ABSTRACT
Secondary malignancies are a well-known late complication occurring in patients who undergo bone marrow transplant (BMT) during childhood. A boy with acute lymphoblastic leukemia experienced a BM relapse at the age of 14 years and underwent an autologous BMT conditioned with TBI and melphalan. Sixteen years later a malignant mesothelioma of the peritoneum was diagnosed. A surgical approach according to the Sugarbaker technique and hyperthermic peritoneal perfusion with CDDP and Adriamycin were performed. The patient is alive and well after a follow-up of 20 months. To the authors' knowledge this is the first case of mesothelioma as a secondary malignancy after BMT.
Subject(s)
Abdominal Neoplasms/etiology , Bone Marrow Transplantation/adverse effects , Mesothelioma/etiology , Adolescent , Humans , Male , Mesothelioma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/surgery , Transplantation, AutologousABSTRACT
Recent evidences suggest that malignant mesothelioma may be sensitive to immunotherapy; however, little is known about malignant mesothelioma-associated tumour antigens. Focusing on cancer/testis antigens, the expression of well-characterised immunogenic tumour-associated antigens was investigated in malignant mesothelioma cells. At variance with MAGE-4 and NY-ESO-1, malignant mesothelioma cells frequently expressed MAGE-1, -2 and -3, GAGE 1-2, GAGE 1-6, SSX-2 and SSX 1-5, and distinct malignant mesothelioma cells concomitantly expressed at least four cancer/testis antigens. Additionally, the tumour-associated antigens RAGE-1 was expressed at high levels in both benign and malignant mesothelial cells. Lastly, treatment with the DNA hypomethylating agent 5-aza-2'-deoxycytidine induced and up-regulated the expression of the cancer/testis antigen examined in malignant mesothelioma cells. Overall, these findings strongly suggest that cancer/testis antigens-based immunotherapy may represent a suitable therapeutic approach to malignant mesothelioma, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemo-immunotherapeutic strategies in malignant mesothelioma patients.
Subject(s)
Antigens, Neoplasm/analysis , DNA Methylation , Membrane Proteins , Mesothelioma/immunology , Testis/immunology , Animals , Azacitidine/pharmacology , Female , Humans , Immunotherapy , Male , Melanoma-Specific Antigens , Mesothelioma/therapy , Neoplasm Proteins/analysis , Proteins/analysis , Rabbits , Repressor Proteins/analysisABSTRACT
Recent studies suggested that simian virus 40 (SV40) may cause malignant mesothelioma, although the pathogenic mechanism is unclear. We found that in SV40-positive malignant mesothelioma cells, the hepatocyte growth factor (HGF) receptor (Met) was activated. In human mesothelial cells (HMC) transfected with full-length SV40 DNA (SV40-HMC), Met receptor activation was associated with S-phase entry, acquisition of a fibroblastoid morphology, and the assembly of viral particles. Coculture experiments revealed the ability of SV40-HMC to infect permissive monkey cells (CV-1), HMC, and murine BNL CL cells. Cocultured human and murine SV40-positive cells expressed HGF, showed Met tyrosine phosphorylation and S-phase entry, and acquired a spindle-shaped morphology (spBNL), whereas CV-1 cells were lysed. Cocultured HMC inherited from SV40-HMC the infectivity, as they induced lysis in cocultured CV-1 cells. Treatment with suramin or HGF-blocking antibodies inhibited Met tyrosine phosphorylation in all large T antigen (Tag)-positive cells and reverted the spindle-shaped morphology of spBNL. This finding indicated that Met activation and subsequent biological effects were mediated by an autocrine HGF circuit. This, in turn, was causally related to Tag expression, being induced by transfection with the SV40 early region alone. Our findings suggest that when SV40 infects HMC it causes Met activation via an autocrine loop. Furthermore, SV40 replicates in HMC and infects the adjacent HMC, inducing an HGF-dependent Met activation and cell-cycle progression into S phase. This may explain how a limited number of SV40-positive cells may be sufficient to direct noninfected HMC toward malignant transformation.
