Tumor Growth Pressure

先日のシンポジウムでもう一つ、うわっと思ったのはパリのDr. EFによるコレ。

Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.  Nature 523: 92–95.

The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch[+]Apc[+/1638N] mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and β-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.

そういやこの論文、ちらっとアブストは見た記憶があるけどちゃんと読んでいなかった。ultramagnetic liposomesを利用して、mouse colon tissueに腫瘍形成初期に生じていると考えられるようなmechanical pressureを与えると、その物理的ストレスが刺激となってRet/β-cateninのactivationが起こり、それを介してtumor growthが促されるという話。つまり、組織内でtumor growthが生じると、そのモリモリ増え始めた腫瘍細胞達がその周囲の細胞をぎゅうぎゅう押すことになるわけだけども、押される側の正常な細胞までそのストレスによってtumorousになっちゃうという、このmechanotransductionを介したpositive feedback loopがどんどんpropagateしていくことにより腫瘍組織が広がっていくのであろうと。ほんまかいな、というようなスゴイ話。