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日本におけるイヌの消化管上皮性腫瘍の発生動向と病理発生解明に関する研究

斎藤, 翼 東京大学 DOI:10.15083/0002008321

2023.12.27

概要





の 結













斎藤



ヒトの消化管腫瘍では、腫瘍抑制因子である APC(Adenomatous polyposis coli)
が腫瘍発生に関与するとされる。さらに APC と共に Beta-catenin は WNT/betacatenin シグナル伝達経路の主要な構成要素であり、多くの腸上皮性腫瘍では
APC もしくは CTNNB1(beta-catenin)遺伝子の変異により、WNT 経路が恒常的に
活性化しているとされる。このようなヒトの消化管腫瘍の発がん機構を研究す
る上でモデル動物は有用であり、その候補としてイヌが注目されている。近年、
検査技術の進歩によりイヌやネコ等の伴侶動物における消化管内視鏡検査やポ
リペクトミーの頻度が増え、消化管病変が病理診断に供される機会が増加して
いる。しかし、動物の消化管腫瘍に関する系統だった研究は非常に限られている。
一方、イヌの消化管上皮性腫瘍の一部には APC 遺伝子変異が認められるなど、
ヒトとの類似点が認められるが、詳細な研究は少ない。そこで申請者は、イヌの
上皮性消化管腫瘍に着目し、その特徴を主に病理学的手法により検討した。
提出された博士論文は三章より構成される。第一章では、イヌの消化管上皮性
腫瘍を世界保健機構(WHO)の組織学分類及び肉眼的特徴に基づく polypoid
growth/non-polypoid growth(PG/NPG)の分類に従いそれぞれ分類し、さらに犬
種、年齢、性別、発生部位、浸潤/転移の有無など、その発生動向を精査した。そ
の結果、WHO 組織学分類では、腺腫、腺癌が過半数を占め、未分化癌や粘液腺
癌の発生は稀であった。PG/NPG 分類では過半数が PG 型であった。NPG 型の腫
瘍では全例で浸潤/転移が認められた。ヒトの PG 型は Adenoma-carcinoma
sequence によって、NPG 型は de novo に発生した腫瘍とされている。この仮説で
は APC や CTNNB1(beta-catenin)など、複数の遺伝子変異が多段階的に蓄積す
ることで良性腫瘍から悪性腫瘍が発生すると考えられているが、de novo 癌はそ
の初期病変の検出の難しさから詳細な発生機序は不明である。しかし浸潤や転
移を高頻度で示す他、進展が急速であり短期間で大型の進行癌となるという特
徴は、イヌの消化管上皮性腫瘍と類似点が多い。以上より PG/NPG 分類は、悪性
度や腫瘍発生機序を理解する上で重要な所見と推察している。一方、犬種別の腫
瘍発生については、ジャック・ラッセル・テリアにおける腫瘍発生が多く、大腸
腫瘍に限定するとミニチュア・ダックスフンドにおける発生が多い傾向が確認
された。

第二章では、大腸腫瘍が最も多く認められたミニチュア・ダックスフンドに限
定してその腫瘍発生機序が検討された。本犬種には炎症性ポリープ
(Inflammatory Polyps of Miniature Dachshunds, IPMD)が極めて多く発生するが、
本病態と腫瘍発生との関連は不明であった。そこで内視鏡検査で結直腸に隆起
性病変を認めた症例について病理組織学検査を行うとともに、その臨床歴を精
査され、IPMD と腫瘍発生との関連性が検討された。組織学的に IPMD の病巣中
には、異型上皮細胞や上皮細胞の塊状増殖がみられ、一部の症例では腫瘍病変が
観察された。さらに IPMD 症例の約半数例は、大腸に病変(IPMD/腺腫/腺癌)が
再発した。その過半数は IPMD を伴う腫瘍病変であり、腫瘍と IPMD は同一組
織から発生したことが示唆された。次に IPMD から腫瘍に進展する機序を明ら
かにする目的で APC、beta-catenin 及び p53 について免疫組織化学的に検索した。
Beta-catenin 及び p53 の核陽性率は、病態の進行に伴い有意な増加を示した。さ
らに、beta-catenin 核陽性を示す領域では APC の染色性の低下が認められたこと
から、APC/beta-catenin の発現異常が腫瘍発生及び病態の進行へ関与している可
能性が示された。
第三章では、すべての犬種の消化管腫瘍組織を対象に beta-catenin および p53
の関与が免疫組織学的に検討された。その結果、beta-catenin の反応性は、胃と大
腸の腫瘍で異なり、特に大腸における上皮性腫瘍の発生に関与していることが
示唆された。さらに大腸腫瘍の beta-catenin 反応性は、PG 腺癌の全例で核陽性所
見が認められたのに対し、印環細胞癌、粘液腺癌、未分化癌を含む NPG 腺癌で
は 1 例を除きすべて陰性であった。これら NPG 腺癌のすべての症例には浸潤/転
移病変が認められ増殖パターンの差異が腫瘍発生機序や悪性度に関連すること
が示唆された。以上の結果よりイヌの PG 腺癌では adenoma-carcinoma sequence
による発がん機序、一方 NPG 腺癌では de novo 癌等の APC/beta-catenin 以外の要
因を介した発がん機序により発生すると考えられた。
以上本論文の一連の研究成果は、イヌの消化管上皮性腫瘍の臨床および病理
的特徴を理解し、その診断治療を行うための基礎情報として活用されるものと
期待される。またヒトとイヌの消化管上皮性腫瘍の類似点及び相違点、特に
PG/NPG 型の増殖形態およびその腫瘍細胞の免疫組織学的特徴は、ヒトとイヌの
消化管腫瘍の発生機序を理解する上で、有用な比較病理学的情報を供与するも
のと評価される。これらの学術情報は、医学分野および獣医分野における消化管
腫瘍の研究に寄与するところが少なくない。よって、本論文は博士(獣医学)の
学位請求論文として合格と認められる。

この論文で使われている画像

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