Organ Transplantation Linked to Increased Cancer Risk

A new study, which describes a novel mechanism that elucidates why organ transplantation often leads to cancer has been discovered, suggesting that targeted therapies may reduce or prevent that risk.

Researchers at Harvard Medical School (HMS, Boston, MA, USA) tested the ability of the immunosuppressive drug cyclosporine (CsA) to promote growth of preexisting tumors in mice implanted with 786-0 human renal cancer cells. The researchers found that mice treated with the agent formed tumors faster than untreated mice; however, antivascular endothelial growth factor (VEGF) therapy substantially reduced that excessive growth. Not surprisingly, cyclosporine also increased expression of VEGF by inducing transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving the PKC zeta and PKC delta isoforms. Moreover, CsA promoted the association of PKC zeta and PKC delta with the transcription factor Sp1, and was dependant on it.

Finally, to evaluate the in vivo significance of CsA-induced VEGF over-expression in terms of post-transplantation tumor development, the researchers injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully mismatched cardiac transplants. The therapeutic doses of CsA increased tumor size and VEGF expression, and enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. The researchers stressed that several inhibitors of VEGF are already in use in human cancer therapy.
The study was published in the July 15, 2008, issue of Cancer Research.

"We think PKC-mediated VEGF transcriptional activation is a key component in the progression of cyclosporine-induced post-transplantation cancer,” said lead author Soumitro Pal, Ph.D., an assistant professor at HMS's transplantation research center. "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.”

"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence,” added Dr. Pal. "Once the organ has stabilized, it may be possible to lower the level of VEGF expression to prevent tumor growth. 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 preexisted or could have been a recurrence of a previous cancer (in both cases, the 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 calcineurin inhibitors (which include cyclosporine) appear to promote cancer development, often in organs that are not transplanted, but the cause of this is unclear. 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.


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