Glypican-3 (GPC-3) is a heparin sulfate proteoglycan located extracellularly and anchored to the cell membrane of transformed hepatocytes. GPC-3 is not expressed in normal or cirrhotic liver tissue but is overexpressed in hepatocellular carcinoma (HCC). Because of this, GPC-3 is one of the most important emerging immunotargets for treatment and as an early detection marker of HCC. To determine if GPC-3 domains associated with serum small extracellular vesicles (sEVs) could be used as an HCC diagnostic marker, we predicted in silico GPC-3 structural properties and tested for the presence of its full-length form and/or cleaved domains in serum sEVs isolated from patients with HCC. Structural analysis revealed that the Furin cleavage site of GPC-3 is exposed and readily accessible, suggesting the facilitation of GPC-3 cleavage events. Upon isolation of sEVs from both hepatocytes, culture media and serum of patients with HCC were studied for GPC-3 content. This data suggests that Furin-dependent GPC-3 cleaved domains could be a powerful tool for detection of initial stages of HCC and serve as a predictor for disease prognosis.

Background/Objectives: Prolonged use of immunosuppressive drugs (IMDs) is correlated with increased risk of cancer in transplant patients. However, detailed side-by-side analysis of cancer risk associated with individual IMDs in the same population is not available. The aim of this study was to identify drug-specific risks of cancer for commonly used transplant IMDs. Methods: We analyzed the risk of cancer for the IMDs commonly used in transplant patients (tacrolimus (TAC), cyclosporin (CY), sirolimus (SIR), mycophenolate (MMF), and their combinations) in Texas Medicare beneficiaries between 2007 and 2018. Results: Of 7721 transplant recipients receiving an IMD of interest, 2261 developed cancer. There was an increased risk of any cancer diagnosis with the use of TAC (HR: 1.49; 95% CI: 1.25–1.78) and CY (HR: 1.51; 95% CI: 1.19–1.92), and decreased risk with use of MMF (HR: 0.77; 95% CI: 0.67–0.89). Cancer-specific models revealed increased risk of liver cancer (HR: 5.25, 95% CI: 2.03–13.61) and decreased risk of ovarian/uterine cancer (HR: 0.25, 95% CI: 0.07–0.84) with TAC; increased risk of lung cancer with CY (HR: 5.06, 95% CI: 1.47–17.41); and increased risk of lymphoma associated with SIR (HR: 2.80, 95% CI: 1.00–7.81). Conclusions: TAC increases cancer risk, and MMF decreases cancer risk. Individual cancer types also vary in risk associated with individual IMDs. This study provides new information on IMD-specific cancer risk that can guide individualized screening/treatment decisions to reduce the risk associated with specific cancers after transplantation.

Background: Immunosuppressive drugs (ISDs) are essential for preventing organ rejection but have been reported to increase cancer risk with prolonged use. This study compares cancer risk between ISDs used for long-term maintenance after transplantation (T-ISDs) and those prescribed for non-transplant chronic conditions including cell-mediated (C-ISDs) and receptor-mediated (R-ISDs) ISDs. We hypothesized that cancer risk would differ between T-ISDs and both C-ISD and R-ISD groups. Methods: Using the TriNetX database, solid organ transplant recipients treated with tacrolimus (TAC), cyclosporine (CY), rapamycin (RAPA), or mycophenolate (MMF) were compared to propensity-matched R-ISDs (adalimumab, infliximab, etc.) or C-ISDs (methotrexate, azathioprine, etc.) for at least 24 encounters to determine risk of malignancy. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the three-year cancer risk. Results: After matching, T-ISDs were associated with higher malignancy risk compared to both R-ISDs (n = 29,748; HR 2.616, 95% CI 2.427–2.820) and C-ISDs (n = 31,704; HR 1.271, 95% CI 1.195–1.351). Each individual immunosuppressant in the T-ISD cohort was associated with increased cancer risk compared to R-ISDs, while only TAC and CY showed higher risk than C-ISDs (TAC: n = 9846, HR 1.354, 95% CI 1.228–1.492; CY: n = 1801, HR 1.234, 95% CI 1.007–1.512). Organ-specific analyses showed consistent patterns across systems. Conclusions: Overall, T-ISDs are associated with increased malignancy risk compared to R-ISDs and modestly compared to C-ISDs. TAC and CY confer the greatest risk, while MMF demonstrates relatively lower relative risk. These findings underscore the need to individualize ISD regimens to minimize long-term cancer risk.