UAM, Madrid, Spain

    José L Bella

  4. Department of Pathology, Hospital Universitario de la Princesa, Facultad de Medicina, UAM, Madrid, Spain

    Carlos Gamallo

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  1. Mar Pons
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  2. Juan C Cigudosa
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Correspondence to Miguel Quintanilla.

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Pons, M., Cigudosa, J., Rodríguez-Perales, S. et al. Chromosomal instability and phenotypic plasticity during the squamous–spindle carcinoma transition: association of a specific T(14;15) with malignant progression. Oncogene 24, 7608–7618 (2005). https://doi.org/10.1038/sj.onc.1208903

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