Molecular Basis of Posttransplant Squamous Cell Carcinoma: The Potential Role of Cyclosporine A in Carcinogenesis

Abstract

Cyclosporine (CSA) is a widely used immunosuppressive agent, predominantly for transplant patients. It is well recognized that transplant patients are prone to develop squamous carcinoma of the skin and mucosa, and this high incidence of squamous carcinoma in the transplant population cannot be explained by immunosuppression alone. We hypothesize that CSA may play a significant role in the transformation of normal epidermal squamous cells to carcinoma. CSA is a specific ligand for calcineurin, a ubiquitously expressed cellular serine/threonine phosphatase, that plays important roles in the immune system and cardiac muscles. Using global gene-profiling methods, we studied the short-time CSA effect on the squamous cell line (SCC-015) using Affymetrix human gene chips (Human U133, 2.0 plus chip). Multiple groups of genes were identified to be responsive to CSA treatment, including many genes of unknown functions. We then used reverse transcriptase-polymerase chain reaction and immunoblot analyses to selectively confirm the results from the chips analyses with emphasis on the regulatory molecules important for cellular functions of apoptosis, DNA damage repair, and cellular transformation. This global gene-profiling study indicated that CSA not only functions as an immunosuppressant on the immune system, but also activates/inhibits a wide array of genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor activation. These functions of CSA on skin and mucosa systems at the molecular level are likely important in the pathogenesis of squamous carcinoma in transplant patients.

Matrix metalloproteinase‐26 is present more frequently in squamous cell carcinomas of immunosuppressed compared with immunocompetent patients

“…MMP‐26 may function to promote inflammation, 26 and this may influence the more aggressive phenotype of the SCCs of IS patients in addition to the fact that MMP‐26 is known to activate MMP‐9, one of the most critical MMPs in the growth of SCC 21 . Interestingly, MMP‐26 staining was significantly more intense in the tumors of patients using cyclosporine agreeing with recent Affymetrix data on a SCC cell line of the oral cavity 27 . That study showed in cell culture differential regulation of various MMPs after treatment with cyclosporine that not only functions as an immunosuppressant but also was shown to activate/inhibit genes important for cell cycle regulation, apoptosis and oncogene/tumor‐suppressor activation.…”

Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer

“…Although calcineurin inhibitors are excellent immunosuppressive agents to inhibit allograft rejection, they may promote the growth of different tumors (7, 9-11, 40). In this study, we define a mechanism in human cancer cells by which CsA can promote tumor growth through VEGF overexpression and angiogenesis, having direct relevance for the development of post-transplantation cancer.…”

Calcineurin Inhibitors Activate the Proto-Oncogene Ras and Promote Protumorigenic Signals in Renal Cancer Cells

“…In support of direct mechanism(s), it has been shown that the treatment of tumor xenografts in T- and B-cell deficient SCID mice with CNI enhanced tumor growth and progression (9). CNI may also activate/inhibit genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor function (21). There are some reports that oncogenes may become activated in immunosuppressed transplant patients (21–23).…”

“…CNI may also activate/inhibit genes important for cell-cycle regulation, apoptosis, and oncogene/tumor-suppressor function (21). There are some reports that oncogenes may become activated in immunosuppressed transplant patients (21–23). However, very little is known about the signaling mechanism(s) of CNI-mediated direct tumorigenic pathways.…”