Dr. Janusz Rak

Brain cancer cells emit tiny bubbles – known as oncosomes – that contain cancer-causing proteins. Oncosomes carry high concentrations of these malevolent molecules, which may float inside or adhere to the outer surfaces of other cells, causing them to misbehave. Culprits on the surface can attach to normal cells or less malignant cells, triggering the spread of cancer or making it worse.

Like a mini-bus, oncosomes transport molecular passengers from the cancer cells that shed them to distant sites throughout the body. Because they float in the blood, they are easy to collect. Studying the contents of these “cancer bubbles” may help to identify the characteristics of tumours that surgeons cannot sample due to their unreachable location – a factor that may help to develop or improve cancer treatments.

Dr. Janusz Rak, his team of researchers at the Montreal Children’s Hospital Research Institute, and collaborators at the University of Toronto discovered these properties of oncosomes while studying glioblastoma multiforme, an aggressive form of brain cancer that afflicts children and adults. The outlook for the disease is dismal; most patients do not survive more than a year after diagnosis. Research into brain tumours has yet to make an impact on this incurable disease.

From blood vessels to brain tumours

Dr. Rak developed a fascination for the mysterious ways in which the vascular system interacts with cancer early in his career. For more than 20 years, he and his research teams have contributed to our knowledge of how blood vessels affect tumour growth.

“It’s an amazing network of interrelationships,” he observes. “Diseases are not simple things. They are very intricate and interconnected and many things have to happen together to cause a disease, especially cancer.

“One question leads to five questions, each of which leads to five more questions,” he adds. “It’s a cascading process and a very fascinating one, I have to say.”

Dr. Rak’s interest in studying brain cancer in children was partly inspired by Dr. Abhijit Guha, a prominent neurosurgeon and scientist at Toronto’s Hospital for Sick Children, and is now conducted in close collaboration with star neuro-oncologist Dr. Nada Jabado at Montreal Children’s Hospital (MCH). At the MCH Research Institute, his team searched for links between the vascular system and relentless growth of glioblastoma multiforme – and found one.

“It caught our eye that blood clots occur in cancer patients, so we asked the question, does this relate to cancer-causing genes? The answer was, amazingly, yes. We began to look at the mediators of clotting – these little particles that tumour cells emit into the circulation, and more malignant cells indeed produced them” he says.

“It turns out that circulating bubbles are extremely interesting entities. Apart from the blood-clotting aspect, which they seem to participate in, they actually carry a whole repertoire of molecules representative of cancer cells themselves. Much to our amazement, we found they contain cancer-causing proteins (oncoproteins).”

Some brain cancer cells have an oncoprotein known as epidermal growth factor receptor variant III (EGFRvIII) on their surface. The detection of this mutated receptor is associated with aggressive tumour growth.

Dr. Rak and his colleagues tagged EGFRvIII on brain cancer cells with a gellyfish-derived glowing protein [green fluorescent protein (GFP)]. By following this molecular trail, they were able to show that brain cancer cells “bubble off” regions of the cellular membrane that contain EGFRvIII. It sits on the outer surface of oncosomes, as they float through the blood, and eventually attaches to a normal cell or one in the early stages of cancer. Once taken up by cells, EGFRvIII starts a chain of biochemical reactions that induces a cancer-like state in target cells or intensifies their malignancy.

The discovery of oncosomes that carry EGFRvIII may explain how brain cancer cells communicate with one another and spread so rapidly.

Tumours acquire the ability to form oncosomes somewhere along the path of cancer development. “We think it happens relatively early and intensifies over time,” says Dr. Rak. “The more aggressive the tumour becomes, the more of these oncosomes it can emit.”

Molecule-rich oncosomes offer snapshot of tumour

Dr. Rak believes that researchers can derive an overall picture of a particular tumour’s stage and composition by looking at how many and what kinds of oncosomes circulate in the blood of cancer patients.

This work opens new doors in cancer research, shattering the old paradigm that cancer cells are unique, self-contained (autonomous) sources of malignancy. “In fact, they have a broader influence,” says Dr. Rak. “They can affect their surroundings in a very profound and unusual way by spreading oncoproteins around the body and into the adjacent tissue.”

Dr. Rak believes that studying oncosomes may lead to simpler diagnostic tests, more informed decisions about treatment, and new ways to monitor the effects of new cancer therapies, for instance, so-called targeted agents.

Targeted therapies hit the genes and proteins involved in causing cancer. Before they can be put to work, doctors need to know whether a patient’s tumour contains the specific molecular target of a particular drug. During treatment, they need a way to figure out how well the drug is hitting its target.

Because oncosomes give a snapshot of what’s inside tumour cells, Dr. Rak believes that, in future, a simple blood test could help doctors to find specific drug targets before recommending a treatment. This step would advance the treatment of brain tumours, which doctors can see with imaging technology but are rarely able to biopsy for tissue samples.

Simple blood tests could also collect oncosomes during treatment to assess how patients respond to therapy.

Dr. Rak and his team, Khalid Al-Nedawi, Brian Meehan and others have shown that it’s possible in mice. “We can sample oncosomes in the blood as long as treatment is going on and really get a sense of whether or not the drug is actually doing what it should, biochemically, whether the drug target – the particular molecule – is being attacked, and what are the consequences.”

Other cancer researchers are beginning to investigate whether oncosomes transport other oncoproteins and whether other types of tumours rely on these bubbles to spread or intensify cancer.

“It would be very advantageous to know what kind of oncosomes cancer stem cells make and how they impact the regrowth of cancer,” Dr. Rak observes.

Dr. Rak’s current research focuses on how cancer cells form oncosomes. His work is funded by the Canadian Cancer Research Society and Canadian Institutes of Health Research.

For further information, please contact Dr. Janusz Rak using the Email contact form or by phone at 514 412-4400