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Effect of cyclosporin A on the tumor microenvironment

Tumor angiogenesis is a hallmark of cancer, and plays a critical role in tumor growth, expansion, and metastasis. Both physiological and pathological angiogenesis is assumed to be regulated by the balance between pro and anti-angiogenic factors. One of the best characterized and most potent pro-angiogenic regulators is vascular endothelial growth factor, or VEGF. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by increased expression of its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis. However, a potent pharmacological calcineurin inhibitor, the commonly used immunosuppressant cyclosporin A (CsA), significantly increases the incidence of cancer in organ transplant recipients. The mechanism by which CsA promotes cancer in this patient population is not well understood and despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, we show that long-term CsA treatment promotes tumor growth and angiogenesis. Further our data indicate that treatment of endothelial cells in vitro with CsA increases proliferation and migration, in a calcineurin-independent manner. Our studies reveal that CsA-induced endothelial cell activation was due to the interaction of CsA with cyclophilin D located on the mitochondrial inner membrane. CsA treatment in endothelial cells increased mitochondrial membrane potential and mitochondrial reactive oxygen species production, and was associated with sustained mitogen-activated protein kinase (MAPK) activity. Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings show that CsA functions independent of calcineurin to potentiate tumor growth by promoting tumor angiogenesis via mitochondrial reactive oxygen species production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants may inhibit the tumor promoting effects of CsA. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Sandra W. Ryeom Second Advisor J A. Diehl This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1526 Subject Categories Cell Biology | Medicine and Health Sciences This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1526 EFFECT OF CYCLOSPORIN A ON THE TUMOR MICROENVIRONMENT Yao Zhou A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2014 Supervisor of Dissertation _ Sandra W. Ryeom, PhD Assistant professor of Cancer Biology Graduate Group Chairperson _ Dan Kessler, PhD Associate Professor of Cell and Molecular Biology Dissertation Committee: J. Alan Diehl, PhD (Chair), Professor of Cancer Biology Douglas Wallace, PhD, Professor of Pathology and Laboratory Medicine Todd Ridky, MD, PhD, Assistant Professor of Dermatology Meenhard Herlyn, D.V.M., D.Sc., Wistar Institute Professor of Dermatology EFFECT OF CYCLOSPORIN A ON THE TUMOR MICROENVIRONMENT COPYRIGHT © 2014 Yao Zhou