Secret of Cell Replacement Signaling Discovered

Monday, June 19, 2017

Dying cells ensure that they will be replaced, and now a study has shown for the first time how they do it — a discovery that also suggests an ingenious new approach to shrinking cancerous tumors. A research team from Rush University Medical Center published a paper in the June 19 issue of the journal Developmental Cell describing these two groundbreaking discoveries.

“I believe this discovery is going to have important ramifications for cancer biology and cancer drug development, and for the treatment of other diseases, such as diabetic foot ulcers,” said Sasha Shafikhani, PhD, associate professor in the Department of Internal Medicine at Rush Medical College, who headed the study.

Dying cells release messengers to prompt their replacement

The team made its two-pronged discovery while investigating how an opportunistic microbe kills cancer cells. For years, Shafikhani’s lab has been studying Pseudomonas aeruginosa, a bacterium that can be lethal, but only to people who are already wounded or sick.

This pathogenic bacterium secretes several toxins that allow it to cause infection. One such toxin, ExoT, inhibits cell division and can severely impede wound healing, but it’s also known to kill cancer cells.

The researchers were trying to figure out ExoT’s lethal mechanisms against cancer when they unlocked, almost by accident, a mystery researchers have been trying to solve for decades.  Before cells die, they alert their neighbors of the need to replace them and compensate for their demise, ensuring the organism’s survival. Medical researchers have been wondering for at least 20 years how cells manage to do it.

While shining a light on the lethal habits of Pseudomonas aeruginosa, Shafikhani’s team discovered what actually happens in that process, called compensatory proliferation signaling (CPS). The investigators saw — and have shown in amazing videos they produced — that during CPS, dying cells release microvesicles (a type of sac) containing the protein CrkI. These microvesicles travel to neighboring cells and upon contact cause them to create new cells to replace the ones that are dying.

Removing protein in microvesicle halts cell replacement

In addition, Shafikhani and his colleagues demonstrated that when they knocked out the CrkI protein during CPS, either genetically or with the ExoT toxin, they could stop cell compensatory proliferation cold. That’s a trick Pseudomonas aeruginosa uses to take advantage of damaged tissues, but it has exciting possibilities for disease treatment as well.

The death of cells, called apoptosis, is a normal part of life. “In the course of normal tissue turnover in humans, about one million cells die every second, through a highly-regulated process of apoptotic programmed cell death (PCD),” the new paper states. However, apoptosis is not the only type of cell death, and not all cells dying of apoptosis are capable of CPS.

Apoptosis is of particular interest to cancer researchers, because the majority of the current cancer drugs kill cancer cells by apoptosis.

However, CPS can dog apoptosis in cancer treatment. Treated cancer cells can be induced to die, but before they do, they call on nearby cancer cells to replace them, so the cancer-fighting drug loses its effectiveness and the tumor persists.

The hope, Shafikhani says, is that if the communication between the dying cancer cells and neighboring cancer cells is blocked, the treated cancer cells would not be replaced when they die, and the tumor would dissolve.      

“Knowing that it’s possible to uncouple CPS from apoptosis, we now can develop new drugs that would improve the effectiveness of treatments already in use,” Shafikhani says.     

In cancer cells, the CPS process and communication would need to be interrupted to prevent the development of new cancer cells; but in other conditions, the CPS process could be enhanced to accelerate the healing process. Shafikhani says that one of the possible long-term benefits of the discoveries set out in the new Developmental Cell article could be to use these vesicles to encourage cell proliferation — for example, in diabetic wounds where healing is not going well because tissue cells are dysfunctional and have reduced ability to regenerate.           

All the researchers on the new study were from Rush University Medical Center.