RESUMO
Primary central nervous system lymphoma (PCNSL) in immunocompetent patients is highly malignant and has a poor prognosis. The PCNSL molecular features are reminiscent to some degree of diffuse large B-cell lymphoma (DLBCL), yet PCNSL shows unique molecular profiles and a distinct clinical behavior. This article characterizes the histopathology and expression profiles of metallothionein-I + II (MT-I + II) and their receptor megalin along with proliferation, oxidative stress, and apoptosis in PCNSL and in central nervous system (CNS) lymphomas due to relapse from DLBCL (collectively referred to as CNS lymphoma). We show for the first time that MT-I + II and megalin are significantly altered in CNS lymphoma relative to controls (reactive lymph nodes and non-lymphoma brain tissue with neuropathology). MT-I + II are secreted in the CNS and are found mainly in the lymphomatous cells, while their receptor megalin is increased in cerebral cells. This morphology likely reflects the CNS lymphoma microenvironment and molecular interactions between lymphomatous and neuronal cells.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Linfoma Difuso de Grandes Células B/patologia , Metalotioneína/análise , Estresse Oxidativo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ciclo Celular/análise , Proliferação de Células/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/metabolismo , Proteínas de Ligação a DNA/análise , Guanina/análogos & derivados , Guanina/análise , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Malondialdeído/análise , Pessoa de Meia-Idade , Componente 7 do Complexo de Manutenção de Minicromossomo , Proteínas Nucleares/análise , Tirosina/análogos & derivados , Tirosina/análiseRESUMO
The antiapoptotic, antioxidant, proliferative, and angiogenic effects of metallothionein (MT)-I+II has resulted in increased focus on their role in oncogenesis, tumor progression, therapy response, and patient prognosis. Studies have reported increased expression of MT-I+II mRNA and protein in various human cancers; such as breast, kidney, lung, nasopharynx, ovary, prostate, salivary gland, testes, urinary bladder, cervical, endometrial, skin carcinoma, melanoma, acute lymphoblastic leukemia (ALL), and pancreatic cancers, where MT-I+II expression is sometimes correlated to higher tumor grade/stage, chemotherapy/radiation resistance, and poor prognosis. However, MT-I+II are downregulated in other types of tumors (e.g. hepatocellular, gastric, colorectal, central nervous system (CNS), and thyroid cancers) where MT-I+II is either inversely correlated or unrelated to mortality. Large discrepancies exist between different tumor types, and no distinct and reliable association exists between MT-I+II expression in tumor tissues and prognosis and therapy resistance. Furthermore, a parallel has been drawn between MT-I+II expression as a potential marker for prognosis, and MT-I+II's role as oncogenic factors, without any direct evidence supporting such a parallel. This review aims at discussing the role of MT-I+II both as a prognostic marker for survival and therapy response, as well as for the hypothesized role of MT-I+II as causal oncogenes.