Role of bone marrow-derived cells during pancreatic tumorigenesis

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590754
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: 医療法人 徳洲会 札幌東徳州会病院付属臨床研究センター (2012); Asahikawa Medical College (2010-2011)
• Principal Investigator: MIZUKAMI Yusuke 医療法人 徳洲会 札幌東徳州会病院付属臨床研究センター, 再生医療研究部, 部門長 (30400089)
• Co-Investigator(Renkei-kenkyūsha): II Masaaki 大阪医科大学, 大阪医科大学, 講師 (10442922)
• Project Period (FY): 2010 – 2012
• Keywords: 膵癌 / 間質 / 骨髄 / 遺伝子改変マウス

Research Abstract

Tumor-derived factors affect the stroma of cancer tissue. One of the key components of this response is the mobilization of the progenitors from the bone marrow (BM), which contribute toward the development of desmoplastic stroma. These BM-derived cells are involved in normal physiological processes such as tissue repair and wound healing; however, in cancer bearing hosts, these cells actively contribute toward the chaotic microenvironment. Using genetically engineered mice models for pancreatic cancer, we found that BM-progenitors are passively activated by even early stage tumors. We have identified the signaling pathways by which BM-derived cells are recruited and activated to establish malignant stroma in later stages of tumor development.

Research Products

• [Journal Article] Autofluorescence imaging and the quantitative intensity of fluorescence for evaluating the dysplastic grade of colonic neoplasms (2012)
  • Author(s): Moriichi K, Fujiya M, Sato R, Nata T, Nomura Y, Ueno N, Ishikawa C, Inaba Y, Ito T, Okamoto K, Tanabe H, Mizukami Y, Watari J, Saitoh Y, Kohgo Y.
  • Journal Title: International Journal of Colorectal Disease Volume: 27 Pages: 325-330
  • DOI: DOI: 10.1007/s00384-011-1311-8
  • Peer Reviewed
• [Journal Article] Competence and sporulation factor derived from Bacillus subtilis improves epithelial cell injury in intestinal inflammation via immunomodulation and cytoprotection (2012)
  • Author(s): Okamoto K, Fujiya M, Nata T, Ueno N, Inaba Y, Ishikawa C, Ito T, Moriichi K, Tanabe H, Mizukami Y, Chang EB, Kohgo Y.
  • Journal Title: International Journal of Colorectal Disease Volume: 27 Pages: 1039-1049
  • DOI: DOI: 10.1007/s00384-012-1416-8
  • Peer Reviewed
• [Journal Article] Xavier RJ, ChungDC. Oncogenic KRAS regulates BMP4 expression in colon cancer cell lines (2012)
  • Author(s): Duerr EM, Mizukami Y, Moriichi K, Gala M, Jo WS, Kikuchi H
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 302 (10) Pages: G1223-30
  • DOI: DOI: 10.1152/ajpgi.00047. 2011
  • Peer Reviewed
• [Journal Article] Analysis of vanin-1 upregulation and lipid accumulation in hepatocytes in response to a high-fat diet and free fatty acids (2012)
  • Author(s): Motomura W, Yoshizaki T, Takahashi N, Kumei S, Mizukami Y, Jang SJ, Kohgo Y
  • Journal Title: J Clin Biochem Nutr Volume: 51 Pages: 163-9
  • DOI: DOI:10.3164/jcbn.12-06
  • Peer Reviewed
• [Journal Article] Bone marrow-derived proangiogenic cells in pancreatic cancer (2012)
  • Author(s): Mizukami Y
  • Journal Title: J Gastroenterol Hepatol Volume: Suppl 2 Pages: 23-6
  • DOI: DOI: 10.1111/j. 1440-1746.2011.07012.x
  • Peer Reviewed
• [Journal Article] Abnormal tumor vasculatures and bone marrow-derived pro- angiogenic cells in cancer (2012)
  • Author(s): Mizukami Y, Sasajima J, Ashida T, Kohgo Y.
  • Journal Title: International Journal of Hematology Volume: 95 Pages: 125-130
  • DOI: DOI: 10.1007/ s12185-012-1017-x
  • Peer Reviewed
• [Journal Article] Localization of the most severely dysplastic/ invasive lesions and mucin phenotypes in intraductal papillary mucinous neoplasm (IPMN) of the pancreas (2011)
  • Author(s): Mizukami Y, Tokusashi Y, Koizumi K, Ishizaki A, Imai K, Yoshikawa D, Kino S, Sasajima J, Tanno S, Matsumoto K, Miyokawa N, Kono T, Kohgo Y, Furukawa H.
  • Journal Title: Pancreas Volume: 40 Pages: 588-594
  • DOI: DOI: 10.1097/MPA.0b013e31820d1a03
  • Peer Reviewed
• [Journal Article] Heat-killed body of lactobacillus brevis SBC8803 ameliorates intestinal injury in a murine model of colitis by enhancing the intestinal barrier function. (2011)
  • Author(s): Ueno N, Fujiya M, Segawa S, Nata T, Moriichi K, Tanabe H, Mizukami Y, Kobayashi N, Ito K, Kohgo Y.
  • Journal Title: Inflamm Bowel Dis Volume: 17 Pages: 2235-2250
  • DOI: DOI: 10.1002/ ibd.21597
  • Peer Reviewed
• [Journal Article] Loss of ABCB7 gene: pathogenesis of mitochondrial iron accumulation in erythroblasts in refractory anemia with ringed sideroblast with isodicentric (X)(q13). (2011)
  • Author(s): Sato K, Torimoto Y, Hosoki T, Ikuta K, Takahashi H, Yamamoto M, Ito S, Okamura N, Ichiki K, Tanaka H, Shindo M, Hirai K, Mizukami Y, Otake T, Fujiya M, Sasaki K, Kohgo Y.
  • Journal Title: Int J Hematol Volume: 93 Pages: 311-318
  • DOI: DOI: 10.1007/ s12185-011-0786-y
  • Peer Reviewed
• [Journal Article] The diagnostic accuracy of high-resolution endoscopy, autofluorescence imaging and narrow-band imaging for differentially diagnosing colon adenoma. (2011)
  • Author(s): Sato R, Fujiya M, Watari J, Ueno N, Moriichi K, Kashima S, Maeda S, Ando K, Kawabata H, Sugiyama R, Nomura Y, Nata T, Itabashi K, Inaba Y, Okamoto K, Mizukami Y, Saitoh Y, Kohgo Y.
  • Journal Title: Endoscopy Volume: 43 Pages: 862-868
  • DOI: DOI: 10.1055/s-0030-1256510
  • Peer Reviewed
• [Journal Article] Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. (2010)
  • Author(s): Nakamura K, Sasajima J, Mizukami Y, Sugiyama Y, Yamazaki M, Fujii R, Kawamoto T, Koizumi K, Sato K, Fujiya M, Sasaki K, Tanno S, Okumura T, Shimizu N, Kawabe J, Karasaki H, Kono T, Ii M, Bardeesy N, Chung DC, Kohgo Y.
  • Journal Title: PLoS One Volume: 5 Pages: e8824
  • DOI: DOI: 10.1371/journal.pone.0008824
  • Peer Reviewed
• [Journal Article] Immunoprecipitation of nucleosomal DNA is a novel procedure to improve the sensitivity of serum screening for the p16 hypermethylation associated with colon cancer. (2010)
  • Author(s): Sakamoto J, Fujiya M, Okamoto K, Nata T, Inaba Y, Moriichi K, Tanabe H, Mizukami Y, Watari J, Ashida T, Kohgo Y.
  • Journal Title: Cancer Epidemiology Volume: 34 Pages: 194-199
  • DOI: DOI: 10.1016/ j.canep.2010.01.004
  • Peer Reviewed
• [Journal Article] Expression of the antimicrobial peptide alpha-defensin/cryptdins in intestinal crypts decreases at the initial phase of intestinal inflammation in a model of inflammatory bowel disease, IL-10-deficient mice. (2010)
  • Author(s): Inaba Y, Ashida T, Ito T, Ishikawa C, Tanabe H, Maemoto A, Watari J, Ayabe T, Mizukami Y, Fujiya M, Kohgo Y.
  • Journal Title: Inflammatory Bowel Disease Volume: 16 Pages: 1488-1495
  • DOI: DOI: 10.1002/ibd.21253
  • Peer Reviewed
• [Journal Article] Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm. (2010)
  • Author(s): Tanno S, Nakano Y, Sugiyama Y, Nakamura K, Sasajima J, Koizumi K, Yamazaki M, Nishikawa T, Mizukami Y, Yanagawa N, Fujii T, Obara T, Okumura T, Kohgo Y.
  • Journal Title: Pancreatology Volume: 10 Pages: 173-178
  • DOI: DOI: 10.1159/000231982
  • Peer Reviewed
• [Journal Article] Pancreatic ductal adenocarcinomas in patients with branch duct intraductal papillary-mucinous neoplasms (2010)
  • Author(s): Tanno S, Nakano Y, Koizumi K, Yamazaki M, Nakamura K, Sasajima J, Nishikawa T, Mizukami Y, Yanagawa N, Fujii T, Obara T, Okumura T, Kohgo Y.
  • Journal Title: Pancreas Volume: 39 Pages: 36-40
  • DOI: DOI: 10.1097/MPA.0b013e3181b91cd0
  • Peer Reviewed
• [Journal Article] Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors (2010)
  • Author(s): Sasajima J, Mizukami Y, Sugiyama Y, Nakamura K, Kawamoto T, Koizumi K, Fujii R, Motomura W, Sato K, Suzuki Y, Tanno S, Fujiya M, Sasaki K, Shimizu N, Karasaki H, Kono T, Kawabe JI, Ii M, Yoshiara H, Kamiyama N, Ashida T, Bardeesy N, Chung DC, Kohgo Y.
  • Journal Title: Cancer Research Volume: 70 Pages: 6283-6292
  • DOI: DOI: 10.1158/0008-5472.CAN-10-0412
  • Peer Reviewed
• [Presentation] Bone marrow-derived proangiogenic cells in pancreatic cancer. The 6th International Symposium on ALPD and Cirrhosis (2011)
  • Author(s): Mizukami Y.
  • Organizer: Session1:Stem cells in ALD, liver and pancreatic cancer.
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 20111020-21
• [Presentation] Transplantion of pro-angiogenic monocytes to pancreatic cancer-bearing mice attenuates resistance to chemotherapy/radiotherapy (2011)
  • Author(s): Mizukami Y, Kawamoto T, Sugiyama Y, Sasajima J, Koizumi, K, Moriichi K, Fujiya M, Bardeesy N, Chung DC, Kohgo K.
  • Organizer: 2011 Gastrointestinal Cancers Symposium
  • Place of Presentation: San Francisco, CA.
  • Year and Date: 20110120-22
• [Presentation] Angiogenesis & Stemness in Pancreatic Cancer: Role of Bone Marrow-derived Cells. (2011)
  • Author(s): 水上裕輔
  • Organizer: 第63回日本細胞生物学会大会 MS5 血管の多様性～組織発生から疾患におけるダイナミクス
  • Place of Presentation: 札幌
  • Year and Date: 2011-06-29
• [Presentation] The paracrine effect of hedgehog on bone marrow-derived stromal cells occurs at later stages of pancreatic tumorigenesis (2011)
  • Author(s): Sugiyama Y, Mizukami Y, Kawamoto T, Sasajima J, Koizumi K, Nomura Y, Moriichi K, Fujiya M, Bardeesy N, Chung DC, Kohgo Y.
  • Organizer: Digestive Disease Week 2010, Topic Forum; Biology of the Pancreas
  • Place of Presentation: Chicago, IL
  • Year and Date: 2011-05-11
• [Presentation] 腫瘍血管「修復」による低酸素の解除 (2011)
  • Author(s): 水上裕輔
  • Organizer: 第8回がんとハイポキシア研究会 シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2011-01-29
• [Presentation] ANGIOGENESIS & STEMNESS IN PANCREATIC CANCER: THERAPEUTIC IMPLICATIONS (2010)
  • Author(s): Mizukami Y.
  • Organizer: The 1st JSGE International Topic Conference, Plenary Session III, Pancreas (1)
  • Place of Presentation: Kamakura
  • Year and Date: 2010-10-25
• [Presentation] 腫瘍血管リモデリングは腫瘍低酸素を解除し、がん幹細胞様形質を軽減する (2010)
  • Author(s): 水上裕輔、笹島順平、高後 裕
  • Organizer: JDDW2010 S10(日本消化器病学会)消化器癌における幹細胞研究の現状
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-14
• [Presentation] Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduced hypoxia in tumors (2010)
  • Author(s): Mizukami Y, Sasajima J, Sugiyama Y, Nakamura K, Kawamoto T, Koizumi, K, Sato K, Suzuki Y, Fujiya M, Sasaki K, Torimoto Y, Karasaki H, Kono T, Kohgo K.
  • Organizer: 9th International Conference of The Asian Clinical Oncology Society (ACOS), Mini Symposium 8; Recent advances in pancreatic cancer
  • Place of Presentation: Gifu
  • Year and Date: 2010-08-26
• [Presentation] Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduced hypoxia in tumors (2010)
  • Author(s): Mizukami Y.
  • Organizer: 16th International Vascular Biology Meeting. Plenary session; Status quo in Tumor Angiogenesis
  • Place of Presentation: Los Angeles, CA
  • Year and Date: 2010-06-24
• [Presentation] 膵癌間質におけるHedgehogのparacrine経路は自然発症膵発癌の後期段階で活性化する (2010)
  • Author(s): 水上裕輔、笹島順平、杉山祥晃、河本 徹、伊井正明、高後 裕
  • Organizer: 第19回日本がん転移学会学術集会
  • Place of Presentation: 金沢(ポスター発表)
  • Year and Date: 2010-06-19
• [Presentation] The Tumor Vasculature is a Paracrine Target of Hedgehog in Pancreatic Cancer (2010)
  • Author(s): Sugiyama Y, Mizukami Y, Sasajima J, Kawamto T, Koizumi K, Fujiya M, Tanno S, Karasaki H, Kono T, Bardessy N, Chung DC, and Kohgo Y.
  • Organizer: NOTCH AND SHH SIGNALING IN GASTROINTESTINAL HOMEOSTASIS
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2010-05-04
• [Presentation] Heat-Killed Body of Lactobacillus brevis Sbc8803 Contributes to Maintain Intestinal Homeostasis and Improve Intestinal Injury in a Murine Model of Colitis (2010)
  • Author(s): Ueno N, Fujiya M, Segawa S, Nata T, Inaba Y, Moriichi K, Tanabe H, Mizukami Y, Kobayashi N, Ito K, Kohgo Y.
  • Organizer: AGA Poster Session
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2010-05-04
• [Presentation] Activation of Hedgehog pathway in tumor vasculature is a late event of pancreatic tumorigenesis (2010)
  • Author(s): Sasajima J, Mizukami Y, Nakamura K, Sugiyama Y, Kawamoto T, Koizumi K, Sato K, Tanno S, Karasaki H, Kono T, Ii M, Chung DC, Bardessy N, and Kohgo Y.
  • Organizer: AACR Annual Meeting 2010, Poster Session 19
  • Place of Presentation: Washington DC
  • Year and Date: 2010-04-20
• [Remarks]
  • URL: http://www.higashi-tokushukai.or.jp/clinical_study/index.php