Perhaps the key to fighting some cancers is to reactivate a process that normally prevents cell proliferation. Now in the case of large B-cell lymphoma, scientists have found such a mechanism.
In a report about their work published online this week in Nature Communications, the researchers describe how they found a new tumor-suppressive role for a protein called Smurf2 that is known to enforce cell aging (senescence) in a subset of diffuse large B-cell lymphoma (DLBCL).
Senior author Hong Zhang, assistant professor of cell and developmental biology at University of Massachusetts (UMass) Medical School, says:
“It’s possible that restoration of Smurf2 expression may provide therapeutic benefits for patients and help encourage remission in difficult to treat cases.”
He explains that normally this pathway regulates cell aging and stops B cells dividing and multiplying.
But humans with DLBCL show low expression of Smurf2, and such low activity of the protein affects a pathway that promotes unchecked cell division and tumor growth.
DLBCL is the most common form of non-Hodgkin’s lymphoma, a group of cancers that start in the lymph nodes and lymphatic system.
The study estimates that around 70,000 Americans will be diagnosed with non-Hodgkin’s lymphoma in 2013, around half of whom will not respond to current treatments or will relapse within 5 years.
Co-author Rachel Gerstein, associate professor of microbiology & physiological systems at UMass Medical School, says:
“The average age at the time of diagnosis with DLBCL is mid-60s. Therefore, it’s particularly exciting to connect a glitch in cellular aging within DLBCL to this cancer that preferentially affects the elderly.”
In previous work, the team had already established that mice lacking the Smurf2 gene developed spontaneous B-cell lymphoma and other tumors.
So with this new study, they wanted to take this further and look for possible links between Smurf2 and human DLBCL, and perhaps even discover which molecular pathway was involved.
They found that a significant subset of tumor samples from patients with DLBCL showed a marked reduction in Smurf2 expression. And, they also found lower levels of the protein were linked to poorer survival prognosis.
They suggest these two findings point to a strong role for Smurf2 in human DLBCL.
When the researchers looked more closely at the underlying molecular mechanisms, they discovered a complex pathway, involving a well-known cancer gene, c-Myc, and the transcriptional regulator YY1.
They suggest that normally the three proteins Smurf2, c-Myc and YY1 team up to control cell proliferation and division, but somehow, in a subset of DLBCL patients, this collaboration goes wrong.
The team then tested some of their ideas, for instance when they restored restored Smurf2 expression in human DLBCL cells, it stopped them multiplying.
This finding raises hopes that adding a drug that increases Smurf2 expression in lymphomas, could improve the effectiveness of current treatments and help more DLBCL patients achieve remission.
The team now wants to screen for molecules that either increase or mimic Smurf2 expression.
They also intend to find out if the Smurf2-YY1-c-Myc pathway has the same effect in other cancers, such as of the liver.
Prof. Zhang says:
“This is another example of a basic biological discovery having important clinical applications. When we started this line of inquiry we were interested in the role of Smurf2 in cellular aging. We never expected the clinical relevance to be so immediate and striking.”
Earlier this year, a team of UK researchers discovered that reducing the level of Smurf2 in melanoma cancer cells resulted in a 100-fold increase in their sensitivity to a class of experimental drug called “MEK inhibitors.” These drugs are currently undergoing clinical trials to find out why they are not as effective at killing cancer cells as they should be.