RESUMO
The Epstein-Barr Virus (EBV) is a gammaherpesvirus involved in the etiopathogenesis of a variety of human cancers, mostly of lymphoid and epithelial origin. The EBV infection participates in both cell transformation and tumor progression, also playing an important role in subverting immune responses against cancers. The homeostasis of the immune system is tightly regulated by inhibitory mechanisms affecting key immune effectors, such as T lymphocytes and NK cells. Collectively known as immune checkpoints, these mechanisms rely on a set of cellular receptors and ligands. These molecules may be candidate targets for immune checkpoints blockade-an emergent and promising modality of immunotherapy already proven to be valuable for a variety of human cancers. The EBV was lately suspected to interfere with the expression of immune checkpoint molecules, notably PD-1 and its ligands, found to be overexpressed in cases of Hodgkin lymphoma, nasopharyngeal, and gastric adenocarcinomas associated with the viral infection. Even though there is compelling evidence showing that the EBV interferes with other immune checkpoint regulators (e.g., CTLA-4, LAG-3, TIM-3, and VISTA), the published data are still scarce. Herein, we discuss the current state of the knowledge on how the EBV interferes with the activity of immune checkpoints regulators, as well as its implications considering the immune checkpoints blockade for clinical management of the EBV-associated malignancies, notably lymphomas.
Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Neoplasias Gástricas , Herpesvirus Humano 4 , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Transtornos Linfoproliferativos/complicaçõesRESUMO
AIM: To correlate Helicobacter pylori (H. pylori), Epstein-Barr virus (EBV) and human papillomavirus (HPV) with gastric cancer (GC) cases in Pará State, Brazil. METHODS: Tissue samples were obtained from 302 gastric adenocarcinomas. A rapid urease test was used to detect the presence of H. pylori, and the presence of the cagA gene in the HP-positive samples was confirmed by PCR. An RNA in situ hybridization test designed to complement Eber1 RNA was used to detect the presence of EBV in the samples, and the L1 region of HPV was detected using nested PCR. Positive HPV samples were genotyped and analyzed for E6 and E7 viral gene expression. Infections were also correlated with the clinical and pathological characteristics of the patients. RESULTS: The majority of the 302 samples analyzed were obtained from men (65%) aged 55 years or older (67%) and were classified as the intestinal subtype (55%). All three pathogens were found in the samples analyzed in the present study (H. pylori: 87%, EBV: 20%, HPV: 3%). Overall, 78% of the H. pylori-positive (H. pylori +) samples were cagA+ (H. pylori-cagA +), and there was an association between the cytotoxic product of this gene and EBV. Coinfections of H. pylori-cagA + and EBV were correlated with the most advanced tumor stages. Although only 20% of the tumors were positive for EBV, infection with this virus was associated with distant metastasis. Only the HPV 16 and 18 strains were found in the samples, although no expression of the E6 and E7 oncoproteins was detected. The fundus of the stomach was the region least affected by the pathogens. CONCLUSION: HPV was not involved in gastric tumorigenesis. Prophylactic and therapeutic measures against H. pylori and EBV may prevent the development of GC, especially the more aggressive forms.
Assuntos
Adenocarcinoma/epidemiologia , Coinfecção/epidemiologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Helicobacter/epidemiologia , Infecções por Papillomavirus/epidemiologia , Neoplasias Gástricas/epidemiologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Brasil/epidemiologia , Coinfecção/microbiologia , DNA Bacteriano/isolamento & purificação , DNA Viral/isolamento & purificação , Infecções por Vírus Epstein-Barr/virologia , Feminino , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
Whereas the pathological aspects of Gastric Adenocarcinomas (GACs) have been well defined, the actual knowledge of its genesis and evolution remains to be translated to better diagnosis and to more effective therapeutics. As a consequence, the current treatment modalities are not yet able to modify the natural history of the disease, which still presents high mortality-rates worldwide. In this review we highlight the current status of relevant epidemiologic, therapeutic and genomics aspects of GACs and point to some of the current knowledge gaps that, if fully addressed, could contribute to a more effective treatment and better management of the patients that suffer from this often-lethal disease (AU)