Host epigenetic modifications by oncogenic viruses

Epigenetic alterations represent an important step in the initiation and progression of most human cancers, but it is difficult to differentiate the early cancer causing alterations from later consequences. Oncogenic viruses can induce transformation via expression of only a small number of viral genes. Therefore, the mechanisms by which oncogenic viruses cause cancer may provide clues as to which epigenetic alterations are critical in early carcinogenesis.     

致瘤病毒编码产物对细胞周期的调控

细胞周期失调是肿瘤形成的重要原因.致瘤病毒通过干扰、模拟、失活许多重要的细胞周期调节蛋白,使宿主细胞周期紊乱,诱导细胞不断增殖,发生癌变.     

miRNAs in the pathogenesis of oncogenic human viruses

Tumor viruses are a class of pathogens with well established roles in the development of malignant diseases. Numerous bodies of work have highlighted miRNAs (microRNAs) as critical regulators of tumor pathways and it is clear that the dysregulation of cellular miRNA expression can promote tumor formation. Tumor viruses encode their own miRNAs and/or manipulate the expression of cellular miRNAs to modulate their host cell environment, thereby facilitating their respective infection cycles. The modulation of these miRNA responsive pathways, however, often influences certain signal transduction cascades in ways that favor tumorigenesis. In this review, we discuss the roles of virally-encoded and virally-regulated cellular miRNAs in the respective viral life cycles and in virus associated pathogenesis.     

Increase in cellular RNA in cells infected with DNA oncogenic viruses

The amount of RNA per cell has been measured by flow microfluorometry in cultured cells stimulated by serum or infected with DNA oncogenic viruses (SV40, polyoma virus, and adenovirus). While all four agents stimulate, although to a different extent, cellular DNA synthesis in quiescent cells, the accumulation of cellular RNA varies. Serum, SV40, and polyoma virus cause a marked increase in total cellular RNA that is already apparent in G1 cells before entry into S. On the other hand, adenovirus 2, while capable of stimulating cellular DNA synthesis, fails to detectably increase the amount of RNA per cell. These results suggest that adenovirus 2 may act on quiescent cells through mechanisms different from those of serum, SV40, or polyoma virus.     

Clinical and immunohistochemical analysis of patients with unknown primary tumour. A search for prognostic factors in UPT

BACKGROUND: The unknown primary tumour (UPT) is an intriguing clinical finding in approximately 5% of all newly diagnosed patients with cancer. To evaluate a correlation between the specific immunohistochemical alterations in UPT cells and the unique clinical features of UPT patients, to define the natural history of UPT and to verify prognostic factors, we undertook a detailed clinical and immunohistochemical analysis of patients with the diagnosis of adenocarcinoma of UPT. RESULTS: Patients with UPT present with a short history and have a poor prognosis. Univariate analysis was performed with clinical, biological and immunohistochemical variables. Patients with a higher age (>60 years), a poor performance score (2-3), liver metastases or more than two organ sites involved, or patients with elevated LDH-levels, were found to have worse prognosis. We confirm that the prognostic model published by Culine is a valuable model for the prediction of prognosis in patients with UPT. Immunohistochemical detection of proliferation (MIB-1), p53, vascular endothelial growth factor-A, CD34, CD44v6 and Her2neu indicated that these factors were of no prognostic value. CONCLUSION: In conclusion, patients with UPT have a very poor median prognosis of 12 weeks. Prognostically favourable factors are young age, good performance status, no liver metastases and normal LDH level. We found no relationship with immunohistochemical factors.     

A novel monoclonal antibody for detection of galectin-9 in tissue sections: application to human tissues infected by oncogenic viruses

Background

Galectin-9 is a mammalian lectin which possesses immunosuppressive properties. Excessive production of galectin-9 has been reported in two types of human virus-associated diseases chronic hepatitis C and nasopharyngeal carcinoma associated to the Epstein-Barr virus. The objective of this study was to produce new monoclonal antibodies targeting galectin-9 in order to improve its detection in clinical samples, especially on tissue sections analysed by immunohistochemistry.

Methods

Hybridomas were produced through immunization of mice with the recombinant c-terminus part of galectin-9 (residues 191 to 355 of the long isoform) and semi-solid fusion of spleen cells with Sp2/0 cells. Monoclonal antibodies were characterized using ELISA, epitope mapping, western blot and immunohistochemistry.

Results

We selected seven hybridomas producing antibodies reacting with our recombinant c-terminus galectin-9 in ELISA. Five of them reacted with the epitope ??TPAIPPMMYPHPA?? (common to all isoforms, residues 210 to 222 of the long isoform) and stained all three isoforms of galectin-9 analysed by western blot. One of them, 1G3,demonstrated very good sensitivity and specificity when used for immunohistochemistry. Using 1G3, we could confirm the intense and constant expression of galectin-9 by Epstein-Barr virus positive malignant cells from nasopharyngeal carcinomas. In most samples, specific staining was detected in both cytoplasm and nuclei. Galectin-9 was also detected in liver biopsies from patients infected by the human hepatitis C or B viruses with expression not only in inflammatory leucocytes and Kupffer cells, but also in hepatocytes. In contrast, galectin-9 was virtually absent in non-infected liver specimens.

Conclusion

The 1G3 monoclonal antibody will be a powerful tool to assess galectin-9 expression and distribution especially in diseases related to oncogenic viruses.     

The search for the primary tumor in patients with skeletal metastases of unknown origin

Forty-six patients who had been evaluated because of skeletal metastases of unknown origin, were reviewed. Twenty-six of the patients were referred to an orthopedic surgeon before confirmation of the metastases by biopsy; 20 others were referred to an oncology clinic after a diagnosis of bone metastases had been established. A simple diagnostic sequence consisting of a medical history, physical examination, routine laboratory studies, chest roentgenogram, technetium 99m phosphonate bone scintigram, and intravenous pyelogram identified the site of the primary tumor in 14 patients; 7 of the primaries were lung carcinomas, 4 were hypernephromas, 2 were breast carcinomas, and 1 was a prostate carcinoma. In two other patients, the histologic findings from the biopsy study were diagnostic; one had a thyroid carcinoma and one, a prostate carcinoma. Further extensive diagnostic workups revealed the site of origin in only four additional patients; two had hypernephromas which were discovered by computed axial tomography of the abdomen; one had an ovarian carcinoma and one had a hepatoma, both of which were found at laparotomy. On the basis of this study, a simple diagnostic strategy is recommended for patients with histopathologically confirmed skeletal metastases of unknown origin: medical history, physical examination, routine laboratory studies, chest radiograph, and technetium 99m phosphonate bone scintigram, followed by computed axial tomographic examination of the abdomen and pelvis. In female patients, it may be judicious to use mammography. If this regimen fails to reveal the primary site, it is unlikely that it will be identified with further extensive diagnostic procedures.     

Leukocyte migration inhibition among breast cancer patients in response to various oncogenic viruses

The direct leukocyte migration inhibition (LMI) test was done with leukocytes from healthy women and from patients with primary operable breast cancer, benign breast disease, or head and neck cancer. Purified preparations of murine mammary tumor virus (MuMTV), Mason-Pfizer monkey virus (MPMV), and murine leukemia virus (MuLV) were used. For each virus, the lowest 10th percentile of the LMI responses of controls was used to discriminate positive from negative responses. Leukocytes from 46 of 94 (49%) breast cancer patients responded to MuMTV, which was significantly different from each of the other test groups: Positive reactions were observed in only 9 of 67 (13%) healthy persons, 2 of 32 (6%) patients with benign breast tumors, and 2 of 20 (10%) patients with head and neck cancer. Although leukocytes from 29% of the breast cancer patients responded to MPMV, this response did not significantly differ from that observed in healthy women (14%), in patients with benign disease (20%), or in patients with head and neck cancer (20%). The leukocytes from the breast cancer patients were not reactive to MuLV. LMI tests to both MuMTV and extracts of MCF-7 cultured breast cancer cells were done in 36 breast cancer patients and 40 healthy women simultaneously. Of the breast cancer patients, 75% responded to MuMTV and/or MCF-7 antigen as compared to 18% of the controls (P less than 0.005). These data suggest that leukocytes from breast cancer patients are presensitized to MuMTV and antigen(s) present in MCF-7 breast cancer cell line, but not to MPMV or MuLV.