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  2. 吉村 久志

吉村 久志

ヨシムラ ヒサシ  (Hisashi YOSHIMURA)

基本情報

所属
日本獣医生命科学大学 獣医学部 獣医保健看護学科 応用部門 病態病理学研究分野 准教授
学位
博士（獣医学）(日本獣医生命科学大学)
J-GLOBAL ID
200901036410736384
researchmap会員ID
6000014246
外部リンク

JCVP認定獣医病理学専門家

 

日本獣医生命科学大学 獣医保健看護学科 病態病理学研究分野の私設ホームページはこちら

 

●奄美群島の稀少な野生動物死亡例の病理学的研究 2017年～現在

　奄美群島の動物病院の先生方などからのご依頼により、アマミノクロウサギやアマミトゲネズミなどの稀少な野生動物が死亡しているのが見つかった場合や、傷病で保護後に治療の甲斐なく死亡した場合に、その死因について病理学的に調査しています。これにより野生下で危険な伝染病が発生していないかのモニタリングや、今後の保護個体の治療法の改善に役立てています。

・J Comp Pathol. 2023 Accept.
Infective endocarditis with systemic bacterial embolism caused by Staphylococcus aureus in a free-ranging Amami rabbit (Pentalagus furnessi)
M. Konnai, M Yamamoto (co-first author), K. Ito, H. Yamabe, T. E. Kishimoto, H. Aoki, Y. Machida, M. Michishita, M. Haritani, H. Yoshimura.
・Int J Parasitol Parasites Wildl. 2022 18:194-200.
Three new species of Eimeria (Apicomplexa: Eimeriidae) from the Amami rabbit, Pentalagus furnessi (Mammalia: Leporidae)
T. Tokiwa, S. Chou, H. Kitazoe, K. Ito, R. Torimoto, Y. Shoshi, C. Sanjoba, M. Yamamoto, H. Yoshimura.
・Int J Parasitol Parasites Wildl. 2019 9:244-247.
Toxoplasma gondii infection in Amami spiny rat on Amami-Oshima Island, Japan
T. Tokiwa, H. Yoshimura (co-first author), S. Hiruma, Y. Akahori, A. Suzuki, K. Ito, M. Yamamoto, K. Ike.
・Parasitol Int. 2020 76:102058.
Alien parasitic infections in the endangered Ryukyu long-furred rat (Diplothrix legata) on Amami-Oshima Island, Japan
T. Tokiwa, H. Yoshimura, K. Ito, S. Chou, M. Yamamoto.

 

●動物園飼育下ニホンライチョウに発生する疾病の病理学的研究 2015年～現在

国の特別天然記念物に指定されているニホンライチョウは、地球温暖化などの影響により急激に生息数が減少しています。そこで環境省により保護増殖事業計画が策定され、2015年からニホンライチョウを動物園で飼育・繁殖し、将来的に野生に再導入する試み（生息域外保全）が始まりました。しかし、高山帯の冷涼な環境に生息するニホンライチョウは感染症に弱いなど、飼育を成功させるにはニホンライチョウに発生する疾病を解明する必要があります。当研究室は動物園飼育開始時から本事業に協力し、ニホンライチョウの疾病を病理学的に研究しています。

 

●イヌの乳腺腫瘍の分子病理学的研究 2010年～現在

　雌イヌにおいて発生頻度の高い腫瘍である乳腺腫瘍を研究テーマの一つにしています。近年、ヒト医療では癌に高発現する分子を狙い撃ちにする分子標的治療法が発展しています。イヌの乳腺腫瘍においても、癌の進行に重要な役割を果たし、治療標的になり得る候補分子を探索しています。

　S100蛋白の一つであるS100A4は、イヌの正常乳腺や良性の乳腺病変では発現しないにもかかわらず、一部の悪性乳腺腫瘍、特に退形成癌と呼ばれる最も悪性度の高い乳腺腫瘍の亜型において発現がみられました。S100A4を発現するイヌの乳腺癌から新たな培養細胞株NV-CMLを樹立し、RNA干渉技術を用いてS100A4の発現をノックダウンしたところ培養細胞の増殖能や遊走能が低下しました。このことからS100A4がイヌの乳腺癌の増殖や運動機能に関わっており、治療標的分子候補となる可能性が示唆されました。

　NestinはVI型中間径フィラメントに分類される細胞骨格蛋白で、神経幹細胞のマーカーとされていました。イヌの乳腺におけるnestinの発現を検討したところ、正常乳腺や良性の乳腺増殖性病変の腺上皮細胞には発現されないにもかかわらず、3割程度の悪性乳腺腫瘍、特に転移や増殖活性が高いなどの高悪性度の性質を持つ乳腺癌の腺上皮細胞には発現していることがわかりました。またnestinの発現は、間葉系マーカーであるvimrntinの発現と相関性を示しました。さらにイヌの乳腺癌培養細胞におけるnestinの発現を、RNA干渉技術によりノックダウンしたところ、nestinの発現が低下した癌細胞は、増殖能や移動能などが低下することが判明しました。このようにnestinがイヌの乳腺癌の悪性挙動の一部に関与している可能性が示唆されました。

・Vet Pathol. 2019 56(3):389-398.
Expression and Roles of S100A4 in Anaplastic Cells of Canine Mammary Carcinomas
H. Yoshimura, A. Otsuka, M. Michishita, M. Yamamoto, M. Ashizawa, M. Zushi, M. Moriya, D. Azakami, K. Ochiai, Y. Matsuda, T. Ishiwata, S. Kamiya, K. Takahashi.
・Vet Pathol. 2021 58(5):994-1003.
Involvement of Nestin in the Progression of Canine Mammary Carcinoma
H. Yoshimura, M. Moriya, A. Yoshida, M. Yamamoto, Y. Machida, K. Ochiai, M. Michishita, T. Nakagawa, Y. Matsuda, K. Takahashi, S. Kamiya, T. Ishiwata.

 

●イヌの乳腺腫瘍の分類に関する病理学的研究 2010年～現在

1999年のイヌの乳腺腫瘍のWHO分類では、比較的悪性度の高い組織型とされた単純癌（simple carcinoma）は「腺上皮あるいは筋上皮細胞のどちらか一方のみからなる癌」と定義されていました。また腺上皮と筋上皮が混在する腫瘍において、出現する筋上皮成分は異型性をほとんど示さないと考えられていました。しかしその後、腺上皮と筋上皮を免疫染色で鑑別できるいくつかの有用な抗体がみつかり、これまで形態学的に腺上皮と考えられていた異型性の高い細胞の中に、筋上皮由来のものがあることがわかってきていました。

そこで単純癌の一亜型である充実癌（solid carcinoma）と過去に診断されていた72症例を免疫染色結果に基づき再分類したところ、23症例が腺上皮由来の単純性充実癌（真の単純癌）、11症例が筋上皮由来の単純癌（悪性筋上皮腫）、38症例が腺上皮と筋上皮が混在した二相癌であることが判明しました。そして腺上皮由来の単純癌に比べて、筋上皮成分を含む残り二つの型は予後不良を示唆する病理学的指標がはるかに良好でした。このように腺上皮由来の単純性充実癌と筋上皮成分を含む二つの型は、予後を予測するためにも別の分類にする必要があることを提案しました。

これらの成果などにより、現在のイヌの乳腺腫瘍分類では単純癌は「腺上皮のみから成る癌」と定義され、筋上皮のみからなる癌は悪性筋上皮腫に分類されています。また腺上皮と筋上皮の両方に悪性の所見を示す二相性の癌は、癌及び悪性筋上皮腫（carcinoma & malignant myoepithelioma）という分類が設けられています。

・Vet Pathol. 2014 51(6):1090-5.
Differences in indicators of malignancy between luminal epithelial cell type and myoepithelial cell type of simple solid carcinoma in the canine mammary gland
H. Yoshimura, R. Nakahira, T.E. Kishimoto, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi.

 

●ヒトの膵癌における長鎖ノンコーディングRNAの研究 2012年～2020年

長鎖ノンコーディングRNAは蛋白質をコードしないRNAで、以前は役割を持たないと考えられていましたが、近年様々な機能が発見されて注目されています。最も難治性の癌の一つであるヒトの膵癌の培養細胞において、マイクロアレイにより転移に関係する遺伝子発現を調べたところ、長鎖ノンコーディングRNAの一つであるH19が見出されました。またin situ hybridization法によりヒトの膵癌の臨床検体において、特に高グレードの症例でH19の発現がみられることを確認しました。そこでヒト膵癌培養細胞においてH19の発現を上下させたところ、運動能が変化することがわかりました。さらにH19の発現を低下させた細胞株は、免疫不全マウスに移植しても転移巣形成が著しく少ないことがわかりました。このように長鎖ノンコーディングRNA H19はヒト膵癌の転移に重要な役割を果たしていることが示唆されました。

・Lab Invest. 2018 98(6):814-824.
Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis
H. Yoshimura, Y. Matsuda, M. Yamamoto, M. Michishita, K. Takahashi, N. Sasaki, N. Ishikawa, J. Aida, K. Takubo, T. Arai, T. Ishiwata.
・Front Biosci (Landmark Ed). 2018 23:614-625.
Expression and role of long non-coding RNA H19 in carcinogenesis
H. Yoshimura, Y. Matsuda, M. Yamamoto, S. Kamiya, T. Ishiwata.

 

●ペットのジャンガリアンハムスターの乳腺腫瘍の病理学的検索 2008年～2015年

アニメの人気で日本で飼育数が増えたジャンガリアンハムスターには、しばしば乳腺腫瘍が発生します。病理検査に提出されたジャンガリアンハムスターの乳腺腫瘍45症例を病理組織学的に分類したところ腺腫14例、腺癌18例、脂質産生癌1例、腺扁平上皮癌2例、悪性腺筋上皮腫2例、良性混合腫瘍1例、癌肉腫7例といった多様な亜型に分けられました。特に比較的発生頻度の高かった癌肉腫は、風船様細胞（balloon cell）と名付けた特徴的な大型空胞を有する腫瘍細胞が混じる独特の組織像を呈していました。また上皮成分と間葉成分の間に移行像が認められることから、これらは真の癌肉腫ではなく、上皮間葉転換により生じる腫瘍であることが示唆されました。

・Vet Pathol. 2015 Nov;52(6):1227-34.
Characterization of Spontaneous Mammary Tumors in Domestic Djungarian Hamsters (Phodopus sungorus)
H. Yoshimura, N. Kimura-Tsukada, Y. Ono, M. Michishita, K. Ohkusu-Tsukada, Y. Matsuda, T. Ishiwata, K. Takahashi.
・J Vet Diagn Invest. 2010 22(2):305-9.
Lipid-rich carcinoma in the mammary gland of a Djungarian hamster (Phodopus sungorus)
H. Yoshimura, N. Kimura, R. Nakahira, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi.

 

●イヌやネコの乳腺腫瘍における癌間質微小環境の研究 2008年～2015年

癌組織は癌細胞だけではなく間質を構成する細胞や細胞外基質が含まれています。近年、癌細胞は正常な細胞である間質細胞に働きかけ、癌細胞と間質細胞の相互作用により癌が進行していくと考えられるようになってきました。特に癌間質の線維芽細胞は癌関連線維芽細胞（cancer associated fibroblasts; CAFs）と呼ばれて、重要視されています。

イヌの乳腺腫瘍におけるCAFsの出現を調べるために、CAFsがα-smooth muscle actin（αSMA）を発現する筋線維芽細胞の性質を示すことを指標に検討したところ、高悪性度の乳腺腫瘍において間質に筋線維芽細胞が有意に多く出現していることがわかりました。またヒトの癌の浸潤に関わるとされる細胞外基質蛋白であるテネイシン-cを免疫染色で調べたところ、イヌの乳腺腫瘍では間質における発現と基底膜における発現の二つのパターンがあり、間質におけるテネイシン-c発現は高悪性度の乳腺癌で有意に多い一方で、基底膜におけるテネイシン-c発現は良性の乳腺腫瘍でもしばしば認められました。二重免疫染色や、免疫染色-in situ hybridization重染色を実施してテネイシン-cの産生細胞を検討したところ、間質のテネイシン-cは筋線維芽細胞が産生していることがわかりました。このようにイヌの高悪性度の乳腺癌において、間質に出現する筋線維芽細胞がテネイシン-cを産生することで癌の進展に寄与している可能性が示唆されました。一方で、良性の乳腺腫瘍における基底膜領域に発現するテネイシン-cは筋上皮細胞が産生していることが判明し、筋線維芽細胞が産生するテネイシン-cとは別の機能があるのではないかと考えられました。

また同様の検討をネコの乳腺癌でも行ったところ、イヌの乳腺癌と比べて間質における筋線維芽細胞の出現とその周囲における細胞外基質テネイシン-cの発現が明らかに多く、ネコの乳腺癌の悪性度の高さを反映する結果が得られました。

・Vet Pathol. 2011 48(1):313-21.
Increased presence of stromal myofibroblasts and tenascin-C with malignant progression in canine mammary tumors.
H. Yoshimura, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi.
・Histol Histopathol. 2011 26(3):297-305.
Appearance and distribution of stromal myofibroblasts and tenascin-C in feline mammary tumors.
H. Yoshimura, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi.
・Vet Pathol. 2015 52(1):92-6.
Cellular sources of tenascin-C in canine mammary carcinomas.
H. Yoshimura, M. Michishita, K. Ohkusu-Tsukada, Y. Matsuda, T. Ishiwata, Z. Naito, K. Takahashi.

研究キーワード

 3

研究分野

 3

経歴

 9
もっとみる

学歴

 3

委員歴

 7

受賞

 3

主要な論文

 71
  • Hisashi Yoshimura, Kazushi Torikai, Anna Takahashi, Masaki Michishita, Takuya E Kishimoto, Masami Yamamoto, Makoto Haritani, Kimimasa Takahashi, Shinji Kamiya
    Journal of Comparative Pathology 201 28-32 2023年1月  査読有り筆頭著者
  • Hisashi Yoshimura, Maiko Moriya, Ayaka Yoshida, Masami Yamamoto, Yukino Machida, Kazuhiko Ochiai, Masaki Michishita, Takayuki Nakagawa, Yoko Matsuda, Kimimasa Takahashi, Shinji Kamiya, Toshiyuki Ishiwata
    Veterinary Pathology 58(5) 994-1003 2021年5月31日  査読有り筆頭著者
    Nestin, a class VI intermediate filament protein, is known to be expressed in various types of human neoplasms, including breast cancer, and is associated with their progression. However, its expression and role in canine mammary tumors remain unknown. We analyzed nestin expression in canine mammary tumors using in situ hybridization and immunohistochemistry. We also investigated its role in a canine mammary carcinoma cell line using RNA interference. Nestin expression was not observed in luminal epithelial cells of any of the 62 cases of benign mammary lesions examined, although myoepithelial cells showed its expression in most cases. In 16/50 (32%) primary mammary carcinomas and 6/15 (40%) metastases of mammary carcinomas, cytoplasmic nestin expression was detected in luminal epithelial cells. In luminal cells of primary mammary carcinomas, its expression was positively related to several pathological parameters that indicate high-grade malignancy, including histological grading ( P < .01), vascular/lymphatic invasion ( P < .01), Ki-67 index ( P < .01), and metastasis ( P < .05). Immunohistochemistry revealed that nestin expression was related to vimentin expression in mammary carcinomas ( P < .01). This relationship was confirmed using reverse transcription-quantitative polymerase chain reaction using 9 cell lines derived from canine mammary carcinoma ( P < .01). Finally, nestin knockdown in canine mammary carcinoma cells using small interfering RNA inhibited cell proliferation and migration based on WST-8, Boyden chamber, and cell-tracking assays. These findings suggest that nestin may at least partially mediate these behaviors of canine mammary carcinoma cells.
  • Toshihiro Tokiwa, Hisashi Yoshimura (co-first author), Sayoko Hiruma, Yukie Akahori, Ayami Suzuki, Keiko Ito, Masami Yamamoto, Kazunori Ike
    International Journal for Parasitology: Parasites and Wildlife 9 244-247 2019年6月  査読有り
  • Hisashi Yoshimura, Aya Otsuka, Masaki Michishita, Masami Yamamoto, Minori Ashizawa, Manami Zushi, Maiko Moriya, Daigo Azakami, Kazuhiko Ochiai, Yoko Matsuda, Toshiyuki Ishiwata, Shinji Kamiya, Kimimasa Takahashi
    Veterinary pathology 56(3) 389-398 2019年5月  査読有り
    S100A4 (metastasin), a member of the S100 protein family, was initially identified in metastatic cells and is well established as a marker of aggressive human cancer. However, expression and roles of S100A4 in canine mammary tumors have not been clarified. In this study, expression of S100A4 was examined immunohistochemically in normal, hyperplastic, and neoplastic mammary glands of dogs. In all normal and benign lesions, S100A4 was restricted to a few stromal fibroblasts and inflammatory cells. However, in 7 of 57 (12%) of the malignant tumors examined, cytoplasmic and nuclear expression of S100A4 was observed in epithelial tumor cells and stromal cells. Particularly, the frequency of S100A4-positive anaplastic carcinomas was high (4/8 cases, 50%). Next, we established a novel cell line, named NV-CML, from a S100A4-positive canine mammary carcinoma. The cultured NV-CML cells and the tumors that developed in the immunodeficient mice after subcutaneous injection of the cells maintained the immunophenotype of the original tumor, including S100A4 expression. Using this cell line, we examined the cellular functions of S100A4 using RNA interference. S100A4 expression level in NV-CML cells transfected with small interfering RNA (siRNA) targeting canine S100A4 (siS100A4) was reduced to about one-fifth of those with negative-control siRNA (siNeg). Cell proliferation in WST-8 assay and cell migration in Boyden chamber assay were significantly decreased in siS100A4-transfected cells compared with siNeg-transfected cells. These findings suggest that S100A4 may be related to progression of canine mammary carcinomas via its influence on cell growth and motility.
  • Hisashi Yoshimura, Yoko Matsuda, Masami Yamamoto, Masaki Michishita, Kimimasa Takahashi, Norihiko Sasaki, Naoshi Ishikawa, Junko Aida, Kaiyo Takubo, Tomio Arai, Toshiyuki Ishiwata
    Laboratory investigation; a journal of technical methods and pathology 98(6) 814-824 2018年6月  査読有り
    H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold) and represented the only non-protein coding gene among 11 genes identified that were elevated over 10-fold in lung-metastasis-derived pancreatic cancer cells compared with their parental cells using a mouse metastatic model. Subsequently, we further clarified the roles of H19 in pancreatic cancer growth and metastasis using in vitro and in vivo techniques. In situ hybridization showed that H19 was detected in 23 of 139 invasive ductal carcinomas (17%), and that H19 expression positively correlated with higher histological grades (P < 0.0001). Overexpression of H19 in PANC-1 pancreatic cancer cells induced higher motilities, whereas H19 inhibition using shRNA and siRNA showed opposite results; however, cell growth rates were not impacted. Intravenous injection of H19 shRNA vector-transfected PANC-1 cells yielded marked inhibition of metastasis in the liver and lungs of immunodeficient mice. These findings suggest that H19 has important roles in pancreatic cancer metastasis, and that inhibition of H19 represents a novel candidate for pancreatic cancer therapy.
  • Hisashi Yoshimura, Yoko Matsuda, Masami Yamamoto, Shinji Kamiya, Toshiyuki Ishiwata
    Frontiers in Bioscience - Landmark 23(4) 614-625 2018年1月1日  査読有り
    With the recent advent of whole genome and transcriptome sequencing technologies, long noncoding RNAs have been brought into the spotlight in molecular biology. H19 was one of the first reported long non-coding RNAs its expression is high in embryonic organs and absent or greatly reduced in most adult tissues. Accumulating evidence suggests that H19 plays crucial roles in embryogenesis. However, its levels are increased in different cancers, including breast, hepato-gastrointestinal, urological, respiratory, and brain tumors. Although there have been several controversial reports as to whether H19 is oncogenic or tumor-suppressive, most studies have indicated that H19 is associated with growth, migration, invasion, and/or metastasis in many cancers however, its reported functional mechanisms vary among cancer types. Furthermore, serum H19 levels in patients with certain cancers have been suggested to be useful for diagnosis and prognosis. Thus, H19 long non-coding RNA might be a candidate for development of promising therapeutic and diagnostic modalities for several cancers. The purpose of this review is to provide an inclusive report on the functional role of H19 in different cancers.
  • H. Yoshimura, N. Kimura-Tsukada, Y. Ono, M. Michishita, K. Ohkusu-Tsukada, Y. Matsuda, T. Ishiwata, K. Takahashi
    VETERINARY PATHOLOGY 52(6) 1227-1234 2015年11月  査読有り
    Mammary tumors that spontaneously occurred in domestic Djungarian hamsters (Phodopus sungorus) were histologically examined. Forty-five mammary tumors included 14 adenomas, 18 adenocarcinomas, 1 lipid-rich carcinoma, 2 adenoacanthomas, 2 malignant adenomyoepitheliomas, 1 benign mixed tumor, and 7 balloon cell carcinosarcomas. The latter 4 types were newly recognized neoplasms in Djungarian hamsters. The relatively high incidence of spontaneous mammary carcinosarcomas in domestic Djungarian hamsters is intriguing. Carcinosarcomas exhibited anomalous histological features made up of a mixture of glandular cells, polygonal cells (including balloon cells), and sarcomatous spindle cells in varying proportions. Transitional features from glandular cells to polygonal cells and subsequently to sarcomatous spindle cells were observed. Using immunohistochemistry, we observed that glandular cells exhibited an epithelial phenotype (cytokeratin(+)/vimentin(-)), spindle cells exhibited a mesenchymal phenotype (cytokeratin(-)/vimentin(+)), and polygonal cells exhibited an intermediate phenotype (cytokeratin(+)/vimentin(+)). Reduction or loss of beta-catenin expression and gain of S100A4 expression were observed in polygonal and spindle cells. The polygonal cell population included a varying number of characteristic cells that were expanded by large intracytoplasmic vacuoles. Electron microscopy revealed that these balloon cells had large cytoplasmic lumens lined by microvilli. These observations suggest that epithelial-mesenchymal transition may account for the pathogenesis of mammary carcinosarcomas in Djungarian hamsters.
  • H. Yoshimura, M. Michishita, K. Ohkusu-Tsukada, Y. Matsuda, T. Ishiwata, Z. Naito, K. Takahashi
    VETERINARY PATHOLOGY 52(1) 92-96 2015年1月  査読有り
    Tenascin-C (Tn-C) is an extracellular matrix glycoprotein implicated in the progression of several human cancers. In canine mammary carcinomas, accumulation of Tn-C has been recognized in 3 different areas: regions of proliferating myoepithelial cells in complex carcinoma, basement membrane zone in low-grade simple carcinoma, and reactive stroma in high-grade simple carcinoma. To identify the Tn-C synthesizing cells in these areas, we utilized double-labeling immunohistochemistry, branched DNA in situ hybridization, and in situ hybridization-immunohistochemistry double-labeling techniques. In complex carcinomas, Tn-C was generated by proliferating myoepithelial cells. Tn-C in low-grade simple carcinomas was also derived from myoepithelial cells existing as a basal monolayer. However, stromal Tn-C in high-grade carcinomas was mainly synthesized by fibroblasts/myofibroblasts, similar to human breast cancer. Thus, the origin of Tn-C in canine mammary carcinomas differs between low- and high-grade malignancies. The role of myoepithelial cell-generated Tn-C is not yet understood.
  • H. Yoshimura, R. Nakahira, T. E. Kishimoto, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi
    VETERINARY PATHOLOGY 51(6) 1090-1095 2014年11月  査読有り
    Routinely diagnosed simple solid carcinoma (SSC) of the canine mammary gland comprises a heterogeneous group of tumors. Seventy-two cases that had been diagnosed as SSC based on hematoxylin and eosin-stained tissue sections were reclassified immunohistochemically on the basis of myoepithelial markers p63 and -smooth muscle actin, as well as a luminal epithelial marker cytokeratin 8. Only 23 cases (32%) were true SSC, composed only of luminal epithelial cells, whereas 11 cases (15%) were malignant myoepithelioma (MM), composed predominantly of myoepithelial cells, and 38 cases (53%) were biphasic carcinoma (BC), characterized by biphasic proliferation of luminal epithelial and basal/myoepithelial components. As the pathological parameters were compared between the reclassified tumor types, infiltrative potential, vascular/lymphatic invasion, lymph node metastasis, and Ki-67 labeling index were higher in true SSC compared with MM and BC, suggesting that the former may exhibit a poorer prognosis compared with the latter two.
  • Hisashi Yoshimura, Masaki Michishita, Kozo Ohkusu-Tsukada, Kimimasa Takahashi
    HISTOLOGY AND HISTOPATHOLOGY 26(3) 297-305 2011年3月  査読有り
    Myofibroblasts and extracellular matrix protein tenascin-C (Tn-C) are known to be implicated in cancer progression in human cancer. In feline mammary tumors that are a suitable model for human breast cancer, however, little is known about stromal myofibroblasts and no information is available on the expression of Tn-C. Feline samples of normal mammary glands and proliferating mammary lesions were routinely processed and serial sections were cut and immunostained with anti-alpha-smooth muscle actin (alpha-SMA) or Tn-C antibody. Myofibroblasts were not included in the stroma of 90% (9/10) of normal mammary gland tissues, 92% (12/13) of adenosis, and 63% (5/8) of simple adenomas. On the other hand, all 40 simple carcinomas contained stromal myofibroblasts to a varied extent. Tn-C expression was detected in the stroma of 92% (37/40) of carcinomas, and its global distribution almost coincided with that of myofibroblasts. In addition, Tn-C immunoreactivity was occasionally observed in the basement membrane zone around ducts in some cases of normal mammary glands and benign lesions, but barely observed in the stroma. These results suggest that stromal myofibroblasts may be a major cellular source of Tn-C and be involved in malignant progression of feline mammary tumor.
  • H. Yoshimura, M. Michishita, K. Ohkusu-Tsukada, K. Takahashi
    VETERINARY PATHOLOGY 48(1) 313-321 2011年1月  査読有り
    The aims of this study were to determine whether the appearance of stromal myofibroblasts and the expression of tenascin-C (Tn-C) correlate with the grade of malignancy in canine mammary tumors and to determine the main cellular source of Tn-C in these tumors. Single or double immunostaining using antibodies against alpha-smooth muscle actin (alpha-SMA) and Tn-C was performed on serial sections of normal canine mammary glands as well as those with lobular hyperplasia, simple adenoma, and simple carcinoma. Thirty-nine of 42 simple carcinomas (93%) exhibited stromal alpha-SMA-positive myofibroblasts and Tn-C expression. Only 6 of 11 cases of simple adenoma (55%) showed these changes, whereas no changes were observed in normal mammary gland tissue or cases of lobular hyperplasia. The distribution of stromal Tn-C correlated with the presence of myofibroblasts. However, Tn-C immunoreactivity was also occasionally observed in the basement membrane zone surrounding the myoepithelial layer in normal tissue, benign lesions, and tubulopapillary carcinomas. This pattern of staining was not related to the presence of myofibroblasts. The appearance of stromal myofibroblasts and expression of Tn-C were significantly correlated with higher histological grades of malignancy and vascular/lymphatic invasion in simple carcinomas. Stromal myofibroblasts appear to be a major cellular source of Tn-C and play an important role in the development of canine mammary tumors. The Tn-C expressed in the basement membrane zone of normal, hyperplastic, and neoplastic mammary tissue, which is likely produced by neighboring myoepithelial cells, may differ functionally from the Tn-C produced by myofibroblasts.
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