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Cancer cells spread by releasing "bubbles"Isabelle Kling

A new fundamental mechanism of how tumour cells communicate has just been discovered by the team of Dr. Janusz Rak at the Research Institute of the McGill University Health Centre (MUHC) in collaboration with Dr Guha from the University of Toronto.

The cancer cells are able to communicate with their more healthy counter-parts by releasing vesicles. These bubble-like structures contain cancer-causing (oncogenic) proteins that can trigger specific mechanisms when they merge into non or less-malignant cells. These findings could change our view on how cancerous tissues work and lead to major clinical innovations. They were published on April 20 in the on-line edition of Nature Cell Biology.

The surface of some brain tumour cells has long been known to express a mutated version of what is called the variant III epidermal growth factor receptor (EGFRvIII). Although this factor is expressed only in a fraction of tumour cells, it has a major impact on the malignancy of the whole tumor. How could this cellular minority have such an important impact? This mechanism was still unknown… until now.

This study shows that the mutated EGFRvIII triggers production of small vesicles that project from the cell membrane and that carry mutated copies of EGFRvIII on their surfaces. They were baptised "oncosomes." Surprisingly enough, this shows that oncoproteins are not always confined to the cell that produced them. In this case they even migrate!

Oncosomes will migrate until they fuse with another cell, either healthy or benign tumoral. Oncogenic protein AGFRvIII then becomes integrated in the membrane of the "recipient" cell and starts stimulating specific metabolic pathways to make it act in an aberrant and malignant way. Although this may be a transient event, the changes could impact tumor behaviour by more rapid increases in cell numbers and by stimulation of blood vessel growth, hallmarks of malignant brain tumors.

"With this information we can imagine that many mutant proteins are not necessarily confined to the cells that make them, but rather can migrate and spread around as cargo of oncosomes, a process that could be referred to as formation of the "oncogenic field effect," explained Dr. Rak. "It demonstrates that cancer is a multi-cell process, where the cells talk to one another extensively. This goes against the traditional view that a single 'mutated' cell will simply multiply uncontrollably to the point of forming a tumour. This discovery opens exciting new research avenues, but we also hope that it will lead to positive outcomes for patients."

Indeed, the presence of oncosomes (containing EGFRvIII or other proteins) in blood of cancer patients could become a clinical marker, meaning that doctors could screen for a tumour's molecular characteristics instead of having to perform invasive surgery or biopsy. Currently, in the case of brain cancer, this very precise assessment cannot be performed without removing the tumour and therefore opening a patient's skull. However, the assay and analysis of oncosomes would potentially only require taking a small sample of blood or cerebrospinal fluid. This would be a step in ensuring patient comfort and choosing the best therapeutic strategy for them, factors that are key in the journey towards personalized medicine in a hopefully not-too-distant future.

Dr Rak would like to highlight the outstanding work done by Dr Khalid Al-Nedawi the lead author and Brian Meehan the coauthor of the study, from the Research Institute of the MUHC.

Dr. Janusz Rak is a researcher in the Cancer Axis at the Research Institute of the McGill University Health Centre.

This study was funded by the National Cancer Institute of Canada and the Canadian Cancer Society.

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The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.

The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santé du Québec.

Isabelle Kling | MUHC
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