Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and in various disease conditions. Tumor exosomes contain intact and functional mRNAs, small RNAs (including miRNAs), and proteins that can alter the cellular environment to favor tumor growth. Molecular profiling may increase our understanding of the role of exosomes in melanoma progression and may lead to discovery of useful biomarkers. In the present study, we used mRNA array profiling to identify thousands of exosomal mRNAs associated with melanoma progression and metastasis. Similarly, miRNA array profiling identified specific miRNAs, such as hsa-miR-31, -185, and -34b, involved in melanoma invasion. We also used proteomic analysis and discovered differentially expressed melanoma exosomal proteins, including HAPLN1, GRP78, syntenin-1, annexin A1, and annexin A2. Importantly, normal melanocytes acquired invasion ability through molecules transported in melanoma cell-derived exosomes. Our results indicate that melanoma-derived exosomes have unique gene expression signatures, miRNA and proteomics profiles compared to exosomes from normal melanocytes. To the best of our knowledge, this is the first in-depth screening of the whole transcriptome/miRNome/proteome expression in melanoma exosomes. These results provide a starting point for future more in-depth studies of tumor-derived melanoma exosomes, which will aid our understanding of melanoma biogenesis and new drug-targets that may be translated into clinical applications, or as non-invasive biomarkers for melanoma.

Purpose: The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. Patients and Methods: Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). Results: In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. Conclusion: No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viralmRNAexport, and cell cycle disruption.

The PTEN/Akt signal pathway plays an important role in tumorigenesis. Mutations or deletions of PTEN have been observed in up to 60% of melanoma cell lines, resulting in PI3K/Akt activation. The Fo...

This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon (IFN) therapy. Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas. Post hoc analysis was performed by a prospective multi-institutional randomized study of observation versus adjuvant IFN therapy for melanoma. All patients underwent sentinel lymph node biopsy; completion lymphadenectomy was performed for patients with sentinel lymph node metastasis. Patients were stratified by Breslow thickness, ulceration, and nodal status. Kaplan-Meier analysis of DFS and OS was performed and included univariate and multivariate analyses. A total of 1769 patients were analyzed (1311 without ulceration, 458 with ulceration) with a median follow-up of 71 months. Ulceration was associated with significantly worse DFS and OS in both node-negative and node-positive patients. Kaplan-Meier analysis of node-negative and node-positive patients by ulceration status revealed that the only significant impact of interferon was improved DFS in the ulcerated node-positive patients (P = 0.0169). IFN therapy had no significant impact on OS regardless of ulceration status, however. On multivariate analysis, IFN treatment was a significant independent predictor of DFS among ulcerated patients (odds ratio, 0.51; 95% confidence interval, 0.30-0.83; P = 0.0053), but not among patients without ulceration. These data support the conclusion that ulceration is a predictive marker for response to adjuvant IFN therapy. Future studies to evaluate specifically the differential effect of IFN on patients with ulcerated melanomas may allow us to focus this therapy on patients most likely to benefit from it.