iNOS‐dependent DNA damage in patients with malignant fibrous histiocytoma in relation to prognosis

Abstract

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...

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

“…These results agree with the observation of a significant association of iNOS and Metalloproteinase-9 expression with HCC recurrence [121] , and iNOS overexpression with poor prognosis for gastric cancer [129] , adenoid cystic carcinoma of salivary glands [130] , fibrous histiocytoma [131] , colorectal cancer [132] . These iNOS effects seem to be mediated by its angiogenic properties and intensified by Cycloxygenase 2 (COX2) upregulation [133] .…”

8-Nitroguanine, a Potential Biomarker to Evaluate the Risk of Inflammation-Related Carcinogenesis

“…Thus, 8-nitroguanine is a potentially mutagenic DNA lesion, which can participate in initiation and promotion in the infection-related carcinogenesis (Loeb & Preston, 1986;. Our studies have demonstrated that 8-nitroguanine is formed at the sites of carcinogenesis in humans and experimental animals (Ma et al, 2004;Pinlaor et al, 2004b;Ding et al, 2005;Horiike et al, 2005;Ma et al, 2006;Hoki et al, 2007a;Hoki et al, 2007b;Fujita et al, 2008;Ma et al, 2008;Tanaka et al, 2008;Ma et al, 2009;Ma et al, 2010). Moreover, our studies have demonstrated that 8-nitroguanine was formed in Oct3/4-positve stem cells in S. haematobium-associated cystitis and cancer tissues.…”

“…We have firstly demonstrated that 8-nitroguanine is formed at the sites of carcinogenesis regardless of etiology, and we have proposed the possibility that 8-nitroguanine is a potential biomarker to evaluate the risk of inflammation-associated carcinogenesis . In clinical specimens, 8-nitroguanine was formed in the gastric grand epithelial cells of patients with gastritis caused by Helicobacter pylori (H. pylori) infection (Ma et al, 2004), hepatocytes of patients with chronic hepatitis C (Horiike et al, 2005), oral precancerous lesions oral lichen planus (OLP) (Chaiyarit et al, 2005) and oral leukoplakia , soft tissue sarcoma (Hoki et al, 2007a;Hoki et al, 2007b) and Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) .…”

8-Nitroguanine as a potential biomarker for progression of malignant fibrous histiocytoma, a model of inflammation-related cancer

“…RNS mediate 8-nitroguanine formation, a marker of nitrative DNA damage (5). 8-Nitroguanine has been reported to be formed in association with inflammationrelated carcinogenesis (6)(7)(8)(9), including malignant fibrous histiocytoma (MFH), as reported previously (10). MFH is the most commonly diagnosed soft-tissue sarcoma in adults (11,12) and has a poor prognosis (13,14).…”

“…The sections were deparaffinized and automated immunohistochemistry was performed with a NexES IHC (Ventana Medical Systems, Inc., Tucson, AZ, USA) as previously described (10). The rabbit polyclonal anti-8-nitroguanine antibody produced by this laboratory (21) was used as the primary antibody at a concentration of 2 μg/ml.…”