Circulating TGF-β1 and VEGF and risk of cancer among liver transplant recipients.

Eric A. Engels,James F. Trotter,Nicholas Onaca,Anil K. Chaturvedi,Ruth M. Pfeiffer,Ligia A. Pinto,Linda Jennings,Goran B. Klintmalm,Michelle Acker,Troy J. Kemp

doi:10.1002/cam4.455

Abstract

Transplant recipients have elevated cancer risk, perhaps partly due to direct carcinogenic effects of immunosuppressive medications. Experimental evidence indicates that calcineurin inhibitors given to transplant recipients increase cellular expression of transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF), which could promote cancer. To assess the potential role of these pathways in the transplantation setting, we conducted a case–control study nested in a cohort of liver recipients. Cases had nonmelanoma skin cancer (N = 84), cancer of the lung (N = 29), kidney (N = 20), or colorectum (N = 17), or melanoma (N = 3). We selected N = 463 recipients without cancer as controls. TGF-β1 and VEGF levels were measured in sera obtained, on average, approximately 3 years before case diagnosis/control selection. We also measured platelet factor 4 (PF4), a marker of ex vivo platelet degranulation, because TGF-β1 and VEGF can be released from platelets, and we developed a statistical model to isolate the platelet-derived fraction from the remaining circulating component. Compared with controls, lung cancer cases had higher levels of TGF-β1 (median 22.8 vs. 19.4 ng/mL, P = 0.02) and VEGF (277 vs. 186 pg/mL, P = 0.02). However, lung cancer cases also had higher platelet counts (P = 0.08) and PF4 levels (P = 0.02), while residual serum levels of TGF-β1 and VEGF, after accounting for PF4, were unassociated with lung cancer (P = 0.40 and P = 0.15, respectively). Associations were not seen for other cancers. In conclusion, TGF-β1 and VEGF levels were increased in association with lung cancer among transplant recipients, which may be explained by increased platelet counts and platelet degranulation in lung cancer cases.

Highlights

Solid organ transplantation provides life-saving therapy for patients with end-stage organ disease
Some epidemiological research suggests that calcineurin inhibitors (CNIs), an immunosuppressive medication class widely used in transplantation, may especially increase cancer risk [2, 3]
In this case–control study among liver recipients, lung cancer cases had higher serum levels of transforming growth factor b1 (TGF-b1) and vascular endothelial growth factor (VEGF) than recipients without cancer. These elevations were present an average of 6.8 years before the development of lung cancer. These findings extend upon limited prior studies in nontransplant populations, which found elevated levels of TGF-b1 for lung cancer cases [10, 14]

Summary

Introduction

Solid organ transplantation provides life-saving therapy for patients with end-stage organ disease. Cancer risk is elevated in transplant recipients [1], largely due to loss of immune control of oncogenic viruses arising from immunosuppressive medications administered to prevent organ rejection. These medications may vary in their effects on cancer risk. Some epidemiological research suggests that calcineurin inhibitors (CNIs), an immunosuppressive medication class widely used in transplantation, may especially increase cancer risk [2, 3]. Not all the cancers that are increased in transplant recipients are caused by viruses [1], and the medications used in transplantation may affect cancer risk independently of the immunosuppression.

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Results

Conclusion