The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions.
The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions.
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DOI：
10.1158/2159-8290.cd-11-0239
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发表时间：
2012-08
期刊：
影响因子：
28.2
通讯作者：
Weinberg RA
中科院分区：
文献类型：
--
作者：
Shibue T;Brooks MW;Inan MF;Reinhardt F;Weinberg RA
已经外渗到组织实质中的播散性癌细胞必须与其细胞外基质（ECM）组分有效地相互作用，以便存活、增殖并形成肉眼可见的转移。使这种相互作用的生物化学和细胞生物学机制仍然知之甚少。我们发现，癌细胞渗出到肺实质形成细长的含整合素β1的粘附斑，通过活化粘着斑激酶（FAK）使这些细胞增殖。这些斑块起源于丝状伪足样突起（FLP）形成后才出现，FLP沿着其轴携带整合素β1。细胞凋亡调节蛋白Rif和mDia2对这些突起的形成起关键作用，从而使外渗的癌细胞增殖。因此，FLP的形成代表了随后发生肉眼可见转移的关键限速步骤。
Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix (ECM) components in order to survive, proliferate and form macroscopic metastases. The biochemical and cell-biological mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated, integrin β1-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase (FAK). These plaques originate in and appear only after the formation of filopodium-like protrusions (FLPs) that harbor integrin β1 along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells. Hence, the formation of FLPs represents a critical rate-limiting step for the subsequent development of macroscopic metastases.