增高之靜水壓對細胞移動的影響：水通道蛋白活化的角色

細胞周圍環境的機械性質對細胞行為有非常大的影響，腫瘤細胞的其中一個物理特性即是擁有較高的間質液靜水壓力。過高的間質液壓力會導致藥物或抗體的攝取降低，因此造成癌症治療效果不張，但是較高的間質液壓力對癌細胞行為的直接影響我們尚未參透，了解他們之間的關係有助於癌症治療的進步和發展。在本實驗中，我們發展出一套細胞培養系統，能對活體細胞模擬靜水壓力 0 到 20 毫米汞柱，去觀測細胞的行為表現。結果顯示，較高的間質液靜水壓力會增加肺癌細胞的移動速度、攤開的面積、絲狀偽足的數目和單隻細胞的體積大小。相對來說，在正常的肺細胞中，較高的間質液壓力對上述的各種影響和肺癌細胞相比沒有明顯差異，從分子生物的觀點來探討，我們利用西方點墨法觀測到，高間質液靜水壓力透過 ERK1/2 上調 aquaporin-1 進而促進肺癌細胞的移動，但在正常細胞中並無觀察到上述現象。綜合物理和分子生物觀察到的數據結果，我們證明較高的間質液靜水壓力主要是透過 ERK1/2 的磷酸化進而活化AQP1，促使改變面積、絲狀偽足的數目和單隻細胞體積大小，因此可大幅增強肺癌細胞的侵襲力和行動能力。

關鍵字

細胞移動；靜水壓；間質液壓；肺癌細胞；正常肺細胞；水通道蛋白；胞外信號調節激酶

並列摘要

Mechanical cues from microenvironment of cells have a great influence on the cell’s behaviors. Many solid tumors are characterized by high interstitial fluid pressure (IFP), which leads to a reduced uptake of therapeutic drugs or antibodies into the tumors and results in a significant obstacle in cancer therapy. However, whether the increased IFP plays a direct role in behaviors of cancer cells remains unclear. Understanding of relationships between the increased IFP and cancer cell’s behaviors holds the promise of improvement of strategies for cancer therapy. In this work, we developed a cell-culturing system that imposed various hydrostatic pressures (HPs) ranging from 0 to 20 mmHg on cultured cells to simulate the increased IFP and examined the changes in cell’s behaviors. We found that high HP enhances the migration speed, spreading area, number of filopodia, and volume of individual lung cancer cells. By contrast, those changes in normal lung cells were not significant after exposure to high HP. Biochemical studies using western blotting revealed that high HP promoted motility of lung cancer cells via ERK1/2-mediated activation of aquaporin-1 (AQP1), whereas high HP elicited minimal changes in cell motility and morphology in normal lung cells. Our data indicate that high HPs significantly change the invasiveness of lung cancer cells and highlighted the role of ERK1/2-dependent activation of AQP1 in these changes.

並列關鍵字

Cell migration ； Hydrostatic pressures ； Interstitial fluid pressure ； Lung cancer cell ； Lung normal cell ； Aquaporin1 ； ERK1/2

參考文獻

1. McBeath R, P.D., Nelson CM, Bhadriraju K, Chen CS, Cell Shape, Cytoskeletal Tension, and RhoA Regulate Stem Cell Lineage Commitment. Developmental Cell, April 2004. Vol. 6: p. 483–495.

2. Schindler M, A.I., Kamal J, Nur-E-Kamal A, Grafe TH, Young Chung H, Meiners S, A synthetic nanofibrillar matrix promotes in vivo-like organization and morphogenesis for cells in culture. Biomaterials, October 2005. Vol. 26: p. 5624–5631.

3. Guyton AC, C.T., Regulation on interstitial fluid volume and pressure. Annals of the New York Academy of Sciences, August 1968. Vol. 150: p. 537-547.

4. Less JR, P.M., Boucher Y, Borochovitz D, Wolmark N, Jain RK, Interstitial Hypertension in Human Breast and Colorectal Tumors. Cancer Research, November 1992. Vol. 52: p. 6371-6374.

6. Nathanson SD, N.L., Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Annals of Surgical Oncology, July 1994. Vol. 1: p. 333 - 338.

國際替代計量

增高之靜水壓對細胞移動的影響：水通道蛋白活化的角色

全文下載

主題瀏覽