Dec 17, 2012 - 8:43 pm
Genes are not the only drivers of colon cancer. A new study suggests cellular factors play an equally important part, and these not only drive tumor growth, but also affect how well the disease responds to chemotherapy.
Senior study author John Dick, of the Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, and colleagues, write about their findings in a paper published online in Science on Thursday.
Using lab-bred mice with poor immune systems to grow human colorectal cancers, they found biological factors and cell behavior, not just genes, drove tumor growth and contributed to treatment failure and relapse.
Dick, who is also a Professor in the Department of Molecular Genetics at the University of Toronto, says in a press statement that the study represents a "a major conceptual advance in understanding tumor growth and treatment response".
Not All Cancer Cells are Equal
For their study, Dick and colleagues found a way to follow single tumor cells as they developed with time.
They discovered that not all cancer cells are equal. Only some keep the cancer growing, and within this group, there are further differences: for instance some cells drove growth for long periods, up to 500 days, while others stopped after 100 days.
They also found a class of cancer-driving cells that lies dormant before being activated.
And they were surprised to discover that the mutated genes were the same for all the different cell behaviors.
Cells Responded Differently to Chemo
Dick and colleagues then tested the effect of chemotherapy on the human tumors growing in the immune-deficient mice.
They found that the treatment generally killed off the longer-term tumor-driving cells.
But unexpectedly, instead of killing the shorter-term tumor-driving cells, chemotherapy brought them out of their dormant state into an active state, causing tumors to grow again.
And again, the researchers found the tumor-driving cells that survived had the same mutations as the ones killed off by the treatment.
They say this proves it was cellular factors and not genetic mutation that was responsible for treatment failure.
"Paradigm Shift" Challenges Conventional View
The findings challenge the conventional view that tumor growth and chemotherapy resistance are governed purely by the genetic mutations in the cells of the tumor.
"The data show that gene sequencing of tumours to find the spectrum of their mutations is definitely not the whole story when it comes to determining which therapies will be most effective," says Dick.
He says the findings confirm for him that to design effective personalized cancer treatments, cancer doctors will have to look beyond gene mutations.
"This is a paradigm shift that shows research also needs to focus on the biological properties of cells," explains Dick, who also holds a Canada Research Chair in Stem Cell Biology and is a Senior Scientist at University Health Network's McEwen Centre for Regenerative Medicine and Ontario Cancer Institute, the research arm of the Princess Margaret Cancer Centre.
"For example, finding a way to put dormant cells into growth cycles could make them more sensitive to chemotherapy treatment. Targeting the biology and growth properties of cancer cells could expand the repertoire of usable therapeutic agents and provide better outcomes for patients," he adds.
Dick is a pioneer in cancer stem cell research. He first identified leukemia stem cells in 1994 and in 2006, how stem cells could also be driving colon cancer tumors.
More recently, in 2011, he and his team revealed how they developed a method to convert normal human blood cells into "human" leukemia stem cells.
Funds from the Genome Canada through the Ontario Genomics Institute, various Canadian foundations, the Ontario Ministry of Health and Long-Term Care, and The Princess Margaret Cancer Foundation, helped pay for the research behind the study.
"Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer"; Antonija Kreso, Catherine A. O’Brien, Peter van Galen, Olga Gan, Faiyaz Notta, Andrew M. K. Brown, Karen Ng, Jing Ma, Erno Wienholds, Cyrille Dunant, Aaron Pollett, Steven Gallinger, John McPherson, Charles G. Mullighan, Darryl Shibata, and John E. Dick; Science 1227670 Published online 13 December 2012; DOI:10.1126/science.1227670
Catharine Paddock PhD "Genes Are Not The Only Drivers Of Colon Cancer." Medical News Today. MediLexicon, Intl., 15 Dec. 2012