Soluble receptor activator of nuclear factor-kB ligand : involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment

• Project/Area Number: 21590442
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya City University
• Principal Investigator: FUTAKUCHI Mitsuru 名古屋市立大学, 大学院・医学研究科, 准教授 (60275120)
• Co-Investigator(Renkei-kenkyūsha): FUKAMACHI Katsumi 名古屋市立大学, 大学院・医学研究科, 助教 (90381798)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 腫瘍 / 骨転移 / sRANKL / TGFβ / 乳癌 / 腫瘍間質相互作用 / 骨微小環境 / 腫瘍・間質相互作用

Research Abstract

Understanding how cancer cells induce bone metastases is essential for the identification of new therapies to control bone metastasis. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G to be proteases that are up-regulated at the tumor bone(TB)-interface. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of receptor activator of nuclear factor-KB ligand(RANKL), generating active soluble version(sRANKL) that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G seems to be osteoclasts. Furthermore, we showed that in vivo inhibition of cathepsin G reduces mammary tumor. induced osteolysis.
Next we examined the preventive effects of a competitive inhibitor of sRANKL, osteoprotegrin fusion protein(OCIF) was administered to mice before osteolysis induction by implantation of mammary tumor cells(pre), after osteolysis induction(post) or during the entire experimental period(whole). Tumor growth at the TB-interface was significantly suppressed in the pre as well as the post and whole treatment groups of OCIF. The extent of bone destruction was significantly reduced in the pre, post and whole treatment groups. In addition, significantly fewer osteoclasts wereobserved in the OCIF treatment groups regardless of treatment period.
Together, our data indicate that inhibition of cathepsin G activity at the TB interface could be therapeutic targets, and sRANKL which is generated by cathepsin G is a potentially target for prevention as well as treatment of breast cancer bone metastasis.

Research Products

• [Journal Article] Lack of promoting effect of titanium dioxide particles on chemically-induced skin carcinogenesis in rats and mice (2012)
  • Author(s): Sagawa, Y., Futakuchi, M.
  • Journal Title: J Toxicol Sci Volume: 37 Pages: 317-327
  • NAID: 10030126738
  • Peer Reviewed
• [Journal Article] Lack of promoting effect of titanium dioxide particles on ultraviolet B-initiated skin carcinogenesis in rats (2011)
  • Author(s): Xu, J., Sagawa, Y., Futakuchi, M., Fukamachi, K., Alexander, D. B., Furukawa, F., Ikarashi, Y., Uchino, T., Nishimura, T., Morita, A., et al
  • Journal Title: Food Chem Toxicol Volume: 49 Pages: 1298-1302
  • Peer Reviewed
• [Journal Article] A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases using Gene Expression Profiling (2011)
  • Author(s): Sadanandam, A., Futakuchi, M., Lyssiotis, C. A., Gibb, W. J., and Singh, R. K
  • Journal Title: BMC Cancer Volume: 11 Pages: 304-304
  • Peer Reviewed
• [Journal Article] A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases using Gene Expression Profiling (2011)
  • Author(s): Sadanandam, A., Futakuchi, M.
  • Journal Title: BMC Cancer Volume: 11 Issue: 1 Pages: 304-31
  • DOI: 10.1186/1471-2407-11-304
  • Peer Reviewed
• [Journal Article] Lack of promoting effect of titanium dioxide particles on ultraviolet B-initiated skin carcinogenesis in rats (2011)
  • Author(s): Xu, J., Futakuchi, M.
  • Journal Title: Food Chem Toxicol Volume: 49 Issue: 6 Pages: 1298-302
  • DOI: 10.1016/j.fct.2011.03.011
  • Peer Reviewed
• [Journal Article] Involvement of macrophage inflammatory protein 1alpha(MIP1alpha) in promotion of rat lung and mammary carcinogenic activity of nanoscale titanium dioxide particles administered by intra-pulmonary spraying (2010)
  • Author(s): Xu, J., Futakuchi, M., Iigo, M., Fukamachi, K., Alexander, D. B., Shimizu, H., Sakai, Y., Tamano, S., Furukawa, F., Uchino, T., et al
  • Journal Title: Carcinogenesis Volume: 31 Pages: 927-935
  • Peer Reviewed
• [Journal Article] Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1 (2010)
  • Author(s): Wilson, T. J., Nannuru, K. C., Futakuchi, M., and Singh, R. K
  • Journal Title: Cancer Lett Volume: 288 Pages: 162-169
  • Peer Reviewed
• [Journal Article] Toxicology of Engineered Nanomaterials-A review of Carcinogenic Potential (2010)
  • Author(s): Tsuda, H., Xu, J., Sakai, Y., Futakuchi, M., and Fukamachi, K
  • Journal Title: Asian Pacific J Cancer Prev Volume: 10 Pages: 975-9680
  • Peer Reviewed
• [Journal Article] Cancer prevention by bovine lactoferrin : from animal studies to human trial (2010)
  • Author(s): Tsuda, H., Kozu, T., Iinuma, G., Ohashi, Y., Saito, Y., Saito, D., Akasu, T., Alexander, D. B., Futakuchi, M., Fukamachi, K., et al
  • Journal Title: Biometals Volume: 23 Pages: 399-409
  • Peer Reviewed
• [Journal Article] A medium-term, rapid rat bioassay model for the detection of carcinogenic potential of chemicals (2010)
  • Author(s): Tsuda, H., Futakuchi, M., Fukamachi, K., Shirai, T., Imaida, K., Fukushima, S., Tatematsu, M., Furukawa, F., Tamano, S., and Ito, N
  • Journal Title: Toxicol Pathol Volume: 38 Pages: 182-187
  • Peer Reviewed
• [Journal Article] Mature acinar cells are refractory to carcinoma development by targeted activation of Ras oncogene in adult rats (2010)
  • Author(s): Tanaka, H., Fukamachi, K., Futakuchi, M., Alexander, D. B., Long, N., Tamamushi, S., Minami, K., Seino, S., Ohara, H., Joh, T., and Tsuda, H
  • Journal Title: Cancer Sci Volume: 101 Pages: 341-346
  • NAID: 10026587596
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase(MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface (2010)
  • Author(s): Nannuru, K. C., Futakuchi, M., Varney, M. L., Vincent, T. M., Marcusson, E. G., and Singh, R. K
  • Journal Title: Cancer Res Volume: 70 Pages: 3494-3504
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase (MMP)- 13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface (2010)
  • Author(s): Nannuru, K.C., Futakuchi, M.
  • Journal Title: Cancer Res Volume: 70 Pages: 3494-3504
  • Peer Reviewed
• [Journal Article] Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1 (2010)
  • Author(s): Wilson, T.J., Futakuchi, M.
  • Journal Title: Cancer Letter 288 Pages: 162-169
  • Peer Reviewed
• [Journal Article] Enhanced expression and shedding of receptor activator of NF-kappaB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis (2009)
  • Author(s): Nannuru, K. C., Futakuchi, M., Sadanandam, A., Wilson, T. J., Varney, M. L., Myers, K. J., Li, X., Marcusson, E. G., and Singh, R. K
  • Journal Title: Clin Exp Metastasis Volume: 26 Pages: 797-808
  • Peer Reviewed
• [Journal Article] Construction of a Multi Functional Helper Dependent Adenovirus Based System (2009)
  • Author(s): Long, N., Shirai, T., Hardiville, S., Pierce, A., Fukamachi, K., Futakuchi, M., Alexander, D. B., and Tsuda, H
  • Journal Title: Asian Pacific J Cancer Prev Volume: 10 Pages: 939-960
  • Peer Reviewed
• [Journal Article] Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine (2009)
  • Author(s): Iigo, M., Alexander, D. B., Long, N., Xu, J., Fukamachi, K., Futakuchi, M., Takase, M., and Tsuda, H
  • Journal Title: Biochimie Volume: 91 Pages: 86-101
  • Peer Reviewed
• [Journal Article] Transforming growth factor-beta signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation (2009)
  • Author(s): Futakuchi, M., Nannuru, K. C., Varney, M. L., Sadanandam, A., Nakao, K., Asai, K., Shirai, T., Sato, S. Y., and Singh, R. K
  • Journal Title: Cancer Sci Volume: 100 Pages: 71-81
  • Peer Reviewed
• [Presentation] Crosstalk between TGFbeta and AKT/PTEN signaling pathway in the bone microenvironment ; mechanism for tumor cell proliferation in the bone metastasis of breast cancer (2011)
  • Author(s): Futakuchi, M., Fukamachi, K., and Suzui, M
  • Organizer: The 16th Japan-Korea Cancer Research Workshop
  • Place of Presentation: 札幌
  • Year and Date: 2011-12-09
• [Presentation] Crosstalk between TGFbeta and AKT/PTEN signaling pathway in the bone microenvironment : mechanism for tumor cell proliferation in the bone metastasis of breast cancer (2011)
  • Author(s): Mitsuru Futakuchi Katsumi Fukamachi Masumi Suzui
  • Organizer: The 16th Japan-Korea Cancer Research
  • Place of Presentation: 京王プラザホテル(札幌市)(招待講演)
  • Year and Date: 2011-10-10
• [Presentation] Soluble RANKL ; significance of therapeutic target for tumor growth in the bone microenvironment (2011)
  • Author(s): Futakuchi, M., Fukamachi, K., and Suzui, M
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] Soluble RANKL ; significance of therapeutic target for tumor growth in the bone microenvironment (2011)
  • Author(s): Mitsuru Futakuchi, Katsumi Fukamachi, Masumi Suzui
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-05
• [Presentation] 可溶性RANKL標的療法による骨微小環境での乳がん細胞の増殖および溶骨性変化の抑制とそのメカニズム (2011)
  • Author(s): 二口充, 深町勝巳, 酒々井眞澄
  • Organizer: 第20回日本癌転移学会学術集会
  • Place of Presentation: 浜松
  • Year and Date: 2011-07-11
• [Presentation] 乳癌骨転移巣進展におけるTGFβの役割 (2011)
  • Author(s): 二口充, 深町勝巳, 酒々井真澄, 津田洋幸
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2011-04-29
• [Presentation] 骨微小環境における乳がん細胞の増殖に対する可溶性RANKLの治療標的分子としての意義 (2011)
  • Author(s): 二口充, 深町勝巳, 津田洋幸, 酒々井眞澄
  • Organizer: 平成22年度「個体レベルでのがん支援活動」ワークショップ
  • Place of Presentation: 琵琶湖
  • Year and Date: 2011-02-03
• [Presentation] Soluble receptor activator of nuclear factor-kB ligand : Involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment (2010)
  • Author(s): Futakuchi, M., Suzui, M., Fukamachi, K., and Singh, R.
  • Organizer: The 15th Japan-Korea Cancer Research Workshop, Tumor microenvironment and progress in breast cancer research
  • Place of Presentation: Incheon, Korea
  • Year and Date: 2010-12-23
• [Presentation] Soluble receptor activator of nuclear factor-kB ligand : involvement and significance as therapeutics in the osteolysis associated with breast cancer growth in the bone microenvironment (2010)
  • Author(s): Mitsuru Futakuchi, Masumi Suzui, Katsumi Fukamachi, Rakesh Singh
  • Organizer: The 15^<th> Japan-Korea Cancer Research Workshop
  • Place of Presentation: Incheon, Korea
  • Year and Date: 2010-12-22
• [Presentation] Preventive and therapeutic effect of osteoprotegrin fusion protein on mammary tumor-induced osteolysis (2010)
  • Author(s): Futakuchi, M., Fukamachi, K., Tsuda, H., and Suzui, M
  • Organizer: 69th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] Preventive and therapeutic effect of osteoprotegrin fusion protein on mammary tumor-induced osteolysis (2010)
  • Author(s): Mitsuru Futakuchi, Katsumi Fukamachi, Hiroyuki Tsuda, Masumi Suzui
  • Organizer: 69^<th> Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2010-09-22
• [Presentation] Soluble receptor activator of nuclear factor-kB ligand : the involvement in the osteolysis associated with breast or prostate cancer growth in the bone microenvironment and its significance as therapeutics for bone metastatic cancer (2010)
  • Author(s): Futakuchi, M., Nannuru, K. C., Wilson, T. J., Suzui, M., Fukamachi, K., and Singh, R
  • Organizer: Joint Metastasis Research Society-AACR Conference, Metastasis and the tumor microenvironment
  • Place of Presentation: Philadelphia, PA
  • Year and Date: 2010-09-12
• [Presentation] Significance of TGF-beta as a therapeutic target for breast metastasis of prostate or breast cancer (2010)
  • Author(s): 二口充, 深町勝巳, 津田洋幸
  • Organizer: 第19回日本がん転移学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2010-06-17
• [Presentation] Significance of TGF-beta and sRANKL as therapeutic s for breast cancer bone metastasis (2009)
  • Author(s): Futakuchi, M., Xu, J., Fukamachi, K., and Tsuda, H
  • Organizer: 68th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Book] 動物モデルを用いた骨転移の分子メカニズム解明と創薬応用研究、最新疾患モデルと創薬応用の最前線、遺伝子医学MOOK22号 (2012)
  • Publisher: 株式会社
• [Book] モデル動物利用マニュアル(仮題)、第2章がん、第4項転移浸潤モデル、(3)骨浸潤転移モデル (2012)
  • Publisher: エル・アイ・シー
• [Book] モデル動物利用マニュアル、第2章がん、第4項転移浸潤モデル、(3)骨浸潤転移モデル (2012)
  • Author(s): 二口充
  • Publisher: エル・アイ・シー(印刷中)(仮題)
• [Book] ロビンス基礎病理学第8版日本語翻訳Chapter 8 Environmental and nutritional diseases (2011)
  • Publisher: エルゼビア・ジャパン