Telomere shortening produces an inflammatory environment that promotes tumor invasiveness in zebrafish

Cancer incidence increases exponentially with age, when human telomeres are shorter. Similarly, telomerase mutant zebrafish (tert) 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 non-cell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when WT tumors are generated in tert mutant zebrafish. tert zebrafish show increased levels of senescence (cdkn2a and ink4a/b) and inflammation (TNF-α). In addition, we transferred second generation tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced senescence and increased neutrophil numbers in surrounding larval tissues in a non-cell autonomous manner, creating an inflammatory environment. Considering that inflammation is pro-tumorigenic, we transplanted melanoma-derived cells into second generation tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased micrometastasis. To test if inflammation was necessary for this effect, we treated melanoma transplants with non-steroid anti-inflammatory drugs and show that higher melanoma invasiveness 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.