PHILADELPHIA – Researchers have determined a novel mechanism through which organ transplantation often leads to cancer, and their findings suggest that targeted therapies may reduce or prevent that risk.
In the July 15, 2008, issue of Cancer Research, researchers at Harvard Medical School found in animal and laboratory experiments that the anti-rejection, immunosuppressive drug cyclosporine ramps up expression of vascular endothelial growth factor (VEGF), which signals the growth of new blood vessels that can feed tumors.
They also found that simultaneously administering an anti-VEGF therapy with cyclosporine in mice repressed this tumor growth. Several inhibitors of VEGF are already in use in human cancer therapy.
The findings could offer some good news for the 15 to 20 percent of transplant patients who develop cancer within a decade of receiving new organs, according to the study's senior investigator, Soumitro Pal, Ph.D., an assistant professor at Harvard Medical School's Transplantation Research Center at Children's Hospital in Boston.
"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence," he said.
VEGF expression is markedly increased in patients post-transplantation, and this can aid in the development of a blood supply to a transplanted organ, helping it survive and thrive. "But once the organ has stabilized, it may be possible to lower the level of VEGF expression to prevent tumor growth," he said. "We would need to figure out how to balance benefit and risk to keep cancer at bay."
Tumors that develop after transplantation may have three potential sources: they may have pre-existed or could have been a recurrence of previous cancer – and in both of these cases, a patient's pre-transplant immune system might have kept these cancers in check – or cancer-causing viruses could have come from the donor organ. Physicians have long observed that immunosuppressive agents, such as the class of calcineurin inhibitors that includes cyclosporine, appear to promote cancer development, often in organs that are not transplanted, but the cause of this was unclear. The Harvard team tested the ability of cyclosporine to promote growth of pre-existing tumors in mice implanted with human renal (kidney) cancer cells. Mice treated with the agent formed tumors faster than untreated mice, but anti-VEGF therapy substantially reduced that excessive growth.
Digging deeper into the biological pathway of VEGF activation, the scientists found that cyclosporine activates two of the three forms of the common protein catalyst, protein kinase C, which leads to increased expression of VEGF.
"We think PKC-mediated VEGF transcriptional activation is a key component in the progression of cyclosporine-induced post-transplantation cancer," Pal said. "It is likely not the whole story, but this gives us a clue that we might be able to use existing or novel therapies to reduce cancer risk in transplanted patients."
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.
Journal
Cancer Research