肥満と大腸癌発癌の関係性は疫学的に証明され, 肥満関連大腸癌の存在が示唆されている。しかしながら, 発癌の分子生物学的メカニズムは明らかでない。われわれはこれまでに, サイトカインが肥満関連大腸癌に重要な役割を果たすことを明らかにしてきた。
今回のわれわれの研究成果から, 大腸粘膜においてEph-ephrin signalが肥満状態を引き金に発現が変化することで, 発癌, そしてその後の癌の増殖に強く関与していることと, 肥満状態においては炎症性サイトカインが腸上皮のcrypt構造を変化させ, 癌化に関与していることが証明された。
Excess body weight and obesity are great concern throughout the world and are reported to associate with increase in risk of colorectal cancer. In normal intestinal mucosa, progenitor cells generated from stem cell located in bottom of crypt differentiate and repopulate to the direction of lumen, which are regulated by EPH-ephrin signals. We elucidated following results. In obesity model mice, tumor numbers significantly increased compared with control mice and apoptosis assay revealed there were less apoptotic cell in normal mucosa in both obesity mice and patients with obesity. In immunohistological analysis of normal mucosa, ephrin B1 expression was down-regulated in obesity mice and patients with obesity.
Obesity and its inflammation suggested to induce down-regulation of ephrin signal and leads to mutation of crypt-villus axis, which results in increase of oncogenesis. In addition, in obese state cancer proliferation is promoted concomitantly with silencing of EPH-B2.
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