I just read a paper that features fellow science blogger Chris Patil as an author (although he would be the first to state that he was second on the author's list). The manuscript, which appeared in yesterday's edition of PLoS Biology, describes senescence-associated secretory phenotype (aka SASP), a phenomenon that is associated with cancer cells treated with chemotherapeutic reagents that cause DNA-damage and with cells undergoing senescence. From the paper:
Despite support for the idea that senescence is a beneficial anticancer mechanism, indirect evidence suggests that senescent cells can also be deleterious and might contribute to age-related pathologies [10,23-25]. The apparent paradox of contributing to both tumor suppression and aging is consistent with an evolutionary theory of aging, termed antagonistic pleiotropy . Organisms generally evolve in environments that are replete with extrinsic hazards, and so old individuals tend to be rare in natural populations. Therefore, there is little selective pressure for tumor suppressor mechanisms to be effective well into old age; rather, these mechanisms need to be sufficiently effective only to ensure successful reproduction. Further, tumor suppressor mechanisms could in principle even be deleterious at advanced ages, as predicted by evolutionary antagonistic pleiotropy. Consistent with this view, senescent cells increase with age in mammalian tissues , and have been found at sites of age-related pathologies such as osteoarthritis and atherosclerosis [28-30]. Moreover, in mice, chronically active p53 both promotes cellular senescence and accelerates aging phenotypes [31,32].
How might senescent cells be deleterious? Senescent cells acquire many changes in gene expression, mostly documented as altered mRNA abundance, including increased expression of secreted proteins [33-41]. Some of these secreted proteins act in an autocrine manner to reinforce the senescence growth arrest [37,38,40,41]. Moreover, cell culture and mouse xenograft studies suggest that proteins secreted by senescent cells can promote degenerative or hyperproliferative changes in neighboring cells [35,39,42,43]. Thus, although the cell-autonomous senescence growth arrest suppresses cancer, factors secreted by senescent cells might have deleterious cell-nonautonomous effects that alter the tissue microenvironment.
It turns out that SASP is responsive to oncogenic forms of RAS and loss of p53, two of the most important genetic contributors to cancer.
It will be interesting to tease out whether SASP is solely due to an increase in transcription of a select group of secreted proteins or whether some other aspect of mRNA metabolism is altered (such as a decrease in mRNA turnover). After all, there seems to be a tight connection between stress and mRNA metabolism (see this post). Also it is likely that the secretory potential of the endoplasmic reticulum has to be upregulated and this clearly requires certain branches of the UPR gene regulatory program (unfolded protein response - again another stress response pathway - see this post) to be activated.
Abel Pharmboy has a great post on the article, that I strongly encourage you to go over and check it out.
I should also add that one of the benefits of blogging as a scientist is that it gives you a forum to discuss your published results. In this spirit, I encourage you to head over to Ouroboros and ask Chris about SASP and his latest findings.
Thanks for the nod and commentary, Alex. As I mentioned at Ouroboros, we've got the mRNA metabolism stuff under consideration but as yet it's moved pretty slowly. Both of your linked posts point out aspects of the issue that we hadn't yet been focusing on, so I appreciate them very much.
One thing I forgot to mention about the UPR/ER stress angle is that we're very likely going to look at real-time reporters of ER stress, at least once they're ready for deployment in mammalian cells. Should be lots of fun if it works.