Non-cell-autonomous mechanisms of tumor initiation and relapse by chromosomal instability
Abstract
Chromosomal instability (CIN) is a hallmark of cancer, and a primary cause of genetic heterogeneity in tumors. Depending on the degree of CIN and the affected tissue, CIN can promote or suppress tumor formation, and high CIN induction has been proposed as a therapeutic strategy. How CIN achieves these effects is unclear. Here we use a conditional mouse model of graded CIN in combination with longitudinal monitoring of DMBA/TPA-initiated skin tumors to show that low CIN increases the frequency of skin tumor initiation, while higher CIN accelerates tumor onset and growth rates. Strikingly, gene recombination analysis of the tumors reveals that upon high CIN induction the fast-growing tumors originate from rare low CIN cells, suggesting a strong non-cell-autonomous effect of high CIN. Gene expression analysis and immunohistochemistry show that high CIN causes epidermal hyperplasia, immune evasion, and a regenerative response that stimulates low CIN tumor growth beyond what is achieved by induction of low CIN alone. Such cell-extrinsic effects may be a common mechanism of tumor formation by CIN, as we observe it also in CIN-induced tumors of the intestine, breast, and mesentery. When high CIN is induced in established skin tumors, mimicking CIN-based therapy, tumors regress but relapse quickly. Relapsed tumors, too, arose from rare low CIN cells. Our findings have implications for our understanding of the contributions of CIN to cancer initiation and progression and give caution to the rationale for CIN therapies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Simona J. A. Lafirenze
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Bastiaan van Gerwen
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Ajit I. Quirindongo
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Natasja Costermans
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Aniek Janssen
Center for Molecular Medicine, University Medical Center Utrecht
Banafsheh Etemad
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Pim Toonen
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Marco A. D. Louro
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Wilma H. M. Hoevenaar
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Sameh Youssef
Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University
Alain de Bruin
Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University
Lodewijk A. A. Brosens
Department of Pathology, University Medical Center Utrecht
Nannette Jelluma
Hubrecht Institute 3584 CT Koninklijke Nederlandse Akademie van Wetenschappen 1011 JV and University Medical Center Utrecht
Geert J. P. L. Kops