PUBLICATION
Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish
- Authors
- Lex, K., Maia Gil, M., Lopes-Bastos, B., Figueira, M., Marzullo, M., Giannetti, K., Carvalho, T., Ferreira, M.G.
- ID
- ZDB-PUB-200620-12
- Date
- 2020
- Source
- Proceedings of the National Academy of Sciences of the United States of America 117(26): 15066-15074 (Journal)
- Registered Authors
- Ferreira, Miguel Godinho
- Keywords
- aging, cancer, inflammation, telomerase, telomeres
- MeSH Terms
-
- Humans
- Melanoma/genetics
- Melanoma/immunology
- Melanoma/metabolism*
- Telomere Shortening
- Animals
- Telomere/genetics
- Telomere/metabolism*
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/immunology
- Telomerase/genetics
- Telomerase/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zebrafish/genetics
- Zebrafish/immunology
- Zebrafish/metabolism*
- Disease Models, Animal
- PubMed
- 32554492 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Lex, K., Maia Gil, M., Lopes-Bastos, B., Figueira, M., Marzullo, M., Giannetti, K., Carvalho, T., Ferreira, M.G. (2020) Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 117(26):15066-15074.
Abstract
Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping