研究者詳細 - 秋山　有史

論文 - 秋山　有史

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Gene expression profiles in human gastric cancer: expression of maspin correlates with lymph node metastasis

M Terashima, C Maesawa, K Oyama, S Ohtani, Y Akiyama, S Ogasawara, A Takagane, K Saito, T Masuda, N Kanzaki, S Matsuyama, Y Hoshino, M Kogure, M Gotoh, M Shirane, K Mori

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP ) 92 ( 6 ) 1130 - 1136 2005年03月 [査読有り]

To seek for a candidate gene that would regulate tumour progression and metastasis in gastric cancer, we investigated gene expression profiles by using DNA microarray. Tumour tissue and adjacent normal tissue were obtained from 21 patients with gastric cancer and then examined for their gene expression profiles by the Gene Chip (R) Human U95Av2 array, which includes 12 000 human genes and EST sequences. A total of 25 genes were upregulated and two genes were downregulated by at least four-fold in the tumour tissue. In a further analysis according to lymph node metastasis, the expressed levels of maspin, as well as carcinoembryonic antigen and nonspecific crossreacting antigen were significantly higher in tumours with lymph node metastasis than in those without it. Maspin expression in 85 gastric cancer patients was further investigated by using immunohistochemistry. Maspin expression was not observed in normal gastric epithelia without intestinal metaplasia. In contrast, maspin was expressed in 74 of 85 tumour tissues. There was a significant correlation between the incidence of maspin-positive tumour staining and lymph node metastasis. These results suggest that maspin has a potential role for tumour metastasis in gastric cancer.

DOI

Epigenetic status and aberrant expression of the maspin gene in human hepato-biliary tract carcinomas.

Kentaro Fujisawa, Chihaya Maesawa, Ryo Sato, Kei Wada, Satoshi Ogasawara, Yuji Akiyama, Masaru Takeda, Tomohiro Fujita, Koki Otsuka, Taro Higuchi, Kazuyuki Suzuki, Kazuyoshi Saito, Tomoyuki Masuda

Laboratory investigation; a journal of technical methods and pathology 85 ( 2 ) 214 - 24 2005年02月 [査読有り] [国際誌]

We examined expression of maspin and the epigenetic status of its gene in 40 primary hepato-biliary tract carcinomas and 11 cell lines originating from hepato-pancreatico-biliary tract carcinomas. Aberrant maspin expression was frequently observed immunohistochemically in biliary tract carcinomas (22/25, 88%) but not in hepatocellular carcinomas (HCCs) (0/15, 0%). Aberrant maspin expression by five pancreatico-biliary tract carcinoma cell lines was closely associated with demethylation at the maspin promoter. Five of six HCC cell lines were maspin-negative and exhibited extensive hypomethylation and hypoacetylation at the maspin promoter. Treatment with 5-aza-2'-deoxycytidine did not activate maspin expression in these five maspin-negative HCC cell lines, whereas treatment with Trichostatin A (TSA) activated maspin expression in two of them. Treatment with TSA increased histone acetylation in some HCC cell lines. These results suggest that aberrant maspin expression in biliary tract carcinomas is closely associated with demethylation at the promoter region, but that some HCC cell lines additionally require histone acetylation. In addition, the fact that maspin-negative HCC cell lines remain after treatment with TSA suggests the existence of other repressive factors controlling maspin expression.

PubMed

[A case of liver metastatic recurrence of gastric cancer effectively treated by combined chemotherapy of CPT-11 and CDDP].

Fujiwara H, Aoki K, Nakaya T, Akiyama Y, Kimura Y, Iwaya T, Saito K

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 12 ) 2035 - 8 2004年11月 [査読有り] [国内誌]

The patient was a 72-year-old female with gastric carcinoma. A liver metastatic recurrence was detected 27 months after operation. Although temporary partial responses were obtained by each effective chemotherapy, which was a combination chemotherapy with 5'-DFUR and TXT, TS-1 and TXL, the metastatic lesion proved refractory to all of them. Then we tried combination chemotherapy consisting of CDDP 30 mg/m2 and CPT-11 60 mg/m2, respectively (day 1 and 15, every 4 weeks). A partial response was achieved and continued for 8.5 months, and her complaints abated and quality of life improved. Although gastro-intestinal symptoms and bone marrow suppression were observed as side effects, they were within a tolerable range and did not interfere with the combination therapy. This regimen appears to be feasible and effective for recurrent gastric carcinoma refractory to other regimens.

PubMed

Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma.

Akiyama Y, Maesawa C, Wada K, Fujisawa K, Itabashi T, Noda Y, Honda T, Sato N, Ishida K, Takagane A, Saito K, Masuda T

Oncology reports 11 ( 4 ) 871 - 4 2004年04月 [査読有り] [国際誌]

PinX1 was isolated as a Pin2/TRF1 binding protein that also binds to the telomerase catalytic subunit hTERT. The gene is a potent telomerase inhibitor and a putative tumor suppressor since it inhibits telomerase activity and affects tumorigenicity in nude mice. This study investigated aberrations of PinX1 gene in gastrointestinal tract carcinomas (GITCs). We examined mutations, mRNA expression and promoter methylation of PinX1 gene in 15 GITC cell lines, and 20 patients with primary GITC. We found a missense mutation at codon 254 (AGC/TGC) in a colon and an esophageal carcinoma cell line, and in cancerous and matching normal tissues of 2 patients with primary GITC (10%). It might be a benign polymorphism. No hyper-methylation was found in the promoter region and the treatment by 5-Aza-2'-deoxycytidine did not affect PinX1 mRNA expression level in any of the cell lines. It was concluded that the human PinX1 does not affect tumorigenesis of human GITC.

PubMed

Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers.

Ogasawara S, Maesawa C, Yamamoto M, Akiyama Y, Wada K, Fujisawa K, Higuchi T, Tomisawa Y, Sato N, Endo S, Saito K, Masuda T

Oncogene 23 ( 5 ) 1117 - 24 2004年02月 [査読有り] [国際誌]

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but the biological significance of DNA hypomethylation in carcinogenesis is less understood. The expression of Maspin (mammary serpin) in differentiated normal cells is regulated by epigenetic modifications in a cell-type-specific manner. Paradoxical Maspin expression due to epigenetic modification has been addressed in several cancer cell types. To elucidate the role of the Maspin gene in thyroid cancer, we studied methylation status in the promoter region and its expression in six human undifferentiated thyroid cancer cell lines and in specimens from 92 primary thyroid tumors, consisting of six follicular adenomas, 56 well-differentiated thyroid cancers (WDTCs), 17 poorly differentiated thyroid cancers (PDTCs) and 13 undifferentiated thyroid cancers (UDTCs). Three of the six cell lines overexpressed Maspin mRNA and its protein product, but the remaining three did not. The methylation status at the promoter region was inversely correlated with Maspin expression. In Maspin-negative cell lines, Maspin expression was induced by treatment with 5-aza-2'-deoxycytidine, a DNA demethylating agent. Immunoreactivity for Maspin protein was frequently detected in UDTCs (8/13, 62%) and PDTCs (7/17, 41%). Immunoreactivity for Maspin was diffusely positive in UDTCs, and was restricted to dedifferentiated components of the tumor in PDTCs. Positive immunoreactivity was infrequent in WDTCs (1/56, 2%), and all follicular adenomas and normal thyroid glands were completely negative. Their methylation status evaluated by the methylation-specific PCR method showed a good inverse correlation with their immunoreactivity in surgically resected specimens. Our data suggest that overexpression of Maspin by DNA hypomethylation is closely associated with morphological dedifferentiation in thyroid cancers.

DOI PubMed

Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells.

Akiyama Y, Maesawa C, Ogasawara S, Terashima M, Masuda T

The American journal of pathology 163 ( 5 ) 1911 - 9 2003年11月 [査読有り] [国際誌]

Maspin, a serine protease inhibitor, was originally reported as a tumor suppressor gene in breast and prostatic cancers. We examined maspin expression and/or the allele-specific methylation status in four gastric cancer cell lines, as well as normal, metaplastic, and cancerous epithelia obtained from 50 gastric cancer patients. Three gastric cancer cell lines exhibiting maspin overexpression showed hypomethylation at either both alleles or a haploid allele. Only one cell line (GCIY) was maspin-negative but maspin expression was reactivated after treatment with a demethylating agent, 5-aza-2'-deoxycytidine. Dense and diffuse immunoreactivity for maspin was observed in 40 (80%) of 50 gastric cancers and all gastric normal epithelia (GNE) with intestinal metaplasia (IM), but not in GNE without IM. We further analyzed the allele-specific methylation status in 10 of 50 cases subjected to immunohistochemistry by the crypt isolation technique followed by a bisulfite genome sequencing method. The maspin gene promoter region of all GNE without IM was hypermethylated on both alleles whereas those with IM frequently represented the haploid type of hypomethylation status. In six of seven gastric cancers in which crypt isolation was possible, demethylation frequently occurred and extended to both alleles. Maspin mRNA was amplified from GNE with IM and cancerous crypts but not from GNE without IM. These results suggest that demethylation at the maspin gene promoter disrupts the cell-type-specific gene repression in both GNE and gastric cancer.

DOI PubMed

Randomized study of the benefits of preoperative corticosteroid administration on the postoperative morbidity and cytokine response in patients undergoing surgery for esophageal cancer.

Sato N, Koeda K, Ikeda K, Kimura Y, Aoki K, Iwaya T, Akiyama Y, Ishida K, Saito K, Endo S

Annals of surgery 236 ( 2 ) 184 - 90 2002年08月 [査読有り] [国際誌]

OBJECTIVE: To investigate whether preoperative corticosteroid administration plays a role in attenuating postoperative morbidity. SUMMARY BACKGROUND DATA: There is as yet no consensus on the beneficial effects of steroids in alleviating surgical stress. METHODS: A total of 66 patients undergoing surgery for thoracic esophageal cancer were randomly categorized preoperatively into two groups of 33 patients each. One group was administered an intravenous infusion of methylprednisolone (10 mg/kg body weight) 30 minutes before the surgery (MP group), while the other group received a placebo infusion (control group). The primary endpoint was organ system failure during the first 7 days after surgery. Comparisons of surgery-related complications, cytokine responses, and blood counts were also made between the two groups. RESULTS: The percentage of patients in the MP group who had one or more organ system failures was 33%, significantly lower than the corresponding percentage of 61% in the control group. The surgery-related complication rate and long-term survival rate were similar in the two groups. The peak plasma levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8 were significantly lower in the MP group than in the control group. Changes in the plasma levels of IL-10 were significantly larger in the MP group. No significant differences in the circulating lymphocyte and neutrophil counts were observed between the groups. CONCLUSIONS: The results suggest that prophylactic administration of corticosteroids is associated with a decrease in postoperative morbidity in patients undergoing invasive surgery. The laboratory data suggest that corticosteroids may attenuate surgical stress-induced inflammatory responses both directly by suppressing the release of proinflammatory cytokines and via inducing IL-10 synthesis.

DOI PubMed

Gastrointestinal stromal turnour of the oesophagus: significance of immunohistochemical and genetic analyses of the c-kit gene

S Iijima, C Maesawa, N Sato, K Ikeda, T Inaba, Y Akiyama, K Ishida, K Saito, T Masuda

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 14 ( 4 ) 445 - 448 2002年04月 [査読有り]

Oesophageal gastrointestinal stromal tumours (GISTs) are rare in comparison to those of the stomach and intestines. Recently, it has been clarified that mutations of the c-kit gene resulting in gain of function might be associated with histogenesis of this type of tumour arising in the stomach and intestines. We describe an oesophageal GIST on immunohistochemical and genetic analyses of the gene. A 71-year-old man had an intramural tumour of the middle third of the oesophagus. Tumour cells were composed predominantly of spindle-shaped and partially epithelioid cells. They were diffusely positive for CD117. Six base deletion resulting in in-frame mutation of the c-kit gene was confirmed at codon 556-558 (cag tgg aag to cag) of exon 11. Patients with mutations of the c-kit gene revealed worse prognoses in GISTs arising from other locations. A long-term follow-up observation is needed for the case. (C) 2002 Lippincott Williams Wilkins.

DOI PubMed

Influence of a human protease inhibitor on surgical stress induced immunosuppression.

Sato N, Endo S, Kimura Y, Ikeda K, Aoki K, Iwaya T, Akiyama Y, Noda Y, Saito K

Digestive surgery 19 ( 4 ) 300 - 5 2002年 [査読有り] [国際誌]

BACKGROUND/AIM: Postoperative tissue injury and immunosuppression can occur after major surgery. In this study, we explore the potential benefits of administering a protease inhibitor to treat immunosuppression caused by surgical stress. METHODS: Sixteen patients with esophageal cancer were preoperatively allocated at random into two equal groups. A urinary trypsin inhibitor, ulinastatin (UTI), was intravenously administered to the treatment (UTI) group at a dose of 150,000 U every 12 h from the start of surgery until postoperative day 5, whereas the control group received a placebo. One unit of UTI was defined as the amount of UTI necessary to inhibit the activity of 2 microg of bovine pancreatic trypsin by 50%. We measured the plasma levels of polymorphonuclear neutrophil elastase, interleukin 8, circulating T lymphocyte subsets, and mitogenic activity and in vitro production of tumor necrosis factor alpha in lipopolysaccharide-stimulated whole blood. RESULTS: The postoperative serum value of polymorphonuclear neutrophil elastase was significantly lower in the UTI group, but the interleukin 8 concentrations did not significantly vary between the two groups. On the other hand, the severity of the postoperative immunosuppression was reduced in the UTI group, and immune functions, such as the numbers of T lymphocytes, the mitogenic activity of lymphocytes, and the level of tumor necrosis factor alpha production in whole blood, recovered significantly earlier in the UTI group. CONCLUSION: These data suggest that a protease-modulating therapy may be a new strategy for the treatment of surgical stress induced immune dysfunction.

DOI PubMed

Chemoradiotherapy followed by surgery for thoracic esophageal cancer potentially or actually involving adjacent organs

M Ogawa, K Ikeda, K Ishida, N Sato, K Koeda, K Aoki, Y Kimura, T Iwaya, S Ogasawara, S Iijima, Y Akiyama, R Nakamura, N Uesugi, C Maesawa, K Saito

RECENT ADVANCES IN DISEASES OF THE ESOPHAGUS ( MEDIMOND S R L ) 727 - 730 2001年 [査読有り]

The usefulness of chemoradiotherapy (CRT) followed by surgery was evaluated in patients with clinically T4 esophageal squamous cell carcinoma. Thirty-seven patients received two courses of CRT which comprised cisplatin (70 mg/m(2)) on day 1, 5-fluorouracil (700 mg/m(2)) on days I to 4 and external irradiation (200 cGy/day, total 30 Gy). The response to CRT was complete response in 9 patients, partial response in 19. The median response duration in all responders was 172 days (56-2469). After CRT, 12 out of 13 operated patients could be completely resected. The median duration of survival were 304 days (84-3155) in all patients, 866 days (190-3155) in 13 resected patients and 187 days (84-2630) in 24 non-resected patients. Grade 3 hematological toxicity was noted in 13.5% and there was 1 toxicity-related death (sepsis).

Effects of perioperative great amount of glutamine supplementation by enteral route on amino acids metabolism in esophageal cancer surgery

K Ikeda, H Nitta, K Aoki, N Sato, K Ohtsuka, S Ogasawara, M Ogawa, S Iijima, Y Akiyama, K Ishida, K Saito

RECENT ADVANCES IN DISEASES OF THE ESOPHAGUS ( MEDIMOND S R L ) 715 - 718 2001年 [査読有り]

To clarify the effects of perioperative glutamine (Gln) supplementation, 24 esophageal cancer patients were prospectively randomized to the both pre- and postoperative Gln-supplemented (Pre-Post) group (n=9), the only postoperative Gln-supplemented (Post) group (n=7) and the control (C) group (n=8). Preoperative Gln supplements induced a significant rise in plasma Gln (p<0.05). In all groups, the postoperative arterial Gln, Ala and BCAA levels significantly decreased (p<0.05) and no intergroup differences were observed. Gln and Ala release from skeletal muscle reduced in the Pre-Post or the Post group. Postoperative pneumonia in 4 patients (1 in the C, 2 in the Post, 1 in the Pre-Post), hyperbilirubinemia in 7 (4, 2, 1) and minor leakage in 3 (3, 0, 0, p<0.05) were observed.

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