Survival of salivary pleomorphic adenoma cells under the hypoxia-responsive extracellular matrix biosynthesis

• Project/Area Number: 24592829
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Niigata University
• Principal Investigator: MARUYAMA Satoshi 新潟大学, 医歯学総合病院, 講師 (30397161)
• Co-Investigator(Kenkyū-buntansha): ABE Tatsuya 新潟大学, 医歯学総合病院, レジデント (70634856) ; YAMAZAKI Manabu 新潟大学, 医歯学系, 助教 (10547516) ; CHENG Jun 新潟大学, 医歯学系, 准教授 (40207460) ; SAKU Takashi 新潟大学, 医歯学系, 教授 (40145264)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 実験腫瘍学 / 低酸素 / 唾液腺多形性腺腫 / HIF-1α / 細胞外基質 / SM-AP

Outline of Final Research Achievements

Salivary pleomorphic adenoma is histopathologically characterized by its colorful stroma with myxoid, chondroid, and hyaline appearances, which is realized by its enhanced biosynthesis of extracellular matrix (ECM) molecules as well as by poor vascularity. Thus, pleomorphic adenoma cells embedded in such stromata are supposed to be able to survive in hypoxic conditions. To understand the hypoxia-dependent manner of cellular proliferation in this particular tumor, we analyzed function of perlecan and fibronectin, which are the most abundant ECM molecules, in cell proliferation in hypoxic-conditioned pleomorphic adenoma cells. Hypoxic conditions induce pleomorphic adenoma cells to produce perlecan and fibronectin, which is maintained by high HIF-1α protein levels, which is further realized by perlecan and fibronectin-rich circumstance of the stroma. The results indicate that pleomorphic adenoma cells have to go round in hypoxic circles to survive.

Research Products

• [Journal Article] Keratin 17 is co-expressed with 14-3-3 sigma in oral carcinoma in situ and squamous cell carcinoma and modulates cell proliferation and size but not cell migration. (2015)
  • Author(s): Mikami T, Maruyama S, Abe T, Kobayashi T, Yamazaki M, Funayama A, Shingaki S, Kobayashi T, Jun C, Saku T.
  • Journal Title: Virchows Arch. Volume: 466(5) Issue: 5 Pages: 559-69
  • DOI: 10.1007/s00428-015-1735-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells. (2014)
  • Author(s): Yamazaki M, Maruyama S, Abe T, Essa A, Babkair H, Cheng J, Saku T.
  • Journal Title: Lab Invest. Volume: 94(11) Issue: 11 Pages: 1260-72
  • DOI: 10.1038/labinvest.2014.108
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Radiation-induced undifferentiated high-grade pleomorphic sarcoma (malignant fibrous histiocytoma) of the mandible: Report of a case arising in the background of long-standing osteomyelitis with a review of the literature. (2014)
  • Author(s): Koyama T, Kobayashi T, Maruyama S, Abe T, Swelam WM, Kodama Y, Hoshina H, Takagi R, Hayashi T, Saku T.
  • Journal Title: Pathol Res Pract. Volume: 210(12) Issue: 12 Pages: 1123-9
  • DOI: 10.1016/j.prp.2014.06.028
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Keratin pearl degradation in oral squamous cell carcinoma: reciprocal roles of neutrophils and macrophages (2014)
  • Author(s): Essa AAM, Yamazaki M, Maruyama S, Abe T, Babkair H, Cheng J, Saku T
  • Journal Title: Journal of Oral Pathology and Medicine Volume: in press Issue: 10 Pages: 778-84
  • DOI: 10.1111/jop.12197
  • Peer Reviewed / Open Access
• [Journal Article] Three-dimensional visualization of perlecan-rich neoplastic stroma induced concurrently with the invasion of oral squamous cell carcinoma (2014)
  • Author(s): Maruyama S, Shimazu Y, Kudo T, Sato K, Yamazaki M, Abe T, Babkair H, Cheng J, Aoba T, Saku T
  • Journal Title: Journal of Oral Pathology and Medicine Volume: online published Issue: 8 Pages: 627-36
  • DOI: 10.1111/jop.12184
  • Peer Reviewed / Open Access
• [Journal Article] Amyloid beta (A4) precursor protein expression in human periodontitis-affected gingival tissues. (2014)
  • Author(s): Kubota T, Maruyama S, Abe D, Tomita T, Morozumi T, Nakasone N, Saku T, Yoshie H.
  • Journal Title: Arch Oral Biol. Volume: 59(6) Issue: 6 Pages: 586-94
  • DOI: 10.1016/j.archoralbio.2014.03.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Perlecan-enriched intercellular space of junctional epithelium provides primary infrastructure for leucocyte migration through squamous epithelial cells (2014)
  • Author(s): Maruyama S, Itagaki M, Ida-Yonemochi H, Kubota T, Yamazaki M, Abe T, Yoshie H, Cheng J, Saku T
  • Journal Title: Histochemistry and Cell Biology Volume: online published Issue: 3 Pages: 297-305
  • DOI: 10.1007/s00418-014-1198-x
  • Peer Reviewed / Open Access
• [Journal Article] Hybrid ameloblastoma and adenomatoid odontogenic tumor: report of a case and review of hybrid variations in the literature. (2014)
  • Author(s): Yamazaki M, Maruyama S, Abe T, Babkair H, Fujita H, Takagi R, Koyama JI, Hayashi T, Cheng J, Saku T.
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol. Volume: 118(1) Issue: 1 Pages: e12-e18
  • DOI: 10.1016/j.oooo.2013.08.032
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intramuscular keratocyst as a soft tissue counterpart of keratocystic odontogenic tumor: differential diagnosis by immunohistochemistry. (2013)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Essa A, Babkair H, Mikami T, Shingaki S, Kobayashi T, Hayashi T, Cheng J, Saku T.
  • Journal Title: Hum Pathol. Volume: 45(1) Issue: 1 Pages: 110-8
  • DOI: 10.1016/j.humpath.2013.08.011
  • Peer Reviewed
• [Journal Article] dentification of the Actinomycete 16S RNA gene by polymerase chain reaction in oral inflammatory lesions (2013)
  • Author(s): Kuyama K, Fukui K, Ochiai E, Maruyama S, Iwadate K, Saku T, Yamamoto H
  • Journal Title: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology Volume: 116 Issue: 4 Pages: 485-491
  • DOI: 10.1016/j.oooo.2013.06.027
  • Peer Reviewed
• [Journal Article] Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma (2013)
  • Author(s): Tsuneki M, Yamazaki M, Maruyama S, Cheng J, Saku T
  • Journal Title: Laboratory Investigation Volume: 93 Issue: 8 Pages: 921-932
  • DOI: 10.1038/labinvest.2013.86
  • Peer Reviewed
• [Journal Article] Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells (2013)
  • Author(s): Masayuki Tsuneki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 434 Issue: 1 Pages: 124-130
  • DOI: 10.1016/j.bbrc.2013.03.057
  • Peer Reviewed
• [Journal Article] Hemophagocytosis-mediated keratinization in oral carcinoma in-situ and squamous cell carcinoma: a possible histopathogenesis of keratin pearls (2013)
  • Author(s): Al-Eryani K, Cheng J, Abe T, Yamazaki M, Maruyama S, Tsuneki M, Essa A, Babkair H, Saku T
  • Journal Title: Journal of Cellular Physiology Volume: 228 Issue: 10 Pages: 1977-1988
  • DOI: 10.1002/jcp.24364
  • Peer Reviewed
• [Journal Article] Gene and protein localisation of Tumor Necrosis Factor (TNF) -α converting enzyme in gingival tissues from periodontitis patients with drug-induced gingival overgrowth (2013)
  • Author(s): Tomita T, Kubota T, Nakasone N, Morozumi T, Abe D, Maruyama S, Shimizu T, Horimizu M, Saku T, Yoshie H
  • Journal Title: Archives of Oral Biology Volume: (in press) Issue: 8 Pages: 1014-20
  • DOI: 10.1016/j.archoralbio.2013.02.011
  • Peer Reviewed
• [Journal Article] Keratin-10-positive orthokeratotic dysplasia : a new leukoplakia-type precancerous entity of the oral mucosa (2012)
  • Author(s): Kobayashi T, Maruyama S, Abe T, Cheng J, Takagi R, Saku T.
  • Journal Title: Histopathology Volume: (in press) Issue: 5 Pages: 910-920
  • DOI: 10.1111/j.1365-2559.2012.04283.x
  • Peer Reviewed
• [Journal Article] Parenchymal-stromal switching for extracellular matrix production on invasion of oral squamous cell carcinoma (2012)
  • Author(s): Metwaly H, Maruyama S, Yamazaki M, Tsuneki M, Abe T, Jen KY, Cheng J, Saku T.
  • Journal Title: Human Pathology Volume: 43(11) Issue: 11 Pages: 1973-1981
  • DOI: 10.1016/j.humpath.2012.02.006
  • Peer Reviewed
• [Journal Article] Intraepithelially entrapped blood vessels in oral carcinoma in-situ (2012)
  • Author(s): Funayama A, Maruyama S, Yamazaki M, Al-Eryani K, Shingaki S, Saito C, Cheng J, Saku T.
  • Journal Title: Virchows Archive Volume: 460(5) Issue: 5 Pages: 473-480
  • DOI: 10.1007/s00428-012-1224-0
  • Peer Reviewed
• [Journal Article] Podoplanin expression profiles characteristic of odontogenic tumor-specific tissue architectures (2012)
  • Author(s): Masayuki Tsuneki
  • Journal Title: Pathology-Research and Practice Volume: 208 Issue: 3 Pages: 140-146
  • DOI: 10.1016/j.prp.2011.12.016
  • Peer Reviewed
• [Journal Article] Loss of keratin 13 in oral carcinoma in situ : a comparative study of protein and gene expression levelsusing paraffin section (2012)
  • Author(s): Ida-Yonemochi H, Maruyam S, Kobayashi T, Yamazaki M, Cheng J, Saku T.
  • Journal Title: Modern Pathology Volume: (in press) Issue: 6 Pages: 784-794
  • DOI: 10.1038/modpathol.2011.218
  • Peer Reviewed
• [Journal Article] Short telomeres in an oral precancerous lesion : Q-FISH analysis of leukoplakia (2012)
  • Author(s): Aida J, Kobayashi T, Saku T, Yamaguchi M, Shimomura N, Nakamura KI, Ishikawa N, Maruyama S, Cheng J, Poon SS, Sawabe M, aida T, Takubo K.
  • Journal Title: Journal of Oral Pathology & Medicine Volume: 41(5) Issue: 5 Pages: 372-378
  • DOI: 10.1111/j.1600-0714.2011.01120.x
  • Peer Reviewed
• [Presentation] 口腔天疱瘡はデスモグレイン3とIgG4の点状共局在様式から病理組織 診断でも確定できる. (2014)
  • Author(s): 阿部達也，丸山 智，山崎 学，Babkair Hamzah，程 クン，朔 敬
  • Organizer: 第25回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 新潟市 新潟日報ホール
  • Year and Date: 2014-08-27 – 2014-08-30
• [Presentation] Orthokeratinization-related factors in the oral dysplasia squamous cell carcinoma sequences. (2014)
  • Author(s): Abe T, Maruyama S, Yamazaki M, Babkair H, Cheng J, Saku T
  • Organizer: 17th International Congress on Oral Pathology and Medicine
  • Place of Presentation: Istanbul Turkey
  • Year and Date: 2014-05-25 – 2014-05-30
• [Presentation] 腺様嚢胞癌細胞の転移：KGFシングルによる細胞増殖性と遊走性の相反的制御機構. (2014)
  • Author(s): 丸山 智, 山崎 学, 阿部達也, 程 クン, 朔 敬
  • Organizer: 第68回日本口腔科学会学術集会
  • Place of Presentation: 東京都 京王プラザホテル
  • Year and Date: 2014-05-07 – 2014-05-09
• [Presentation] 口腔扁平上皮癌細胞においてMFG-E8は同種死細胞処理たけでなく腫瘍進展にも関与している. (2014)
  • Author(s): 山崎 学, 程 クン, 丸山 智, 阿部達也, 朔 敬
  • Organizer: 第68回日本口腔科学会学術集会
  • Place of Presentation: 東京都 京王プラザホテル
  • Year and Date: 2014-05-07 – 2014-05-09
• [Presentation] 唾液腺多形性腺腫由来SM-AP細胞の増殖は低酸素応答性パールカン生合成に依存している. (2014)
  • Author(s): 丸山 智, 山崎 学, 阿部達也, Babkair Hamzah, 程 クン, 朔 敬
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 口腔扁平上皮癌細胞におけるMFG-E8発現の意義：過剰発現細胞系による解析. (2014)
  • Author(s): 山崎 学, 程 クン, 丸山 智, 阿部達也, 朔 敬
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 扁平上皮癌シーケンスにおける正角化関連分子の発現動態. (2014)
  • Author(s): 阿部達也, 丸山 智, Essa Ahmed, Babkair Hamzah, 山崎 学, 程 クン, 朔 敬
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市 広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 唾液腺多形腺腫細胞における低酸素応答性の細胞外基質合成 (2013)
  • Author(s): 丸山 智, 山崎 学, 阿部達也, 程 クン, 朔 敬
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] MFG-E8は口腔扁平上皮癌の進展と死細胞貪食を促進する (2013)
  • Author(s): 山崎 学，程 クン, 丸山 智，阿部達也，朔 敬
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] Stromal macrophages in oral squamous cell carcinoma (2013)
  • Author(s): Essa Ahmed, 山崎 学, 丸山 智, 阿部達也, Babkair Hamzah, 程 クン, 朔 敬
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] 口腔扁平上皮癌の側方進展界面における細胞死 (2013)
  • Author(s): 阿部達也, 丸山 智, Essa Ahmed, Babkair Hamzah, 山崎 学, 程 クン, 朔 敬
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
• [Presentation] 下顎腫瘍 (2013)
  • Author(s): 丸山 智, 山崎 学, 阿部達也, 櫻井博理, 下山泰明, 程 クン, 朔 敬
  • Organizer: 第24回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
• [Presentation] 口腔底腫瘍 (2013)
  • Author(s): 山崎 学, 程 クン, 丸山 智, 阿部達也, 池田順行, 永田昌毅, 高木律男, 西山秀昌, 林 孝文, 朔 敬
  • Organizer: 第24回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
• [Presentation] 口蓋腫瘍 (2013)
  • Author(s): 程 クン, 丸山 智, 阿部達也, 山崎 学, 朔 敬
  • Organizer: 第24回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
• [Presentation] 口腔扁平苔癬のいわゆるシバット小体における細胞死関連因子の検討 (2013)
  • Author(s): 阿部達也, 丸山 智, Essa Ahmed, Babkair Hamzah, 程 クン, 朔 敬
  • Organizer: 第24回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
• [Presentation] 口腔扁平上皮癌-間質線維芽細胞の共培養系を用いたパールカン生合成転換機構の解明 (2012)
  • Author(s): 丸山 智
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京都
• [Presentation] 病理診断における免疫組織化学的検討-新潟大学での取り組み (2012)
  • Author(s): 丸山 智
  • Organizer: 第23回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
  • Invited
• [Presentation] 学会奨励賞受賞講演：唾液腺多形性腺腫の浸潤・増殖機構 (2012)
  • Author(s): 丸山 智
  • Organizer: 第23回日本臨床口腔病理学会総会・学術大会
  • Place of Presentation: 東京都
  • Invited
• [Presentation] 口腔扁平上皮癌の浸潤を契機とした細胞外基質産生の実質細胞から間質細胞へのスイッチング機構 (2012)
  • Author(s): 丸山 智
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌市