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Junko Matsuoka,
Masakazu Yashiro,
Yosuke Doi,
Yuhiko Fuyuhiro,
Yukihiro Kato,
Osamu Shinto, Satoru Noda,
Shinichiro Kashiwagi,
Naoki Aomatsu,
Toshiki Hirakawa,
Tsuyoshi Hasegawa,
Kiyoshi Shimizu,
Toshiyuki Shimizu,
Atsushi Miwa,
Nobuya Yamada,
Tetsuji Sawada,
Kosei Hirakawa
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ABSTRACT: Epithelial mesenchymal transition (EMT) is considered to be correlated with malignancy of cancer cells and responsible for cancer invasion and metastasis. We previously reported that distant metastasis was associated with hypoxia in gastric cancer. We therefore investigated the effect of hypoxic condition on EMT of gastric cancer cells. Gastric cancer cells were cultured in normoxia (21% O2) or hypoxia (1% O2) for 24 h. EMT was evaluated as the percentage of spindle-shaped cells in total cells. Effect of transforming growth factor β1 (TGFβ1) or tyrosine kinase inhibitors on the EMT was evaluated. The expression level of TGFβ1 and TGFβR was evaluated by real time RT-PCR. The TGFβ1 production from cancer cells was measured by ELISA. Hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, but not that of OCUM-2M cells. The expression level of TGFβ1 mRNA under hypoxia was significantly higher than that under normoxia in all of three cell lines. The expression level of TGFβR mRNA was significantly increased by hypoxia in OCUM-2MD3 cells, but not in OCUM-2M cells. TGFβR inhibitor, SB431542 or Ki26894, significantly suppressed EMT of OCUM-2MD3 and OCUM-12. TGFβ1 production from OCUM-2MD3 and OCUM-12 cells was significantly increased under hypoxia in comparison with that under normoxia. These findings might suggest that hypoxia stimulates the EMT of gastric cancer cells via autocrine TGFβ/TGFβR signaling.
PLoS ONE 01/2013; 8(5):e62310. · 4.09 Impact Factor
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ABSTRACT: Sequential administration of anthracyclin and taxane for neoadjuvant chemotherapy (NAC) is the standard treatment for operable breast cancer. The pathological complete response (pCR) is a significant predictor of overall survival (OS), regardless of treatment. In this study, the pCR rate was retrospectively examined and compared with the treatment efficacy and the characteristics of pCR patients were analyzed. A total of 54 female patients with operable breast cancer, treated with FEC 100 followed by weekly paclitaxel between December 2005 and May 2009 at the Osaka City University Hospital, Osaka, Japan, were retrospectively reviewed. A total of 21 patients (39%) achieved pCR. The overall response rate was 91%. Only one patient had progressive disease. The pCR rate was significantly higher in those patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors and in those patients who completed the treatment course. An NAC regimen incorporating FEC 100 followed by weekly paclitaxel is effective for treating operable breast cancer.
Oncology letters 10/2012; 4(4):612-616. · 0.11 Impact Factor
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ABSTRACT: Tumor progression has been recognized as the product of evolving crosstalk between cancer cells and the surrounding stromal cells. Cancer-associated orthotopic myofibroblasts may be linked to the progression of gastric carcinomas. To understand the significance of orthotopic myofibroblasts, we examined the effects of cancer-associated orthotopic myofibroblasts on the malignant phenotype of gastric cancer cells. Three human gastric cancer cell lines (OCUM-2MD3, OCUM-12, MKN-45) and four human gastric fibroblast cell lines (cancer-associated orthotopic fibroblast [CaF]-29, CaF-33, normal orthotopic fibroblast [NF]-29, NF-33) were used. The cancer-associated orthotopic fibroblast cell lines CaF-29 and CaF-33 were established from a tumoral gastric wall, and normal orthotopic fibroblast NF-29 and NF-33 were established from a non-tumoral gastric wall. Fibroblasts that were α-smooth muscle actin-positive were defined as myofibroblasts. We examined the effects of cancer-associated orthotopic myofibroblasts on the aggressiveness of gastric cancer cells by wound-healing assay, invasion assay, and RT-PCR. The ratios of myofibroblasts in CaF-29 (33%) and CaF-33 (46%) were significantly (P < 0.001) greater than those in NF-29 (11%) or NF-33 (13%). Although all four orthotopic fibroblast lines increased the motility of gastric cancer cells, including migration and invasion ability, the motility-stimulating activity of cancer-associated fibroblasts (CaF-29 and CaF-33) was significantly higher than that of normal fibroblasts (NF-29 and NF-33). These motility-stimulating activities of cancer-associated orthotopic fibroblasts were downregulated by Smad2 siRNA treatment and anti-transforming growth factor-β neutralizing antibody. These findings suggest that cancer-associated orthotopic myofibroblasts may play an important role in the progression of gastric cancers and that transforming growth factor-β produced by myofibroblasts may be one of the factors associated with the aggressiveness of gastric carcinoma cells.
Cancer Science 02/2012; 103(4):797-805. · 3.33 Impact Factor
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ABSTRACT: Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2-targeted therapy in pancreatic carcinoma.
Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot.
Pancreatic cancer cell lines expressed VEGFR-2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells.
VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.
Annals of Surgical Oncology 12/2011; 19(8):2733-43. · 4.17 Impact Factor
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Yukihiro Kato,
Masakazu Yashiro,
Yuhiko Fuyuhiro,
Shinichiro Kashiwagi,
Junko Matsuoka,
Toshiki Hirakawa, Satoru Noda,
Naoki Aomatsu,
Tsuyoshi Hasegawa,
Taro Matsuzaki,
Tetsuji Sawada,
Masaichi Ohira,
Kosei Hirakawa
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ABSTRACT: The aim of this study was to examine the effects of hypoxia on radiosensitivity and to analyze the mechanisms responsible for radiation resistance in gastric and esophageal cancer.
A gastric cancer cell line, OCUM-12, and an esophageal cancer cell line, TE-6, were used. The effects of hypoxia with irradiation on the growth-activity, cell cycle distribution, and gene expression were examined.
Both acute and chronic hypoxia decreased radiosensitivity of cancer cells. The radiosensitivity of chronic hypoxic cells was significantly enhanced by reoxygenation. Acute and chronic all hypoxia reduced the percentage of cells in the G(2)/M and S phases, respectively. In acute hypoxia, the mRNA expression of BRCA1 and BRCA2 was reduced in cancer cells. Reoxygenation increased the expression of BRCA1 and BRCA2.
Hypoxia is associated with radiation resistance. Therefore, reoxygenation may enhance the radiosensitivity of hypoxic cells. BRCA1 and BRCA2 may be associated with factors for radiation resistance by regulation of cell cycle progression.
Anticancer research 10/2011; 31(10):3369-75. · 1.73 Impact Factor
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ABSTRACT: All patients with peritoneal-free cancer cells (CY1) do not always develop a peritoneal recurrence (P1). The goal of this study was to identify characteristic features of peritoneal-free cancer cells that could develop into peritoneal recurrence.
Of 1,474 patients, 91 were identified with CY1P0, and the remaining 1,383 with CY0P0. Immunohistochemical staining with anti-phosphorylated Smad 2 (p-Smad2) was performed on paraffin-embedded specimens from the 91 CY1P0 patients.
CY1 was significantly correlated with Borrmann's type-4 cancer, clinical T stage, and lymph node metastasis. CY1P0 patients with Borrmann's type-4 cancer more frequently develop peritoneal recurrence than do those with other types of tumors. The 5-year survival rate of patients with Borrmann's type-4 tumors was significantly (p = 0.023) low (6.3%) compared with that of patients with other types of tumors (27.7%). The prognosis for p-Smad2-positive patients was significantly poorer than that of p-Smad2-negative patients. In CY1 and/or P1 patients with Borrmann's type-4 tumors, no significant difference in prognosis was identified between those who had surgery and those who did not.
Activated Smad signaling might be associated with a high potential for peritoneal recurrence in CY1P0 patients. Borrmann's macroscopic criteria and p-Smad2 expression are useful markers for surgeons selecting advanced gastric cancer patients with CY1P0 for gastrectomy.
Annals of Surgical Oncology 05/2011; 18(13):3718-25. · 4.17 Impact Factor
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ABSTRACT: Vimentin expression in epithelial cells is reported to be associated with the malignant phenotype of cancer cells in vitro. However, the clinical significance of vimentin expression in carcinomas is not well understood. The aim of this study was to clarify the significance of vimentin-positive gastric cancer (GC).
A total of 265 GCs were examined by immunofluorescent staining with antibodies against vimentin and carcinoembryonic antigen. GCs were determined to be vimentin-positive when cells were positive for both vimentin and carcinoembryonic antigen staining.
A total of 86 (32%) of 265 GCs were vimentin positive. There was a statistically significant correlation between vimentin-positive GCs and advanced clinical stage (p<0.001), macroscopic scirrhous-type (p < 0.001), histological diffuse-type (p < 0.001), lymph node metastasis (p = 0.008) and lymphatic invasion (p = 0.013). The prognosis of patients with vimentin-positive GCs was significantly (p < 0.001) worse than that with vimentin-negative GCs.
Vimentin expression might contribute to the high invasive phenotype of GC, and may be a useful biomarker to determine the biological aggressiveness of GC.
Anticancer research 12/2010; 30(12):5239-43. · 1.73 Impact Factor
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ABSTRACT: A 61-year-old woman was visited our hospital for a left breast tumor. Ultrasonography (US) demonstrated two tumors comprising a tumor 3.3 cm in diameter in the A area and another one 0.9 cm in diameter in the C area of the left breast, and US-guided core needle biopsy (CNB) was performed. The histological findings showed invasive ductal carcinoma, ER (+)/PR (-)/HER2 (+) in the A lesion and ER (+)/PR (+)/HER2 (-) in the C lesion. At this point in time, US demonstrated a new tumor 1.9 cm in diameter in the outside C area of the left breast, and CNB was performed. The histological findings showed invasive ductal carcinoma, ER (+)/PR (+)/HER2 (-) in the outside C lesion. Chemotherapy was estimated as PD, and an operation was performed (Bt + Ax). Histopathological examination showed pCR in the A lesion, invasive lobular carcinoma in the C lesion and solid-tubular carcinoma in the outside C new lesion. Depend on each subtype, HER2/new targeting trastuzumab therapy, radiation therapy and ER/PR targeting hormone therapy were tried as a post operative treatment.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2010; 37(12):2775-7.
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ABSTRACT: A 70-year-old male presented with gastric cancer with para-aortic lymph node metastasis. The patient was given combination chemotherapy of S-1, paclitaxel and Lentinan. Lymph node metastases were reduced in number at the end of one course. At the end of the eighth course, the lesions were markedly reduced but no further reduction was observed thereafter. The primary lesion was also markedly reduced, and a distal gastrectomy(D1+a)was performed because of remaining tumor tissue detected by biopsy. Pathological findings revealed pT1(SM), pN0, P0, CY0, H0, M0, and Stage IA, respectively. After surgery, this treatment was continued for 4 years and one month from the initiation of this therapy(2 years and six months from gastrectomy). During the period of treatment, there was no relapse nor serious adverse events.
Gan to kagaku ryoho. Cancer & chemotherapy 06/2010; 37(6):1131-4.
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Yosuke Doi,
Masakazu Yashiro,
Nobuya Yamada,
Ryosuke Amano,
Go Ohira,
Masahiro Komoto, Satoru Noda,
Shinichiro Kashiwagi,
Yukihiro Kato,
Yuhiko Fuyuhiro,
Kosei Hirakawa
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ABSTRACT: Vascular endothelial growth factor receptors (VEGFRs) are mainly expressed by endothelial cells, but they are also expressed by some cancer cells, including pancreatic cancer. The objective of this study was to evaluate the significance of VEGFRs expression in pancreatic cancer cells. A total of 107 primary pancreatic tumors were stained with antibodies against VEGFR-1, VEGFR-2, phospho-VEGFR-2 (pVEGFR-2), VEGFR-3, VEGF-A, VEGF-C, and VEGF-D. VEGFR-2 and pVEGFR-2 expression were positive in 74 (69%) and 54 (50%) of 107 pancreatic cancers. There was a significant correlation (P < 0.001) between VEGFR-2 expression and pVEGFR-2 expression. pVEGFR-2 was significantly associated with invasion to the anterior capsule of pancreas (P = 0.032) and arterial invasion (P = 0.012). In contrast, VEGFR-1 and VEGFR-3 expression was only observed in 13 (12%) and 15 (14%) of 107 pancreatic cancers, and was not associated with any clinicopathological features. The prognosis of pVEGFR-2 positive patients with stage IIA tumors was significantly (P = 0.0441) poorer than that of pVEGFR-2-negative patients. VEGF-A, VEGF-C, and VEGF-D expression was positive in 42 (39%), 82 (77%), and 39 (36%) of 107 pancreatic cancers, respectively. The prognosis for VEGF-A-positive patients was significantly (P = 0.0425) poor, but not for VEGF-C-positive and VEGF-D-positive patients. A multivariate analysis indicated pVEGFR-2 expression to be an independent prognostic factor, but not VEGF-A. These findings suggested that VEGFR-2 signaling might therefore be associated with the prognosis of patients with pancreatic cancer. The expression of pVEGFR-2 might be a novel predictive prognostic marker for patients with pancreatic cancers, especially at clinical stage IIA.
Cancer Science 03/2010; 101(6):1529-35. · 3.33 Impact Factor
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ABSTRACT: Gastric cancer cells leaving the primary tumour are exposed to low oxygen levels in the peritoneal cavity; however, peritoneal metastatic phenotypes of hypoxic cancer cells remain unclear. We used 6 gastric cancer cell lines, including 3 diffuse-type gastric cancer (DGC) and 3 non-DGC cell lines. Using adhesion assay, we examined the effect of hypoxic conditions on their ability to adhere to peritoneal components. The expression level of transforming growth factor-beta (TGF-beta) and integrins mRNA of cancer cells was examined using reverse transcriptase-polymerase chain reaction. We further examined the effect of anti-integrin neutralising antibodies and a TGF-beta receptor inhibitor on the adhesion ability of hypoxic cancer cells. The binding ability of DGC cells was higher than that of non-DGC cells; it was significantly increased by hypoxic (1% O2) conditions compared to normoxic (21% O2) conditions. In contrast, no remarkable change in adhesion ability was observed in the non-DGC cells under normoxic and hypoxic conditions. Integrins and TGF-beta expression of hypoxic DGC cells was significantly higher than that of normoxic cells. TGF-beta increased the adhesion ability and alpha2-, alpha3- and alpha5-integrin expression of hypoxic DGC cells, whereas the TGF-beta receptor inhibitor decreased them. Neutralising antibodies against alpha2-, alpha3- and alpha5-integrin inhibited the adhesion ability of DGC cells. These findings suggested that hypoxic conditions promote the adhesion of DGC cells to the peritoneum. The upregulation of alpha2-, alpha3- and alpha5-integrin by TGF-beta under hypoxic conditions may be one of the mechanisms responsible for the high metastatic potential of hypoxic DGC cells to the peritoneum.
European journal of cancer (Oxford, England: 1990) 02/2010; 46(5):995-1005. · 4.12 Impact Factor
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ABSTRACT: Gastric cancers are characterized by a heterogeneously hypoxic environment. Hypoxia might stimulate the malignant potential of cancer cells. The purpose of our study was to clarify the significance of hypoxia in gastric carcinoma by evaluating the expression of a hypoxic marker, namely carbonic anhydrase-9 (CA-9).
A total of 265 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer were enrolled in this study. We evaluated the immunohistochemical expression of CA-9 in the paraffin-embedded specimens of 265 gastric adenocarcinomas.
The CA-9 expression was positive in 88 (33%) of 265 gastric carcinomas. The CA-9 expression level was significantly high in cases of type 4 carcinoma (60%, p < 0.001) and diffuse type carcinoma (41%, p < 0.001), and significantly correlated with the invasion depth (p < 0.001), lymph node metastasis (p < 0.001) and lymphatic invasion p = 0.002). The prognosis for CA-9-positive patients was significantly poorer than that of CA-9-negative patients (p = 0.003, log-rank).
Hypoxia might be associated with aggressive tumor phenotypes of gastric carcinomas. The hypoxic marker CA-9 may be a useful prognostic indicator.
Digestion 01/2010; 82(4):246-51. · 2.05 Impact Factor
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Osamu Shinto,
Masakazu Yashiro,
Takahiro Toyokawa,
Takafumi Nishii,
Ryoji Kaizaki,
Taro Matsuzaki, Satoru Noda,
Naoshi Kubo,
Hiroaki Tanaka,
Yosuke Doi,
Masaichi Ohira,
Kazuya Muguruma,
Tetsuji Sawada,
Kosei Hirakawa
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ABSTRACT: Transforming growth factor β (TGFβ) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFβ receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages.
Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas.
The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor.
The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.
BMC Cancer 01/2010; 10:652. · 3.01 Impact Factor
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ABSTRACT: Fibroblasts, particularly myofibroblasts, affect the malignant progression of cancer cells in vitro. However, to date few reports have addressed the clinical significance of myofibroblasts in the gastric cancer microenvironment. This study examined the correlation between myofibroblast expression and clinicopathological features in gastric carcinoma. A total of 265 primary gastric tumors resected by gastrectomy were stained with antibodies against α-smooth muscle actin and vimentin. Stromal cells positive for vimentin were considered to be fibroblasts. Myofibroblasts were defined as fibroblasts positive for α-smooth muscle staining. Myofibroblast-positive gastric carcinoma was established when myofibroblasts accounted for more than 25% of fibroblasts in the cancer stroma. Myofibroblast expression was positive in 92 (35%) of the 265 gastric carcinomas. Myofibroblast expression showed a significantly (p<0.001) high frequency in advanced gastric cancers (76 of 146), in comparison to the early stage cancers (16 of 119). Taken together, there was a statistically significant correlation between myofibroblast expression and scirrhous type gastric cancer (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p<0.001) and peritoneal dissemination (p=0.005). The prognosis of patients with tumors positive for myofibroblast expression was significantly (p<0.001) worse, while a multivariate analysis revealed that myofibroblast expression was not an independent prognostic factor. These findings suggest that myofibroblasts are associated with scirrhous gastric cancer. Overexpression of myofibroblasts may therefore be a useful prognostic indicator of gastric carcinoma.
Experimental and therapeutic medicine 01/2010; 1(4):547-551.
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Satoru Noda,
Naoshi Kubo,
Hiroaki Tanaka,
Kazuya Muguruma,
Masakazu Yashiro,
Nobuya Yamada,
Kiyoshi Maeda,
Tetsuji Sawada,
Masaichi Ohira,
Tetsuro Ishikawa,
Kosei Hirakawa
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ABSTRACT: The patient was a 55-year-old male, who was diagnosed to have a middle thoracic esophageal squamous cell carcinoma with para-aortic lymph node metastasis. The clinical stage diagnosis was T3N4M1, stage IVb, non-resectable esophageal SCC. Systemic chemotherapy with low-dose nedaplatin/5-FU treatment was started as the initial treatment. After three courses, para-aortic lymph node metastasis was not found by CT scan, and we added radiation therapy. After radiation therapy by 45 Gy, primary lesion and mediasternal lymph node metastasis were not shown by endoscopy and CT scan. We detected an increase of tumor marker after the observation for six months without any treatment, and then we started docetaxel/nedaplatin treatment as secondary chemotherapy. After ten courses, the tumor marker was decreased, and the patient is still in a stable disease state. We concluded that FGP therapy and DGP therapy were a very effective treatment for advanced esophageal SCC.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2009; 36(12):2451-3.
