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吉川 史隆 Fumitaka Kikkawa 名古屋大学大学院医学系研究科産婦人科学・教授・医学博士


専門分野

婦人科腫瘍学

略歴

1981年
名古屋大学医学部 卒業
1986年
名古屋大学大学院医学系研究科 満了
1988年?1990年
米国国立衛生研究所 (NIH)  Visiting Fellow 採用
1990年
名古屋大学医学部付属病院 助手採用
1991年
名古屋大学医学部付属病院 講師昇任
1999年
名古屋大学医学部付属病院 助教授昇任
2002年
名古屋大学大学院 健康社会医学専攻(産婦人科学) 助教授配置換
2004年
名古屋大学大学院 健康社会医学専攻(産婦人科学) 教授昇任

研究課題名

悪性腫瘍の分子標的治療法の開発

これまでの成果と今後の展望

A. 研究目的
近年、がん幹細胞に対しても生態的適所であるニッチが存在し、癌の維持および転移に重要な役割を持つことが示唆されている。卵巣癌において、腹膜は最も重要な転移部位であることから、腹膜中皮細胞がニッチの1つとして機能していると考え、卵巣がん細胞と腹膜中皮細胞との相互作用を検討した。
卵黄嚢腫瘍は発生頻度が低く、細胞株は樹立されていなかったが、当教室において卵黄嚢腫瘍細胞株の樹立に成功した。次いで、卵黄嚢腫瘍細胞株NOY1においてCD133はがん幹細胞マーカーの1つであることを報告した。今回、NOY1を用い、腹膜中皮細胞との相互作用を検討した。

B. 研究成果
はじめに、卵巣癌の原発巣と腹膜播種巣において、癌幹細胞マーカーの1つであるCD133の発現を免疫組織染色で検討した。原発巣では数パーセントであるのに対し、腹膜播種巣では高頻度に発現する傾向がみられた (Fig.1)。この結果から、腹膜中皮細胞がニッチの1つであるという仮説は妥当であると判断した。
NOY1は、磁気細胞分離法を用いてCD133陽性細胞と陰性細胞に分取した。腹膜中皮細胞は、手術検体から作製された不死化細胞株HOmMC (human omentum mesothelial cells)を用いた。 まず、HOmMCとの共培養によるNOY1のCD133の発現の変化を検討した。transwellを用い共培養を行ったところ、NOY1 wild typeおよびNOY1 CD133陽性群において、CD133の発現の亢進が認められた。HOmMCは、NOY1のCD133の発現の維持に関与していることが示唆された。次に、単一dishにNOY1とHOmMCを培養し、NOY1のコロニー形成能を検討した。CD133陽性細胞は、陰性細胞に比べ2.4倍のコロニー形成能を示し、中皮との共培養によりその差は顕著になり、4.3倍となった (Fig.2)。
ここで、ケモカインレセプターの1つであるCXCR4が、NOY1 CD133陰性細胞に比べ陽性細胞で強く発現しており、またHOmMCはそのリガンドであるSDF-1を分泌していることから、相互作用の機序として、SDF1?CXCR4のpathwayに着目した。CXCR4のアンタゴニストであるAMD3100を添加し、コロニー形成能に与える影響を検討した。CD133陽性細胞において中皮との共培養により亢進したコロニー形成能は、AMD3100の添加により阻害された。
次にHOmMC方向への遊走能と浸潤能を検討した。HOmMCを下層にまき、24時間後に上層にNOY1をまき、migration assayおよびinvasion assayを行った。CD133陽性細胞は、陰性細胞に比べ、HOmMC方向への高い遊走能および浸潤能を示した。さらに、下層に、フィブロネクチン、フィブロネクチンにAMD3100を添加、HOmMC、HOmMCにAMD3100を添加、という4種類の条件でのCD133陽性細胞の遊走能と浸潤能を評価した。フィブロネクチンに比べ、中皮細胞で亢進し、AMD3100によってその効果は阻害された (Fig.3.A,B)。
つづいてin vivoにおけるAMD3100の効果を検討した。CD133陽性細胞をヌードマウスに腹腔内注射し、その後AMD3100を投与する群、しない群とで腫瘍形成能を比較した。AMD3100の投与によりCD133陽性細胞の腫瘍形成能は阻害された (Fig.3.C)。
今回の結果より腹膜中皮細胞はNOY1のCD133陽性細胞群により強い影響を与えることが示され、腹膜中皮細胞がNOY1のニッチの1つとして機能している可能性が示唆された。今後は上皮性卵巣癌と腹膜中皮細胞との相互作用も検討していきたい。

主要研究業績

  1. Bayasula, Iwase A, Kiyono T, Takikawa S, Goto M, Nakamura T, Nagatomo Y, Nakahara T, Kotani T, Kobayashi H, Kondo M, Manabe S, Kikkawa F: Establishment of a Human Nonluteinized Granulosa Cell Line that Transitions from the Gonadotropin-Independent to the Gonadotropin-Dependent Status. Endocrinology, in press (2012)
  2. Trinh DT, Shibata K, Hirosawa T, Umezu T, Mizuno M, Kajiyama H, Kikkawa F: Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary. J Obstet Gynaecol Res, in press (2012)
  3. Kajiyama H, Shibata K, Mizuno M, Umezu T, Suzuki S, Yamamoto E, Fujiwara S, Kawai M, Nagasaka T, Kikkawa F: Long-Term Clinical Outcome of Patients With Recurrent Epithelial Ovarian Carcinoma: Is it the Same for Each Histological Type? Int J Gynecol Cancer, 22, 394-399 (2012)
  4. Maeda O, Shibata K, Hosono S, Fujiwara S, Kajiyama H, Ino K, Nawa A, Tamakoshi K, Kikkawa F: Spectrin alphaII and betaII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma. Int J Cancer, 130, 113-121 (2012)
  5. Mitsui H, Shibata K, Suzuki S, Umezu T, Mizuno M, Kajiyama H, Kikkawa F: Functional interaction between peritoneal mesothelial cells and stem cells of ovarian yolk sac tumor (SC-OYST) in peritoneal dissemination. Gynecol Oncol, 124, 303-310 (2012)
  6. Sekiya R, Kajiyama H, Sakai K, Umezu T, Mizuno M, Shibata K, Yamamoto E, Fujiwara S, Nagasaka T, Kikkawa F: Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary. Hum Pathol, in press (2012)
  7. Kajiyama H, Shibata K, Mizuno M, Hosono S, Kawai M, Nagasaka T, Kikkawa F: Fertility-sparing surgery in patients with clear-cell carcinoma of the ovary: is it possible? Hum Reprod, 26, 3297-3302 (2011)
  8. Kajiyama H, Shibata K, Mizuno M, Umezu T, Suzuki S, Nawa A, Kawai M, Nagasaka T, Kikkawa F: Long-term survival of young women receiving fertility-sparing surgery for ovarian cancer in comparison with those undergoing radical surgery. Br J Cancer, 105, 1288-1294 (2011)
  9. Higashi M, Kajiyama H, Shibata K, Mizuno M, Mizuno K, Hosono S, Kawai M, Nakanishi T, Nagasaka T, Kikkawa F: Survival impact of capsule rupture in stage I clear cell carcinoma of the ovary in comparison with other histological types. Gynecol Oncol, 123, 474-478 (2011)
  10. Mano Y, Kotani T, Shibata K, Matsumura H, Tsuda H, Sumigama S, Yamamoto E, Iwase A, Senga T, Kikkawa F: The loss of endoglin promotes the invasion of extravillous trophoblasts. Endocrinology, 152, 4386-4394 (2011)
  11. Manabe S, Iwase A, Goto M, Kobayashi H, Takikawa S, Nagatomo Y, Nakahara T, Bayasula, Nakamura T, Hirokawa W, Kikkawa F: Expression and localization of CXCL16 and CXCR6 in ovarian endometriotic tissues. Arch Gynecol Obstet, 284, 1567-1572 (2011)
  12. Suzuki S, Yoshikawa T, Hirosawa T, Shibata K, Kikkawa F, Akatsuka Y, Nakatsura T: Glypican-3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma. Cancer Sci, 102, 1622-1629 (2011)
  13. Kajiyama H, Shibata K, Mizuno M, Nawa A, Mizuno K, Matsuzawa K, Kawai M, Hosono S, Nagasaka T, Kikkawa F: Fertility-sparing surgery in young women with mucinous adenocarcinoma of the ovary. Gynecol Oncol, 122, 334-338 (2011)
  14. Hirosawa T, Torikai H, Yanagisawa M, Kamei M, Imahashi N, Demachi-Okamura A, Tanimoto M, Shiraishi K, Ito M, Miyamura K, Shibata K, Kikkawa F, Morishima Y, Takahashi T, Emi N, Kuzushima K, Akatsuka Y: Mismatched human leukocyte antigen class II-restricted CD8 cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation. Cancer Sci, 102, 1281-1286 (2011)
  15. Shibata K, Umezu T, Sakurai M, Kajiyama H, Yamamoto E, Ino K, Nawa A, Kikkawa F: Establishment of cisplatin-resistant ovarian yolk sac tumor cells and investigation of the mechanism of cisplatin resistance using this cell line. Gynecol Obstet Invest, 71, 104-111 (2011)
  16. Maeda O, Shibata K, Hosono S, Fujiwara S, Kajiyama H, Ino K, Nawa A, Tamakoshi K, Kikkawa F: Spectrin αII and βII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma. Int J Cancer, 130, 113-121 (2011)
  17. Tsuda H, Takahashi Y, Iwagaki S, Uchida Y, Kawabata I, Hayakawa M, Sumigama S, Hayakawa H, Kotani T, Kikkawa F: Amniotic lamellar body counts can predict the occurrence of respiratory distress syndrome as well as transient tachypnea of the newborn (TTN). J Perinat Med, 39, 245-250 (2011)
  18. Iwase A, Goto M, Manabe S, Hirokawa W, Kobayashi H, Nakahara T, Takikawa S, Kotani T, Sumigama S, Tsuda H, Nakayama T, Suzuki N, Matsushita T, Kikkawa F: Successful fertility management of a patient with factor V deficiency: planned transfusion of fresh frozen plasma under infertility treatment. Fertil Steril, 95, 2124 e5-7 (2011)
  19. Hirokawa W, Iwase A, Goto M, Takikawa S, Nagatomo Y, Nakahara T, Bayasula B, Nakamura T, Manabe S, Kikkawa F: The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. Hum Reprod, 26, 904-910 (2011)
  20. Umezu T, Shibata K, Kajiyama H, Yamamoto E, Nawa A, Kikkawa F: Glypican-3 expression predicts poor clinical outcome of patients with early-stage clear cell carcinoma of the ovary. J Clin Pathol, 63, 962-966 (2010)
  21. Fujiwara S, Nawa A, Luo C, Kamakura M, Goshima F, Kondo C, Kiyono T, Kikkawa F, Nishiyama Y: Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer. Cancer Gene Ther, 18, 77-86 (2010)
  22. Suzuki S, Terauchi M, Umezu T, Kajiyama H, Shibata K, Nawa A, Kikkawa F: Identification and characterization of cancer stem cells in ovarian yolk sac tumors. Cancer Sci, 101, 2179-2185 (2010)
  23. Sakurai M, Shibata K, Umezu T, Kajiyama H, Yamamoto E, Ino K, Nawa A, Kikkawa F: Growth-suppressing function of glypican-3 (GPC3) via insulin like growth factor II (IGF-II) signaling pathway in ovarian clear cell carcinoma cells. Gynecol Oncol, 119, 332-336 (2010)
  24. Iwase A, Hirokawa W, Goto M, Takikawa S, Nagatomo Y, Nakahara T, Manabe S, Kikkawa F: Serum anti-Müllerian hormone level is a useful marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. Fertil Steril, 94, 2846-2849 (2010)
  25. Inaba T, Ino K, Kajiyama H, Shibata K, Yamamoto E, Kondo S, Umezu T, Nawa A, Takikawa O, Kikkawa F: Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy. Gynecol Oncol, 117, 423-428 (2010)
  26. Kajiyama H, Shibata K, Suzuki S, Ino K, Nawa A, Kawai M, Nagasaka T, Kikkawa F: Fertility-sparing surgery in young women with invasive epithelial ovarian cancer. Eur J Surg Oncol, 36, 404-408 (2010)
  27. Umezu T, Shibata K, Shimaoka M, Kajiyama H, Yamamoto E, Ino K, Nawa A, Senga T, Kikkawa F: Gene silencing of glypican-3 in clear cell carcinoma of the ovary renders it more sensitive to the apoptotic agent paclitaxel in vitro and in vivo. Cancer Sci, 101, 143-148 (2010)
  28. Fujiwara S, Nawa A, Nakanishi T, Shimoyama Y, Kajiyama H, Shibata K, Ino K, Nakamura S, Kikkawa F, Yatabe Y. Thyroid transcription factor 1 expression in ovarian carcinomas is an independent prognostic factor. Hum Pathol, 41, 560-565 (2010)
  29. Kajiyama H, Shibata K, Ino K, Mizutani S, Nawa A, Kikkawa F. The expression of dipeptidyl peptidase IV (DPPIV/CD26) is associated with enhanced chemosensitivity to paclitaxel in epithelial ovarian carcinoma cells. Cancer Sci, 101, 347-354 (2010)
  30. Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A, Nagasaka T, Akimoto H, Takikawa O, Kikkawa F. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol Oncol, 115, 185-192 (2009)
  31. Tsukamoto H, Kato T, Enomoto A, Nakamura N, Shimono Y, Jijiwa M, Asai N, Murakumo Y, Shibata K, Kikkawa F, Takahashi M. Expression of Ret finger protein correlates with outcomes in endometrial cancer. Cancer Sci, 100, 1895-1901(2009)
  32. Kotani T, Iwase A, Ino K, Sumigama S, Yamamoto E, Hayakawa H, Nagasaka T, Itakura A, Nomura S, Kikkawa F. Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line. Endocrinology, 150, 4376-4385 (2009)
  33. Iwase A, Goto M, Harata T, Takigawa S, Nakahara T, Suzuki K, Manabe S, Kikkawa F. Insulin attenuates the insulin-like growth factor-I (IGF-I)-Akt pathway, not IGF-I-extracellularly regulated kinase pathway, in luteinized granulosa cells with an increase in PTEN. J Clin Endocrinol Metab, 94, 2184-2191 (2009)
  34. Goto M, Iwase A, Harata T, Takigawa S, Suzuki K, Manabe S, Kikkawa F. IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells. Reproduction, 137, 835-842 (2009)
  35. Yamamoto E, Ino K, Miyoshi E, Inamori K, Abe A, Sumigama S, Iwase A, Kajiyama H, Shibata K, Nawa A, Kikkawa F. N-acetylglucosaminyltransferase V regulates extravillous trophoblast invasion through glycosylation of alpha5beta1 integrin. Endocrinology, 150, 990-999 (2009)
  36. Yoshida N, Ino K, Ishida Y, Kajiyama H, Yamamoto E, Shibata K, Terauchi M, Nawa A, Akimoto H, Takikawa O, Isobe K, Kikkawa F. Overexpression of indoleamine 2,3-dioxygenase in human endometrial carcinoma cells induces rapid tumor growth in a mouse xenograft model. Clin Cancer Res, 14, 7251-7259 (2008)
  37. Shibata K, Kajiyama H, Yamamoto E, Terauchi M, Ino K, Nawa A, Kikkawa F. Establishment and characterization of an ovarian yolk sac tumor cell line reveals possible involvement of Nkx2.5 in tumor development. Oncology, 74, 104-111 (2008)
  38. Kajiyama H, Shibata K, Suzuki S, Ino K, Yamamoto E, Mizuno K, Sakakibara K, Matsuzawa K, Takeda A, Kinoshita Y, Kawai M, Nagasaka T, Nawa A, Kikkawa F. Is there any possibility of fertility-sparing surgery in patients with clear-cell carcinoma of the ovary? Gynecol Oncol, 111, 523-526 (2008)
  39. Suzuki S, Kajiyama H, Shibata K, Ino K, Nawa A, Sakakibara K, Matsuzawa K, Takeda A, Kinoshita Y, Kawai M, Nagasaka T, Kikkawa F. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Ann Oncol, 19, 1284-1287 (2008)
  40. Ino K et al. Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin. Cancer Res. 14: 2310-2317 (2008)
  41. Kajiyama H et al. Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. Int. J. Cancer 122: 91-99 (2008)
  42. Shibata K et al. Twist expression in patients with cervical cancer is associated with poor disease outcome. Ann. Oncol. 19: 81-85 (2008)
  43. Yamamoto E et al. Expression of N-acetylglucosaminyltransferase V in endometrial cancer correlates with poor prognosis. Br. J. Cancer 97: 1538-1544 (2007)
  44. Yamashita M et al. Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo. Int. J. Cancer 120: 2243-2250 (2007)
  45. Hosono S et al. Expression of Twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients. Br. J. Cancer 96: 314-320 (2007)
  46. Ino K et al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br. J. Cancer 95: 1555-1561 (2006)
  47. Iwase A et al. Neutral endopeptidase expressed by decidualized stromal cells suppresses akt phosphorylation and deoxyribonucleic acid synthesis induced by endothelin-1 in human endometrium. Endocrinology. 147: 5153-5159 (2006)
  48. Kikkawa F et al. Clinical characteristics and prognosis of mucinous tumors of the ovary. Gynecol Oncol. 103: 171-175 (2006)
  49. Shido F et al. Endoplasmic reticulum aminopeptidase-1 mediates leukemia inhibitory factor-induced cell surface human leukocyte antigen-G expression in JEG-3 choriocarcinoma cells. Endocrinology 147: 1780-1788 (2006)
  50. Ino K et al. Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br. J. Cancer 94: 552-560 (2006)
  51. Kondo C et al. A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells. Int. J. Cancer 118: 1390-1394 (2006)
  52. Kikkawa F et al. Dipeptidyl peptidase IV in tumor progression. Biochim. Biophys. Acta. 1751: 45-51 (2005)
  53. Suganuma T et al. Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin. Cancer Res. 11: 2686-2694 (2005)
  54. Kajiyama H et al. Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo. Clin. Cancer Res. 11: 1798-1808 (2005)

受賞

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