Replicatively exhausted or genomically compromised cells can enter a stable post-mitotic state called senescence. They condense their chromatin, downregulate cell-cycle genes, and never divide again. This makes sense: cells at greater risk for carrying potentially oncogenic mutations take themselves out of commission, preventing themselves from becoming tumors.
This noble clonal sacrifice, however, precedes an era of downright antisocial behavior. Senescent cells secrete growth factors, inflammatory cytokines, and metalloproteases — ironically (given the presumed justification for their initial growth arrest), it’s as if they’re actively trying to push other cells in their tissue microenvironment over the edge into full-blown neoplasia (or, if they’re already neoplastic, to make metastasis that much easier). The combination of factors secreted by senescent cells has been implicated not only in cancer but in age-related decline as well; for a comprehensive review of the story to date, see here.
To the panoply of misdeeds already attributed to senescent cells, Coppé et al. add one more: stimulation of angiogenesis, via secretion of vascular endothelial growth factor (VEGF).
Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. Nonetheless, the senescence response is thought to be antagonistically pleiotropic, and thus contribute to aging phenotypes, including, ironically, late life cancers. The cancer-promoting activity of senescent cells is likely due to secreted molecules, the identity of which remains largely unknown. Here, we show that senescent fibroblasts, much more than presenescent fibroblasts stimulate tumor vascularization in mice. Weakly malignant epithelial cells co-injected with senescent fibroblasts had larger and greater number of blood vessels compared to controls. Accordingly, increased vascular endothelial growth factor (VEGF) expression was a frequent characheristic of senescent human and mouse fibroblasts in culture. Importantly, conditioned medium from senescent fibroblasts, more than medium from presenescent cells, stimulates cultured human umbilical vein endothelial cells (HUVECs) to invade a basement membrane, a hallmark of angiogenesis. Increased VEGF expression was specific to the senescent phenotype and increased whether senescence was induced by replicative exhaustion, overexpression of p16Ink4a or overexpression of oncogenic RAS. … Our findings may in part explain why senescent cells stimulate tumorigenesis in vivo, and support the idea that senescent cells may facilitate age-associated cancer development by secreting factors that promote malignant progression.
For those of you just joining us, let’s review: Senescent cells secrete growth factors (encouraging cell proliferation), inflammatory factors (deranging anti-cancer immune surveillance), metalloproteases (breaking down the extracellular matrix and facilitating metastasis)…and now we know they also encourage angiogenesis, making sure that nearby tumors are well-vasculated and have a nice rich supply of oxygen.
Some tumor suppressor mechanism.
How could such a system have evolved? One theory is that senescence does, indeed, prevent early-life cancer that would otherwise originate from genotoxically stressed cells — and that after that it really doesn’t matter what they do, including cause cancer, because the strength of selection diminishes in later life. This is antagonistic pleiotropy at work: genes that cause both good and bad phenotypes can be positively selected, as long as the good phenotypes kick in earlier.
Stay tuned for more about good cells doing evil. I have a sneaky suspicion that the field will see a bunch more about this sometime very shortly.
(Disclosure: One of the authors of the paper is a member of my lab, and another is my PI.)