Shigeyuki Kamata

Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis

Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF‐C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF‐C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3‐kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF‐C and VEGF‐A expression in B13LM cells, a lymphatic metastasis‐prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF‐C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF‐A expression was inhibited by all four of these inhibitors. The serum starvation‐induced expression of VEGF‐C was inhibited by rapamycin, whereas that of VEGF‐A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin‐treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF‐C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis. (Cancer Sci 2007; 98: 726–733)

Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancer cells.

AFP-producing gastric carcinoma (AFPGC) is a highly malignant variant of gastric cancer. An effective chemotherapy is needed to improve on the poor outcome of this disease. Survival signals activated by intracellular kinase networks could be involved in chemoresistance in malignant tumors. We investigated the role of a pivotal kinase pathway, the mammalian target of rapamycin complex 1 (mTORC1) pathway, in the effectiveness of chemotherapeutic agents in three AFPGC cell lines (GCIY, FU97, and Takigawa) as well as in four cell lines of conventional-type gastric carcinoma (CGC). AFPGC cells were generally resistant to multiple chemotherapeutic agents, including cisplatin, while CGC cells were generally sensitive. Downstream targets of mTORC1, including p70S6K and 4EBP1, were phosphorylated in all cell lines. Interestingly, cisplatin virtually abolished phosphorylation of p70S6K and 4EBP1 in CGC cells, while phosphorylation was maintained in cisplatin-treated AFPGC cells. The addition of rapamycin, an inhibitor of mTORC1, diminished the remaining activity of mTORC1 and significantly intensified the cytotoxic action of cisplatin in AFPGC cells. These results suggested that persistent activity of mTORC1 signals in cisplatin-treated AFPGC cells is involved in the mechanisms of cisplatin resistance in AFPGC. Finally, combined treatment of rapamycin and cisplatin significantly suppressed the subcutaneously implanted GCIY cells. In conclusion rapamycin may be a potential supplemental agent for the treatment of AFPGC when used in combination with cisplatin.

Expression and localization of ATP binding cassette (ABC) family of drug transporters in gastric hepatoid adenocarcinomas

Aims:  Hepatoid adenocarcinomas are clinically chemoresistant; however, data concerning the mechanisms of chemoresistance are lacking. ATP‐binding cassette (ABC) transporters play a role in the ATP‐dependent outward efflux of drugs, and their function renders tumour cells multidrug resistant. We assumed that the expression of ABC transporters may be accompanied by hepatic differentiation because most ABC transporters are dominantly expressed in hepatocytes. The aim of this study was to investigate the expression of ABC transporters in hepatoid adenocarcinomas.

Advanced moderately differentiated neuroendocrine carcinoma of the rectum with favorable prognosis by postoperative chemoradiation

Rectal neuroendocrine carcinoma is rare with poor prognosis. We report herein a case of advanced moderately differentiated neuroendocrine carcinoma of the rectum with relatively favorable prognosis treated by postoperative adjuvant chemoradiation therapy. A 58-year-old Japanese female was referred and colonofiberscopy revealed an easy-bleeding irregular tumor in the lower rectum, which was pathologically diagnosed as a neuroendocrine carcinoma. Surgical treatment consisted of abdominoperineal resection and lymph node dissection. The tumor invaded deeply into perirectal tissues, and 9 of 11 lymph node metastases were observed. Immunohistochemically, chromogranin A showed diffuse and strong staining, and the MIB-1 labeling index was 18.3 ± 5.6, supporting the high proliferation of the tumor. Some nucleus of the tumor showed positive staining for p21/WAF1. A total dose of 46 Gy of radiotherapy was delivered with 800 mg of daily oral doxifluridine. At 5 years post-surgery, the patient demonstrated no clinical evidence of intrapelvic recurrence or distant metastases.

Hepatoid Adenocarcinoma of the Stomach: Biological Significance of Hepatic Transdifferentiation in Adenocarcinoma Cells

Hepatoid adenocarcinoma is an extrahepatic carcinoma with functionally and structurally distinctive foci of hepatocellular differentiation. The usual presence of adenocarcinoma indicates the emergence of hepatocellular transdifferentiation from adenocarcinoma cells. Hepatoid adenocarcinoma most commonly occurs in the stomach, but other gastrointestinal and genitourinary organs are also common sites of origin. Master transcriptional regulators, particularly liver-enriched nuclear factors, might be involved in the transdifferentiation process, as well as in the biology of hepatoid adenocarcinoma tissues.