Naoyo Nishida

Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma.

Cap43 is a nickel- and calcium-inducible gene that plays important roles in the primary growth of malignant tumors, as well as in invasion and metastasis, most likely through its ability to induce cellular differentiation. This study investigated associations of Cap43 expression with angiogenesis and other clinicopathological factors in cervical adenocarcinoma. The clinical records of 100 women who underwent surgery for cervical adenocarcinoma were reviewed retrospectively. Microvessel density and the expression of Cap43 and VEGF in the surgical specimens were evaluated immunohistochemically. The Cap43 expression level was significantly associated with angiogenesis, tumor diameter, stromal invasion, lymphovascular space invasion, lymph node metastasis, and histopathological differentiation. Kaplan-Meier analysis showed a significant association between the Cap43 expression level and survival: high Cap43 expression was related to poor survival. Our results suggest that increased expression of Cap43 is associated with angiogenesis and may be a poor prognostic indicator in women with cervical adenocarcinoma.

Overexpression of the myc target gene Mina53 in advanced renal cell carcinoma

The myc target gene Mina53 was reported to be overexpressed in esophageal cancer with a poor prognosis. The purpose of the present study was to examined Mina53 expression and its relationship to clinicopathological parameters in human renal cell carcinoma (RCC). Mina53 and Ki‐67 expression was examined on immunohistochemistry for 64 surgically resected RCC and non‐cancerous tissue. In addition, the relationship between Mina53 expression and clinicopathological prognostic factors of RCC such as age, stage, microvenous invasion (MVI), histological subtype, Ki‐67 labeling index (LI), and prognosis, was examined. Mina53 was expressed in the nuclei of tumor cells and tubular nuclei of normal renal tissue. The expression level of Mina53 was significantly higher in patients with poor prognostic factors (stage IV, MVI‐positive, and sarcomatoid RCC, and high Ki‐67 LI). The prognosis of high Mina53‐expressing tumors was significantly poorer than that of non‐Mina53‐high tumors (P < 0.0001). In conclusion, Mina53 is overexpressed in RCC tissue from patients with poor prognostic factors, suggesting that Mina53 overexpression is one of the factors for poor prognosis in RCC.

Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims:  Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated.

Intraductal neoplasm of the intrahepatic bile duct: Clinicopathological study of 24 cases

AIM To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and β-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ, high grade including tumors with microinvasion). RESULTS Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P < 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of β-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.

Antiproliferative Effects of Interferon-αCon1 on Ovarian Clear Cell Adenocarcinoma In vitro and In vivo

Purpose: We examined the antiproliferative effect of IFN-αCon1 and its mechanism on ovarian clear cell adenocarcinoma in vitro and in vivo. Experimental Design: (a) The effects of IFN-αCon1 on growth, morphology, cell cycle, and type I IFN-α receptor (IFNAR-2) expression were examined on two ovarian clear cell adenocarcinoma cell lines (KOC-5C and KOC-7C) in vitro. (b) KOC-5C or KOC-7C cells were transplanted into nude mice, and changes in tumor volume, tumor weight, apoptosis, necrosis, and microvessel density were investigated. The expression of angiogenesis factors was examined in the serum and the developed tumors. Results: Both cell lines expressed IFNAR-2 mRNA, but its protein was detected only in KOC-7C. In KOC-7C cells, antiproliferative effects were observed in a time- and dose-dependent manner and cell division was blocked at the S phase. The KOC-7C tumors showed decreases in tumor volume and weight; a decreasing tendency in basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and interleukin (IL)-8 protein expression in the tumor; a significant decrease in bFGF and IL-8 protein expression in the serum, and of microvessel density; and significant increase in apoptosis and necrosis in the tumor. In the KOC-5C tumors, these in vitro and in vivo changes were not apparent, and the antiproliferative effects of IFN-αCon1 were not obvious. Conclusions: IFN-αCon1 suppresses tumor proliferation by inducing apoptosis, blocking the cell cycle, and inhibiting tumor angiogenesis. Our findings show that the clinical efficacy of IFN-αCon1 can be predicted by examining IFNAR-2 expression on tumor cells, and the efficacy of IFN-αCon1 treatment can be evaluated by measuring serum bFGF and IL-8 levels.

Antiproliferative effects of 5-fluorouracil and interferon-alpha in combination on a hepatocellular carcinoma cell line in vitro and in vivo

Background and Aim:  We investigated the antiproliferative effects of interferon‐alpha (IFN‐α) and 5‐fluorouracil (5‐FU) in combination on a hepatocellular carcinoma (HCC) cell line.

16 - Role of Immunohistochemical Expression of Vascular Endothelial Growth Factor C and Vascular Endothelial Growth Factor Receptor 2 in Ovarian Cancer

This chapter discusses the role of the method of immunohistochemical (IHC) examination to identify the expression of vascular endothelial growth factor (VEGF) family and its receptors (VGEFR). Immunohistochemical examination is a well established technique to exhibit the tissue localization of an immunoreactive antigen. Angiogenesis and lymphangiogenesis have an essential role in the proliferation of the vascular network to supply nutrition, oxygen, and immune cells and also to remove the waste products. The growth factor VEGF is accepted as a powerful angiogenic agent in neoplastic tissues and in normal tissues. Under the influences of some cytokines and other growth factors, the VEGF family appears in the cancer tissue and the adjacent stroma and plays an important role in making the neovascularization. In the absence of vascular support, tumors may become necrotic or even apoptotic among the family, VEGF-A, -B, and -C induce new blood-vessel proliferation and VEGF-C and VEGF-D relate to lymphangiogenesis. These growth factors act with their own VEGF receptor. High tissue expression of VEGF-C and VEGFR-2 reflects the aggressiveness of the spread of tumor in the ovarian carcinoma.