Hirokazu Uetsuka

Heparanase expression correlates with invasion and poor prognosis in gastric cancers

Degradation of basement membrane and extracellular matrix structures are important features of the metastatic process of malignant tumors. Human heparanase degrades heparan sulfate proteoglycans, which represent the main components of basement membranes and the extracellular matrix. Because of the role of heparanase in tumor invasion and metastasis, we examined heparanase expression in primary gastric cancers and in cell lines derived from gastric cancers by immunohistochemistry and RT-PCR, respectively. Four of seven gastric cancer cell lines showed heparanase mRNA expression by RT-PCR. Heparanase protein was detected in both the cytoplasm and the nucleus of heparanase mRNA-positive cells by immunohistochemical staining. Heparanase expression was confirmed in 35 (79.5%) of 44 gastric tumor samples by immunohistochemical staining. However, no or weak heparanase expression was detected in normal gastric mucosa. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Analysis of the clinicopathologic features showed stronger heparanase expression in cases of huge growing tumors, extensive invasion to lymph vessels, and regional lymph node metastasis. In gastric cancer, patients with heparanase expression showed significantly poorer prognosis than those without such expression (p = 0.006). In conclusion, our findings suggest that high expression of heparanase in gastric cancer is a strong predictor of poor survival.

Inhibition of inducible NF-κB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line

5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.

Localization of heparanase in esophageal cancer cells: Respective roles in prognosis and differentiation

In this study, we examined the distribution of heparanase protein in 75 esophageal squamous cell carcinomas by immunohistochemistry and analyzed the relationship between heparanase expression and clinicopathological characteristics. In situ hybridization showed that the mRNA expression pattern of heparanase was similar to that of the protein, suggesting that increased expression of the heparanase protein at the invasive front was caused by an increase of heparanase mRNA in tumor cells. Heparanase expression correlated significantly with depth of tumor invasion, lymph node metastasis, tumor node metastasis (TNM) stage and lymphatic invasion. Overexpression of heparanase in esophageal cancers was also associated with poor survival. In addition to its localization in the cytoplasm and cell membrane, heparanase was also identified in the nuclei of normal epithelial and tumor cells by immunohistochemistry. Furthermore, nuclear heparanase was detected in nuclear extract of cancer cell lines by Western blot and immunohistochemistry. Examination of the role of nuclear heparanase in cell proliferation and differentiation by double immunostaining for proliferating cell nuclear antigen (PCNA) and cytokeratin 10 (CK10) showed significant relationship between nuclear heparanase expression and differentiation (heparanase vs CK10), but not for proliferative state of esophageal cancer cells (heparanase vs PCNA). Our results suggest that cytoplasmic heparanase appears to be a useful prognostic marker in patients with esophageal cancer and that nuclear heparanase protein may play a role in differentiation. Inhibition of heparanase activity may be effective in the control of esophageal tumor invasion and metastasis.

CASE REPORT: Primary Malignant Melanoma of the Esophagus: Long-Term Survival Following Pre- and Postoperative Adjuvant Hormone/Chemotherapy

Primary malignant melanoma of the esophagus (PMME) is rare, accounting for only 0.1–0.2% of all esophageal tumors (1–4). The prognosis of PMME is very poor, due to its aggressive biological behavior and usual advanced stage at the time of diagnosis. Even with radical resection, death usually occurs within 1 year of diagnosis (1), and the 5-year survival rate is less than 5% (5). Previous studies have also indicated that chemotherapy and radiotherapy do not improve patient survival (2). We report a patient with advanced PMME who underwent radical esophageal resection with lymph node dissection, preand postoperative hormone/chemotherapy, and immunohormone therapy. He remains alive nearly 8 years after surgery, with no evidence of recurrence or metastasis.

Three Cases of Adenocarcinoma Arising in Extremely Long-Segment Barrett’s Esophagus

Barrett’s esophagus (BE) is an acquired and premalignant disease of the esophagus, in which esophageal squamous epithelium is changed by injury from reflux to metaplastic intestinal-type columnar epithelium. It is widely accepted that the long-standing reflux of gastric acid due to hiatal hernia, kyphosis, or gastric operation is a catalyst for the development of BE (1–5). We report herein three cases of adenocarcinoma arising in extremely long-segment BE.

A Case of Gastric Necrosis with Gastric Cancer

症例は59歳の男性で, 腹痛を主訴に受診した. 来院時, 上腹部を中心に筋性防御を認め, 板状硬であった. 血液検査では炎症反応の上昇と, 肝機能・腎機能障害およびCKの上昇を認めた. CTでは胃壁の浮腫による著明な肥厚と少量の腹水を認め, 上腹部腸管を原因とする腹膜炎の診断にて審査腹腔鏡を行った. 血性の腹水および胃の虚血性変化を認めたため, 術中胃内視鏡検査を施行した. 胃体中部から前庭部にかけ粘膜の脱落と潰瘍性病変および暗赤色性の変化を認め, 胃壊死と診断, 開腹に移行し胃全摘術を行った. 病理組織学的診断では潰瘍部に中分化腺癌を認め, 深達度はmpであった. また, 膿瘍を形成する好中球浸潤を全層に認め, 一部菌塊を伴っていた. 全層性の壊死を伴っている部位も認めた. 胃壊死の原因としては, 癌の潰瘍部からの感染が考えられた. まれな症例と考えられたので, 文献的考察を加え報告する.