[gdpawel]

In a major breakthrough that will change the way cancer is studied and treated in the future, Toronto scientists have discovered a key reason why many tumours may return after chemotherapy.

In a new study, researchers at the Princess Margaret Cancer Centre have shown that some of the cells that drive tumour growth hide from common chemotherapy drugs by going “dormant” — reigniting the disease when they awaken after treatments end.

“That’s where this paper lies is to begin to add more depth (and) complexity to why cancers come back, why they recur,” says renowned stem cell scientist John Dick, whose paper was released Thursday by the journal Science.

“This will stimulate a lot of activity,” says Dick, the study’s senior author.

Luba Slatkovska, head of research with Canadian Cancer Society’s Ontario division agrees, saying the discovery represents a paradigm shift for research into the disease.

“John Dick is one of those researchers who is really changing the way we think about cancer, and this is another example,” Slatkovska says.

“We think that it’s going to become one of the new hot topics in cancer research,” she says.

Dick, also a molecular geneticist at the University of Toronto, says the newly-discovered dormant cells have precisely the same genetic mutations as those active ones that drove the original tumour to begin with.

Cancers occur when genetic mutations to a cell’s DNA cause them to replicate in an out-of-control fashion.

And it was assumed, Dick says, that cancers returned after chemotherapy because of subsequent genetic mutations that made them resistant to the drugs being used against the original tumours.

“And that is certainly true in many cases,” he says.

But the discovery of the genetically-identical dormant cells shows that other forces are at play in cancer recurrence and that these nongenetic forces must now command the attention of the oncology community.

“We thought that there would have been a different set of (genetic) mutations, a different spectrum of mutations that would have explained why (the recurring) cells were resistant to chemotherapy,” Dick says.

“And in a sense that’s not what we saw. We saw that they seemed to be quite similar or essentially identical (genetically) and so something else was driving their resistance to therapy.”

Dick, who last made headlines in 2011 when he led the team that first isolated blood stem cells, says that “something else” could include the micro-environments in which the dormant cells are located within the tumour.

“Is it that cells are sitting in the tumour in a location that makes them dormant?” he asks.

Dick says that along with cancer cells, tumours contain a number of normal tissues, including blood vessels and immune system agents.

“And it appears that tumour cells can lie in proximity to these non-tumour cells and that can influence their behaviour,” Dick says.

“So that is one of the properties we should be looking for, we should be looking for where tumour cells are sitting, who they’re close to and what kind of signals they are receiving.”

Dick, whose team grew human colorectal cancers in mice for the research, says only one in every several thousand cells in a tumour can actually drive its growth.

And many of these tumour drivers are susceptible to chemotherapies because most of the drugs now used in cancer treatment target cells that multiply at abnormal speeds — a signature of the disease in all its forms.

But if some of these stem-cell-like cancer drivers are dormant — in effect hiding their ability to rapidly replicate — the drugs will pass them over.

“Some of (the cancer driver cells) are actually quite sensitive (to chemotherapy) and other ones, particularly those ones that come from these so-called dormant cells are much more resistant,” Dick says.

“And that can be responsible for relapse.”

Dick says scientists now need to look for ways to kill these skulking cells or to control the factors that can awaken them.

“We need to understand the biological properties — not necessarily the genetic properties — that are driving dormancy,” he says.

An understanding of these nongenetic properties could lead to an entirely new generation of cancer medications, Dick says.

Slatkovska, whose society has funded Dick in the past but was not involved in the current study, says she can imagine the creation of drugs that could wake up the sleeping cells and expose them to killer chemo.

Drugs that could interfere with the external signals that call the dormant cells out of sleep could also become a weapon in the oncology arsenal, Dick says.

“What our paper is saying is that on top of (targeting) the genetic properties of these cells you have to target the biological properties to be more effective,” Dick says. “Everything doesn’t just rest on genetics.”