A protein previously thought to merely hinder the activity of a key cellular protein linked to cancer cell death, now appears to mimic the cellular signaling of that protein; potentially leading to the development of lymphoma.
The findings, published in the Aug. 22 online edition of Proceedings of the National Academy of Sciences (PNAS), demonstrate that a viral protein associated with human herpesvirus 8, or HHV8, may help to cause lymphoma by activating a key pathway involved in the production of lymphocytes, a common cell type found in lymphoid tissue that divide over and over and eventually develop into lymphoma.
The protein, called vFLIP K13, had been thought to protect virally infected cells from attack by the body's own immune system by inhibiting the activity of a cellular protein called caspase 8 that is associated with apoptosis, or programmed cell death. However, when Preet M. Chaudhary, M.D., Ph.D., senior author of the study and professor of medicine at the University of Pittsburgh School of Medicine, and his colleagues analyzed transgenic mice expressing vFLIP K13, they found that vFLIP K13 failed to block cell death pathways and instead mimicked a recently discovered signaling function of caspase 8, which led to the proliferation of lymphocytes.
Dr. Chaudhary and his colleagues observed tumor formation in 59 mice over the course of 30 months. They found that the vFLIP-expressing transgenic mice had more lymphomas than the control group mice; 11.8 percent compared 1.8 percent, respectively.
"We were surprised to see that the mouse model we developed based on vFLIP K13 did not look like the other models in which caspase 8 function was inhibited," said Dr. Chaudhary. "It indicated to us that the main function of this protein is not to block caspase 8 activation."
Further analysis also revealed that instead of inhibiting caspase 8, vFLIP K13 copied its signaling activity resulting in the activation of a distinct cellular pathway called NF-?B that is involved in the development of lymphoma. "In effect, vFLIP K13 actively promoted the growth of cancer cells through this pathway. Based on these findings, we believe the NF-?B pathway may be a promising target for novel therapies directed against HHV8-associated tumors," said Dr. Chaudhary. He added that there is a dire need for new therapies that target this disease since most patients with HHV8-associated lymphomas are highly immune suppressed and are difficult to treat given the toxicity associated with conventional therapies.
In addition to its role in the development of HHV8-associated cancers, the NF-?B pathway also may be implicated in lymphomas that are not caused by HHV8. "There are potentially widespread applications of this finding and our next step will be to discover how involved this pathway is in the development of lymphomas that are not associated with HHV8," said Dr. Chaudhary.
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. They begin with the malignant transformation of a lymphocyte in the lymphatic system. The American Cancer Society estimates that 63,740 people in the U.S. will be newly diagnosed with lymphoma by the end of 2005.
HHV8, originally linked to Kaposi's sarcoma –the most common cancer among AIDS patients – also is associated with lymphoid diseases such as primary effusion lymphoma and multicentric Castleman's disease, a noncancerous but severe disorder characterized by enlargement of the lymph nodes. Recent studies have also linked HHV8 infection to HIV-related solid immunoblastic/plasmablastic lymphomas.
In addition to Dr. Chaudhary, authors on the study include Priti Chugh, Ph.D., Sunny Zachariah, M.S., Arvind Kumar, Ph.D., Alice L. Smith, M.D., and James A. Richardson, Ph.D., Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas; and Hittu Matta, Ph.D., and Sandra Schamus, B.S., Hillman Cancer Center, University of Pittsburgh Cancer Institute.