Scientists at the Cancer Research UK (CRUK) Edinburgh Centre at the University of Edinburgh report that they have discovered that regular cells can take on characteristics of immune cells, which can send warning signs when they are stressed or in danger. The mechanism is part of the body’s system for removing older cells, a natural part of the aging process (senescence).
The researchers, whose study (“The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype”), appears in Science Advances, say the system may also help the body detect cancer cells sooner, so that they can be removed before tumors form.
“Cellular senescence is a stress response program characterized by a robust cell cycle arrest and the induction of a proinflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that, during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models,” the investigators wrote.
“TLR2 promotes cell cycle arrest by regulating the tumor suppressors p53-p21CIP1, p16INK4a, and p15INK4b and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAAs) that, in turn, function as the damage-associated molecular patterns (DAMPs) signaling through TLR2 in OIS.
“Last, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.”
Senescence stops cells from dividing and prevents damaged cells from continuing to grow. The process is prompted by stress to the cell. It is also triggered when oncogenes become active.
The Edinburgh team found that key immune molecules inside cells, called TLR2 and TLR10, detect when oncogenes are switched on. This initiates a cascade of chemical signals that cause inflammation and trigger immune cells to remove the damaged cell.
TLR2 and TLR10 were known to be important for detecting infections such as bacteria and viruses, but this is the first time they have been found to play a key role in ordinary cell aging, according to the scientists
“The results of the study extend our knowledge of molecular mechanisms controlling senescence and may lead to new strategies for development of anticancer and anti-aging therapeutics based on innate-immune receptor manipulation,” explained Juan-Carlos Acosta, PhD, CRUK career development fellow.
“Damaged cancer-causing cells become senescent and are then killed by the body’s own immune system. However, if the immune system does not destroy the senescent cell, the surrounding tissue can become inflamed, promoting cancer development,” added Matthew Hoare, PhD, clinician scientist, CRUK Cambridge Centre and honorary consultant.
“This is a really hot area for research, as senescence has the potential to stop cancer development in the earliest stages. These findings show for the first time that damaged cancer-causing cells use TLR2/10 signaling to become inflamed, presenting potential drug targets that could help the body clear senescent cells before they cause harm.”