Scientists have shown that diffuse large B-cell lymphoma (DLBCL)
may be susceptible to treatment by re-activating the normal aging
program in tumor cells so they can no longer divide.The study took place at the University of Massachusetts Medical School and got published in Nature Communications,
it details a novel, tumor-suppressive role for the Smurf2 protein—which
typically plays an "enforcer" role in cellular aging, also called
senescence —in a subset of DLBCL. Identification of this novel function
for Smurf2 provides a new therapeutic target for treating this cancer.
"Normally, this pathway is responsible for senescence and suppressing
proliferation of B cells," said Hong Zhang, PhD, assistant professor of
cell & developmental biology at UMMS and senior author of the study.
"However, human DLBCL show low levels of Smurf2 expression; these low
levels affect a pathway that encourages un-checked cell division and
tumor growth. It's possible that restoration of Smurf2 expression may
provide therapeutic benefits for patients and help encourage remission
in difficult to treat cases." Diffuse large B-cell lymphoma is the most common form of non-Hodgkin's
lymphoma. An estimated 70,000 people living in the United States will be
diagnosed with non-Hodgkin's lymphoma in 2013, accounting for 30 to 40
percent of all new diagnoses. Roughly 50 percent of those diagnosed will
not respond to conventional treatment or will relapse within five
years. Rachel Gerstein, PhD, associate professor of microbiology and
physiological systems at UMMS, and co-author of the study, notes that
"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." A 2012 Cancer Research study by Drs. Zhang, Gerstein and
colleagues found that mice deficient in Smurf2 gene expression developed
spontaneous tumors, including B-cell lymphoma. To determine if a
similar Smurf2 deficiency was connected to human DLBCL, and better
understand the molecular pathway being disturbed, Zhang and colleagues
initiated a new study to examine Smurf2 expression in patients with
DLBCL. They found that a significant subset of these tumor samples
showed a marked decrease in Smurf2 expression. Furthermore, lower levels
of Smurf2 correlated to poor survival prognosis. Taken together, these
findings indicate a strong role for Smurf2 in human DLBCL. Closer examination by the study authors, including first author
Charusheila Ramkumar, PhD, a doctoral student in the Graduate School of
Biomedical Sciences at UMMS and now a postdoctoral fellow, revealed that
Smurf2 is part of a complex pathway incorporating the transcriptional
regulator YY1 and the regulatory gene c-Myc (also a well known
oncogene). Together, these three proteins collaborate to regulate cell
proliferation and division. However, in a subset of DLBCL patients this
cycle has gone awry. Tumor cells that showed decreased levels of Smurf2 expression also had
increased levels of YY1 and c-Myc expression. These increased levels of
YY1 and c-Myc caused cells, including B-cells, to continue dividing.
Unrestrained cell proliferation is a hallmark of many cancers and in the
case of DLBCL cells with a perturbed Smurf2-YY1-c-Myc pathway, it leads
to tumor formation. Not only does the lack of Smurf2 lead to increased cell division through
this pathway but it also allows the tumor cells to continue dividing
longer. Because Smurf2 (which normally plays a part in cellular aging)
expression levels are already low in DLBCL cells, these tumor cells
don't age normally. As a result, tumor B-cells effectively remain
younger longer, allowing them to proliferate even more. "This enhanced cell proliferation induced by YY1 and c-Myc activation,
coupled with impaired senescence due to low Smurf2 levels helps drive
lymphoma formation," said Zhang. "It also suggests multiple roles for
Smurf2 in tumor suppression in the form of suppressed cell proliferation
and senescence response." To gauge the potential clinical relevance of this basic biological
discovery, Zhang and colleagues restored Smurf2 expression in human
DLBCL cells. Once restored, proliferation of these cells was inhibited,
providing new hope that therapeutics designed to increase expression of
Smurf2 in lymphomas, when coupled with existing treatments, will be a
more effective approach to achieving remission in patients. The next step for Zhang and colleagues is to screen for molecules that
can either increase or mimic the expression of Smurf2. He will also
screen other cancer types, such as liver cancer, for the
Smurf2-YY1-c-Myc pathway to see if they are also susceptible to this
approach. "This is another example of a basic biological discovery having
important clinical applications," said Zhang. "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."Source:Nature Communications
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