In situ force mapping of mammary gland transformation.
In situ force mapping of mammary gland transformation.
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DOI：
10.1039/c1ib00043h
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Weaver VM
中科院分区：
文献类型：
--
作者：
Lopez JI;Kang I;You WK;McDonald DM;Weaver VM
肿瘤进展的特点是组织逐渐变硬。组织僵硬对癌症的重要性已得到认可，但特定组织元素对肿瘤僵硬的贡献及其生理意义仍不清楚。我们在活体和快速冷冻的荧光标记的乳腺组织中进行了高分辨率原子力显微镜压痕，以探索与PYMT小鼠乳腺肿瘤发展相关的组织硬化的起源。肿瘤上皮、肿瘤相关的血管和细胞外基质在乳腺从正常向浸润性癌转变的过程中都是导致乳腺硬化的原因。与细胞外基质僵硬改变细胞张力的概念一致，我们发现分离的转化的乳腺上皮细胞本质上比正常乳腺上皮细胞僵硬，但原位恶性上皮细胞比分离的乳腺肿瘤细胞坚硬得多。此外，使用原位玻璃化冷冻方法，我们确定随着组织从正常到良性再到侵袭性状态的演变，与上皮相邻的细胞外基质逐渐变硬。重要的是，我们还注意到，在转化的组织中，无论是在上皮细胞还是在肿瘤相关的新生血管中，都存在着显著的机械异质性。肿瘤核心内的血管床实质上比侵袭前沿被最坚硬的细胞外基质包围的大的开放血管更坚硬。这些发现阐明了单个乳腺组织元素对癌症组织生物力学格局改变的贡献，并强调了在保持天然相互作用的条件下研究癌细胞进化的重要性。
Tumor progression is characterized by an incremental stiffening of the tissue. The importance of tissue rigidity to cancer is appreciated, yet the contribution of specific tissue elements to tumor stiffening and their physiological significance remains unclear. We performed high-resolution atomic force microscopy indentation in live and snap-frozen fluorescently labeled mammary tissues to explore the origin of the tissue stiffening associated with mammary tumor development in PyMT mice. The tumor epithelium, the tumor-associated vasculature and the extracellular matrix all contributed to mammary gland stiffening as it transitioned from normal to invasive carcinoma. Consistent with the concept that extracellular matrix stiffness modifies cell tension, we found that isolated transformed mammary epithelial cells were intrinsically stiffer than their normal counterparts but that the malignant epithelium in situ was far stiffer than isolated breast tumor cells. Moreover, using an in situ vitrification approach, we determined that the extracellular matrix adjacent to the epithelium progressively stiffened as tissue evolved from normal through benign to an invasive state. Importantly, we also noted that there was significant mechanical heterogeneity within the transformed tissue both in the epithelium and the tumor-associated neovasculature. The vascular bed within the tumor core was substantially stiffer than the large patent vessels at the invasive front that are surrounded by the stiffest extracellular matrix. These findings clarify the contribution of individual mammary gland tissue elements to the altered biomechanical landscape of cancerous tissues and emphasize the importance of studying cancer cell evolution under conditions that preserve native interactions.
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