Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that supports the adaptation of human cancer cells to hypoxia and tumor growth and progression. The overexpression of HIF-1alpha protein has been reported to be associated with a worse prognosis in various cancers. However, the expression of HIF-1alpha in soft-tissue sarcomas has not yet been characterized. The expression of HIF-1alpha protein was immunohistochemically determined in 49 specimens of soft-tissue sarcomas including malignant fibrous histiocytoma (29 patients), synovial sarcoma (12 patients), leiomyosarcoma (four patients), and malignant peripheral nerve sheath tumors (four patients). The 49 samples consisted of 40 primary lesions and nine local recurrences. An immunohistochemical analysis showed the nuclear accumulation of HIF-1alpha protein in 35 (71.4%) samples. The expression of HIF-1alpha was negative in 14 (28.6%) cases, weak in nine (18.4%), moderate in 17 (35.4%), and strong in nine (18.4%). The patients with a strong or moderate expression of HIF-1alpha had a significantly shorter overall survival rate in comparison with those with a weak or negative expression in a univariate analysis (P = 0.029; log-rank test) and multivariate analysis (P = 0.018). This is the first report that demonstrated an overexpression of HIF-1alpha protein to be an independent prognostic factor for soft-tissue sarcomas.
Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas. MFH has been proposed to be a lesion accompanied with inflammatory responses. During chronic inflammation, reactive nitrogen and oxygen species generated from inflammatory cells are considered to participate in carcinogenesis by causing DNA damage. 8-nitroguanine is a mutagenic nitrative DNA lesion formed during chronic inflammation. We examined whether nitrative DNA damage is related to the prognosis of MFH patients. We performed immunohistochemical analyses to examine the distribution of DNA damage and the expression of inflammation-related molecules including inducible nitric oxide synthase (iNOS), nuclear factor-κ κ κ κB (NF-κ κ κ κB), and cyclooxygenase-2 (COX-2) in clinical specimens from 25 patients with MFH. We also analyzed the correlation of DNA damage or the expression of these genes with the prognosis of MFH patients. Immunohistochemical staining revealed that the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2′ ′ ′ ′-deoxyguanosine (8-oxodG), an oxidative DNA lesion, occurred to a much greater extent in MFH tissue specimens from deceased patients than in live patients. iNOS, NF-κ κ κ κB and COX-2 were colocalized with 8-nitroguanine in MFH tissues. It is noteworthy that the statistical analysis using the Kaplan-Meier method demonstrated strong 8-nitroguanine staining to be associated with a poor prognosis. In conclusion, 8-nitroguanine appears to participate in not only the initiation and promotion of MFH, but also in the progression of MFH, and could therefore be used as a promising biomarker to evaluate the prognosis of cancer patients. (Cancer Sci 2007; 98: 163-168) M alignant fibrous histiocytoma has been regarded as one of the most common soft tissue sarcomas occurring in adult patients, (1) and it occurs most frequently in the extremities, trunk and retroperitoneum.(2) MFH is classified into four subtypes including storiform-pleomorphic (60 -70%), myxoid (10 -20%), giant cell (approximately 10%) and inflammatory (relatively rare).(3) MFH has been proposed to be a lesion accompanied with inflammatory responses. The expression of cytokines in a certain type of MFH (inflammatory MFH) may account for the local inflammatory infiltrate and the aggressive nature observed in these malignant cells.(4) In the early phases of experimentally induced rat sarcoma, an inflammatory reaction characterized by an infiltration of lymphocytes, monocytes and macrophages was observed.(5) It has been hypothesized that many malignancies arise from areas of inflammation.(6,7) Moreover, chronic inflammation has also been proposed to contribute to the development of various cancers.(6,7) These findings led us to an idea that the inflammatory responses thus play a role in the pathogenesis of MFH.During chronic inflammation, RNS and ROS are generated from inflammatory and epithelial cells, and therefore are considered to play a key role in both carcinogenesis and tumor progression. (8,9) ROS can induce the formation of 8-oxod), an indi...
We report a 72-year-old woman with a type-1 intra-osseous ganglion in the proximal humerus, extending to the bone surface. We conducted a systemic review of intra-osseous ganglion cases in Japan to identify clinical features and pathogenesis of this condition. The anatomical distribution between intra-osseous ganglia without a communicating soft tissue ganglion (type 1) and those with (type 2) is different. The origins of intra-osseous ganglia vary and depend on their anatomical location. They can arise from within the bone or in the adjacent soft tissue, and can progress to a type-2 lesion in either an outside-in or inside-out fashion.
Abstract. Chronic inflammation is a critical component of carcinogenesis and tumor progression. Reactive nitrogen and oxygen species generated by inflammatory cells form mutagenic DNA lesions, such as 8-nitroguanine, which may play an integral role in inflammation-related carcinogenesis. Hypoxiainducible factor (HIF)-1α has been established as a prognostic biomarker in various tumors, including malignant fibrous histiocytoma (MFH). The aim of this study was to evaluate the impact of 8-nitroguanine formation and HIF-1α expression on the prognosis of patients with inflammation-related cancer. Immunohistochemical analyses were employed to examine the distribution of 8-nitroguanine and HIF-1α, using clinical specimens from 36 patients with MFH as a model of inflammation-related cancer. 8-Nitroguanine formation was predominately observed in the nuclei of tumor cells and inflammatory cells in tumor tissues, while HIF-1α was expressed in the cytoplasm and nuclei of tumor cells. Little or no immunoreactivity of 8-nitroguanine and HIF-1α was observed in adjacent non-tumor tissues. Significantly higher levels of both 8-nitroguanine and HIF-1α were observed in the tissue specimens of deceased patients than in those of living subjects. Survival curves analyzed by the KaplanMeier method differed significantly between the high-and low-staining groups of 8-nitroguanine (p=0.00003) as well as HIF-1α (p=0.01104). These results suggest a significant role of the pathway of iNOS-dependent 8-nitroguanine formation via HIF-1α and NF-κB on the progression of inflammationrelated cancer. In conclusion, 8-nitroguanine is an excellent candidate prognostic and predictive biomarker together with HIF-1α in inflammation-related tumor progression.
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