Evidence for an association between increased oxidative stress and derangement of FOXO1 signaling in tumorigenesis of a cellular angiofibroma with monoallelic 13q14 : a case report

Cellular angiofibroma (CAF) is a rare soft tissue tumor characterized by random arrangement of spindle tumor cells in the stroma with short collagen bundles and thick- and hyalinized small vessels. CAFs share histological characteristics with spindle cell lipomas and mammary type myofibroblastomas. Because these tumors harbor monoallelic 13q14, common genetic and molecular mechanism for tumorigenesis is presumed. In this study, we reported a case of CAF in a 69-year-old man with monoallelic 13q14. Immunohistochemical analysis revealed that FOXO1, which is located in chromosome 13q14, was not expressed in the tumor. We also detected oxidative stress markers and found p38 MAPK activation, which is often induced by cellular stressors such as reactive oxygen species (ROS). Because FOXO1 induces the expression of genes encoding enzymes that generate antioxidants, oxidative stress induced by loss of FOXO1 expression may be common among CAFs, spindle cell lipomas, and mammary type myofibroblastomas

Esophageal xanthoma: presence of M2 macrophages suggests association with late inflammatory and reparative processes

Esophageal xanthoma is a rare lesion which is an asymptomatic small yellowish polyp, and most of the reported cases were solitary lesion. Histologically, aggregations of foam cells are found under the papillary hypertrophic squamous epithelium and the foam cells express CD68. The etiology of esophageal xanthoma is unknown. The focal irritation of the esophageal mucosa and infiltrated inflammatory cells are presumed to contribute to its pathogenesis. Although the pathogenesis may be associated with inflammation, the type and nature of the macrophages remain unclear. Here we report a 46-year-old male with esophageal xanthoma, which was incidentally found by endoscopy. Histologically, acute inflammation was not noted, and immunohistochemistry revealed that the foam cells seen in this case of esophageal xanthoma expressed increased levels of M2 macrophage markers. These findings suggest that esophageal xanthoma is associated with late inflammatory and reparative processes long after the initial inflammation of esophageal squamous epithelium

Co-expression of low-risk HPV E6/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage

Abstract Background Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. Methods We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. Results Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. Conclusions The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions