Aging Tumor Cells May Be Used for Effective Cancer Therapy

Scientists have shown that diffuse large B-cell lymphoma (DLBCL) patients may be treated by reactivating the normal aging program in tumor cells so they can no longer divide.

The study, published October 14, 2013, in the journal Nature Communications, details a novel, tumor-suppressive role for the Smurf2 protein, which typically plays an “enforcer” role in senescence, in a subset of DLBCL. Identification of this unique role 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 and developmental biology at University of Massachusetts Medical School (UMMS; Worchester, USA) and senior author of the study. “However, human DLBCL show low levels of Smurf2 expression; these low levels affect a pathway that encourages unchecked 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 individuals living in the United States will be diagnosed with non-Hodgkin’s lymphoma in 2013, accounting for 30%–40% of all new diagnoses. About 50% of those diagnosed will not respond to conventional treatment or will relapse within five years. Rachel Gerstein, PhD, associate professor of microbiology and physiologic systems at UMMS, and coauthor of the study, noted 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 associated with human DLBCL, and better determine the molecular pathway being disturbed, the researchers began a new study to examine Smurf2 expression in patients with DLBCL. They discovered that a considerable subset of these tumor samples showed a marked decrease in Smurf2 expression. Furthermore, lower levels of Smurf2 correlated to poor survival prognosis. When put together, these findings indicate a strong role for Smurf2 in human DLBCL.

Closer study 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 integrating the transcriptional regulator YY1 and the regulatory gene c-Myc (also a well-known oncogene). These three proteins collaborate to control cell proliferation and division. However, in a subset of DLBCL patients this cycle has gone out of kilter.

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. Uncontrolled cell proliferation is a key characteristic of many cancers and in the instance 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 typically 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 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 Dr. Zhang. “It also suggests multiple roles for Smurf2 in tumor suppression in the form of suppressed cell proliferation and senescence response.”

To assess the potential clinical significance of this biologic discovery, Dr. 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 phase for the investigators is to look for molecules that can either increase or imitate 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,” concluded Dr. 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.”

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