Loss of heterozygosity among tumor suppressor genes in invasive and in situ carcinoma of the uterine cervix.
ABSTRACT The aim of the present study was to further clarify the histogenesis of cervical carcinoma by investigating loss of heterozygosity (LOH) among a number of tumor suppressor genes in invasive and in situ carcinoma of the cervix. Materials consisted of 16 in situ and 29 invasive carcinomas (16 squamous cell carcinomas, nine adenocarcinomas, and four adenosquamous carcinomas). DNA samples were collected by microdissection from ordinary formalin-fixed, paraffin-embedded tissues, both from the lesions and from normal tissues. LOH was analyzed using eight DNA polymorphic tumor suppressor markers. Of the 16 cases of carcinoma in situ, three cases exhibited LOH at one locus. Of the 29 cases of invasive carcinomas, six cases exhibited LOH at two loci and nine cases exhibited LOH at one locus. Overall, LOH was found more frequently in invasive carcinomas than in in situ carcinomas. LOH was most frequently detected at the PTCH (Drosophila patched gene) locus. There was no significant correlation between LOH at a specific site and either histologic subtype or clinical stage. These results suggest that LOH might already occur in a fraction of preinvasive squamous lesions and that accumulation of LOH may in part play a role in carcinogenesis of the cervix.
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ABSTRACT: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and intrinsically oncolytic because of its potent ability to induce apoptosis. Several studies have demonstrated that NDV is selectively cytotoxic to tumor cells but not normal cells due to defects in the interferon (IFN) antiviral responses of tumor cells. Many naturally occurring strains of NDV have an intact IFN-antagonistic function and can still replicate in normal human cells. To avoid potential toxicity issues with NDV, especially in cancer patients with immunosuppression, safe NDV-oncolytic vectors are needed. We compared the cell killing abilities of (i) a recombinant NDV (rNDV) strain, Beaudette C, containing an IFN-antagonistic, wild-type V protein (rBC), (ii) an isogenic recombinant virus with a mutant V protein (rBC-Edit virus) that induces increased IFN in infected cells and whose replication is restricted in normal human cells, and (iii) a recombinant LaSota virus with a virulent F protein cleavage site that is as interferon sensitive as rBC-Edit virus (LaSota V.F. virus). Our results indicated that the tumor-selective replication of rNDV is determined by the differential regulation of IFN-alpha and downstream antiviral genes induced by IFN-alpha, especially through the IRF-7 pathway. In a nude mouse model of human fibrosarcoma, we show that the IFN-sensitive NDV variants are as effective as IFN-resistant rBC virus in clearing the tumor burden. In addition, mice treated with rNDV exhibited no signs of toxicity to the viruses. These findings indicate that augmentation of innate immune responses by NDV results in selective oncolysis and offer a novel and safe virotherapy platform.Journal of Virology 02/2010; 84(8):3835-44. · 4.65 Impact Factor
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ABSTRACT: The hedgehog (Hh)-signaling pathway plays an essential role in normal development. Deregulation of this pathway is responsible for several types of cancers. The aim of this study was to determine the expression pattern and the extent of Hh-signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. A total of 106 uterine cervical cancers and related lesions (37 squamous cell carcinomas, 23 cervical intraepithelial neoplasia (CIN) III, 10 CIN II, four CIN I, 32 normal cervical epithelia) were immunohistochemically analyzed with anti-Shh, Indian Hh (Ihh), Patched (PTCH), Smoothened (Smo), Gli-1, Gli-2, Gli-3 antibodies on paraffin blocks. The results showed that the expression of all the Hh-signaling molecules was greatly enhanced in uterine cervical tumors, including carcinoma and its precursor lesions. The staining pattern was mainly cytoplasmic except for Gli-1/2, whose expression was observed in both cytoplasm and nucleus. In case of Ihh, PTCH, Smo and Gli-1, their expression in normal epithelium was completely absent or rare. The expression of all the seven Hh-signaling molecules mentioned above was significantly increased in CIN II/III and carcinoma, compared with that in normal epithelium (P < 0.05). The expression of Shh was increased by double; the first increase occurred in normal epithelium-CIN transition, and the second, during the progression of CIN to carcinoma. These results strongly suggest that the Hh-signaling pathways were extensively activated in carcinoma and CIN of uterine cervix. In conclusion, the Hh-signaling pathways may be involved in carcinogenesis of squamous cell carcinoma of uterine cervix and can be considered as a potential therapeutic target.Modern Pathology 08/2006; 19(8):1139-47. · 6.36 Impact Factor