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Fumitaka Kikkawa MD, PhDProfessor, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine


Specialized field

Gynecologic oncology

Career Summary

1977 April --- 1981 March
Nagoya University School of Medicine
1982 April --- 1986 March
Nagoya University Graduate School of Medicine
1987 October --- 1988 February
Assistant Staff Doctor, Department of Obstetrics and Gynecology
Nagoya University School of Medicine
1988 February --- 1990 April
Visiting Fellow
National Cancer Institue (USA)
1990 May --- 1998 May
Assistant Professor, Department of Obstetrics and Gynecology
Nagoya University School of Medicine
1998 May --- 1998 April
Associate Professor, Department of Obstetrics and Gynecology
Nagoya University School of Medicine
1999 May --- 1999 December
Assistant Professor, Department of Obstetrics and Gynecology
Nagoya University School of Medicine
1999 December --- 2002 February
Associate Professor,
Department of Maternal and Perinatal Care Medicine
Nagoya University Graduate School of Medicine
2002 March --- 2004 October
Associate Professor, Department of Obstetrics and Gynecology
Nagoya University Graduate School of Medicine
2004 November ---
Professor, Department of Obstetrics and Gynecology
Nagoya University Graduate School of Medicine

Research Theme

Developing molecular target therapy against malignant tumors

Research Summary

Functional interaction between peritoneal mesothelial cells and stem cells of ovarian yolk sac tumor in peritoneal dissemination

A. Objective
In recent years it has been indicated that ecological niches play important roles in the maintenance of cancer stem cells (CSCs). The most common sites of metastasis from a primary ovarian tumor are the abdominal peritoneum and omentum. So, we investigated interactions between peritoneal mesothelial cells and ovarian CSCs with the hypothesis that peritoneal mesothelial cells have the potential to provide one of the niches for ovarian CSCs. Ovarian yolk sac tumor (YST) is rare. Although there had been no cell lines of human ovarian YST, we established a human ovarian YST cell line named NOY1. Then we reported that CD133 is one of the markers of CSCs in ovarian yolk sac tumors. In our study, we examined interactions betseem peritoneal mesothelial cells and ovarian YST.

B. Result
At first, we compared CD133 expression between the primary focus of ovarian cancer and omental metastasis by immunohistochemical staining. Only a small percentage of CD133-expressing cells could be identified in the primary focus. In contrast, CD133-expressing cells in omental metastasis were present at a high frequency (Fig.1). These data indicate that peritoneal mesothelial cells play a role in the maintenance of ovarian cancer, especially cancer stem-like cells.
We used NOY1 and HOmMC (human omentum mesothelial cells) cells. NOY1 were divided into CD133-positive and -negative cells by magnetic cell sorting. HOmMC is a cell line established in the Department of Virology of our university. In addition, we assessed the inhibitory effects of AMD3100, a neutralizing antibody against chemokine receptor (CXCR4). Then, we examined whether AMD3100 affects the tumorigenicity of NOY1-CD133+ in vivo. Using the co-culture of NOY1 and HOmMC cells, we compared the expression of CD133, colony formation, and the capacity for migration and invasion. When NOY1 cells were co-cultured with peritoneal mesothelial cells, we observed the high-level expression of CD133. The number of colonies of NOY1-CD133+cells was 2.4 times as that of NOY1-CD133- cells. In contrast, on co-culture with peritoneal mesothelial cells, it was 4.3 times (Fig.2). When NOY1 were cultivated in the upper layer and peritoneal mesothelial cells were cultivated in the lower chamber, NOY1-CD133+ cells showed a greater capacity for migration and invasion than NOY1-CD133- cells (Fig.3 A). By adding AMD3100 to co-culture systems, the colony formation, migration, and invasion of NOY1-CD133+ cells were inhibited (Fig.3 B). In addition, AMD3100 inhibited the tumorigenicity of NOY1-CD133+ in vivo (Fig.3 C).
Our data suggest that peritoneal mesothelial cells have the potential to provide one of the niches for NOY1. Investigation of the niches of CSCs will help elucidate important targets for therapeutic approaches.

Principal Research Achievement

  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)

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