Ken Tsuboi

Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer.

Objectives Because angiogenesis is essential for tumor growth and metastasis, the development of antiangiogenic agents is an urgent issue in cancer treatment. Zerumbone, a component of subtropical ginger, has been shown to exhibit anticancer activities in various cancer cells; however, little is known about its biological mechanisms against angiogenesis in pancreatic cancer (PaCa). Here, we evaluated the effects of zerumbone on PaCa angiogenesis. Methods The cytotoxicity of zerumbone in PaCa was measured using premix WST-1 cell proliferation assays. The influence of zerumbone on the angiogenic factors vascular endothelial growth factor and interleukin 8 was measured using the reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assays. Changes in nuclear factor-&kgr;B (NF-&kgr;B) activities were measured using NF-&kgr;B transcription factor assays. We also examined the effects of zerumbone on PaCa-induced angiogenesis using angiogenesis assays. Results Zerumbone inhibited mRNA expression and protein secretion of angiogenic factors and NF-&kgr;B activity. Tube formation in human umbilical vein endothelial cells was enhanced by coculture with PaCa cells, and these enhancements were significantly inhibited by zerumbone treatment. Conclusions Zerumbone blocked the PaCa-associated angiogenesis through the inhibition of NF-&kgr;B and NF-&kgr;B–dependent proangiogenic gene products.

Girdin, a regulator of cell motility, is a potential prognostic marker for esophageal squamous cell carcinoma

Girdin, an actin-binding Akt substrate, regulates actin reconstruction and Akt-dependent cell motility in fibroblasts and in a human breast cancer cell line. We examined whether Girdin is also involved in the motility of esophageal squamous cell carcinoma (ESCC) cells. Immunofluorescent staining and migration assays were performed, using KYSE cell lines, to examine whether Girdin is involved in the motility of ESCC cells. Upon EGF stimulation, Girdin colocalized with filamentous actin (F-actin) in the lamellipodia as determined by immunofluorescent staining. In migration assays, cell motility was significantly reduced in KYSE cell lines transfected with Girdin siRNA compared with the negative control. In addition, we examined the relationship between Girdin expression and clinical data, using specimens resected from ESCC patients. In immunohistochemical (IHC) analyses using specimens resected from ESCC patients, overall survival was significantly longer in cases showing lower Girdin expression compared to cases with higher Girdin expression. Collectively, Girdin appears to be involved in the motility of ESCC cells. The levels of Girdin expression correlated inversely with the survival of ESCC patients. Therefore, in ESCC, Girdin may be a prognostic marker and may serve as a therapeutic target as well.

Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists

BackgroundThe CXCL12-CXCR4 signaling axis in malignant tumor biology has increased in importance, and these peptides are implicated in tumor growth, invasion and metastasis. The aim of our study was to examine the important role of the axis in pancreatic cancer (PaCa) cells’ relationship with stromal cells in gemcitabine-resistant (GEM-R) tumors and to confirm the effectiveness of CXCR4 antagonists for the treatment of GEM-R PaCa cells.MethodsWe established two GEM-R PaCa cell lines using MIA PaCa-2 and AsPC-1 cells. The expression of CXCR4 mRNA in PaCa cells and the expression of CXCL12 mRNA in fibroblasts were examined by reverse transcription polymerase chain reaction (RT-PCR). The expression of CXCR4 protein in PaCa cells was examined by immunosorbent assay (ELISA) and immunocytochemistry. Using Matrigel invasion assays and animal studies, we then examined the effects of two CXCR4 antagonists, AMD11070 and KRH3955, on the invasiveness and tumorigenicity of GEM-R PaCa cells stimulated by CXCL12.ResultsWe found that the expression of CXCR4 in GEM-R PaCa cells was significantly enhanced by GEM but not in normal GEM-sensitive (GEM-S) PaCa cells. In RT-PCR and ELISA assays, the production and secretion of CXCL12 from fibroblasts was significantly enhanced by co-culturing with GEM-R PaCa cells treated with GEM. In Matrigel invasion assays, the invasiveness of GEM-R PaCa cells treated with GEM was significantly activated by fibroblast-derived CXCL12 and was significantly inhibited by CXCR4 antagonists, AMD11070 and KRH3955. In vivo, the tumorigenicity of GEM-R PaCa cells was activated by GEM, and it was significantly inhibited by the addition with CXCR4 antagonists.ConclusionsOur findings demonstrate that the CXCL12-CXCR4 signaling axis plays an important role in PaCa cells’ resistance to GEM. CXCR4 expression was significantly enhanced by the exposure to GEM in GEM-R PaCa cells but not in GEM-S PaCa cells. Furthermore, CXCR4 antagonists can inhibit the growth and invasion of GEM-R PaCa cells. These agents may be useful as second-line chemotherapy for GEM-R PaCa in the future.

Xanthohumol inhibits angiogenesis by suppressing nuclear factor-κB activation in pancreatic cancer

Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor‐κB (NF‐κB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF‐κB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF‐κB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin‐8 (IL‐8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC‐3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC‐3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki‐67 expression, CD31‐positive microvessel density, NF‐κB p65 expression, and VEGF and IL‐8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF‐κB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer.

Inflammatory pseudotumor of the liver diagnosed as metastatic liver tumor in a patient with a gastrointestinal stromal tumor of the rectum: report of a case

BackgroundInflammatory pseudotumor (IPT) of the liver is a rare benign lesion. A case of IPT of the liver found in association with a malignant gastrointestinal stromal tumor (GIST) is reported.Case reportA 74-year-old man was admitted to our hospital for a liver tumor. He previously underwent rectal amputation for a malignant GIST. Computed tomography (CT) revealed a low-density area in the liver and dynamic contrast-enhanced MRI (EOB-MRI) showed that the tumor was completely washed out in the delayed phase. 18Fluorine-fluorodeoxyglucose positron emission tomography (FDG-PET) showed strong uptake in the liver. A diagnosis of liver metastasis was made and partial hepatectomy was performed. Microscopic examination showed that the tumor was an IPT.ConclusionDifferential diagnosis between IPT and malignant neoplasms is difficult. Moreover, FDG-PET revealed strong uptake in the tumor. To our knowledge, this is the first patient reported to have an IPT in association with a rectal GIST. This patient is discussed along with a review of the literature.

Laparoscopically resected obturator nerve schwannoma: A case report.

Obturator nerve schwannomas are very rare. To date, only nine cases have been reported in the English‐language literature; none of these were diagnosed preoperatively. A 68‐year‐old woman was admitted with left lower abdominal pain. CT and MRI revealed a mass 30 mm in diameter in the left obturator fossa, suggesting a retroperitoneal tumor. Because CT and MRI revealed clear continuity with the left obturator nerve, this case was diagnosed as an obturator nerve schwannoma. Tumor enucleation was performed by laparoscopy. On histopathological examination, this case was diagnosed as a benign obturator nerve schwannoma. Postoperatively, the patient developed weakness of the adductor muscle but recovered within 6 months with rehabilitation therapy. Preoperative diagnosis of obturator nerve schwannomas is quite difficult, but careful inspection of CT and MRI is important to identify the original nerve of schwannoma preoperatively. Accordingly, laparoscopic resection is a good treatment option.