Shah Arpit D, Bouchard Michael J, Shieh Adrian C
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States of America.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2015 Nov 11;10(11):e0142337. doi: 10.1371/journal.pone.0142337. eCollection 2015.
Hepatocellular carcinoma (HCC) is the most common form of liver cancer (~80%), and it is one of the few cancer types with rising incidence in the United States. This highly invasive cancer is very difficult to detect until its later stages, resulting in limited treatment options and low survival rates. There is a dearth of knowledge regarding the mechanisms associated with the effects of biomechanical forces such as interstitial fluid flow (IFF) on hepatocellular carcinoma invasion. We hypothesized that interstitial fluid flow enhanced hepatocellular carcinoma cell invasion through chemokine-mediated autologous chemotaxis. Utilizing a 3D in vitro invasion assay, we demonstrated that interstitial fluid flow promoted invasion of hepatocellular carcinoma derived cell lines. Furthermore, we showed that autologous chemotaxis influences this interstitial fluid flow-induced invasion of hepatocellular carcinoma derived cell lines via the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine 12 (CXCL12) signaling axis. We also demonstrated that mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling affects interstitial fluid flow-induced invasion; however, this pathway was separate from CXCR4/CXCL12 signaling. This study demonstrates, for the first time, the potential role of interstitial fluid flow in hepatocellular carcinoma invasion. Uncovering the mechanisms that control hepatocellular carcinoma invasion will aid in enhancing current liver cancer therapies and provide better treatment options for patients.
肝细胞癌（HCC）是最常见的肝癌形式（约占80%），并且是美国少数发病率呈上升趋势的癌症类型之一。这种具有高度侵袭性的癌症在晚期之前很难被检测到，导致治疗选择有限且生存率较低。关于生物力学力（如组织液流动（IFF））对肝细胞癌侵袭影响的相关机制，目前知之甚少。我们假设组织液流动通过趋化因子介导的自分泌趋化作用增强了肝细胞癌细胞的侵袭。利用三维体外侵袭试验，我们证明了组织液流动促进了肝癌衍生细胞系的侵袭。此外，我们表明自分泌趋化作用通过C-X-C趋化因子受体4型（CXCR4）/C-X-C基序趋化因子12（CXCL12）信号轴影响这种组织液流动诱导的肝癌衍生细胞系的侵袭。我们还证明了丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）信号传导影响组织液流动诱导的侵袭；然而，该途径与CXCR4/CXCL12信号传导是分开的。这项研究首次证明了组织液流动在肝细胞癌侵袭中的潜在作用。揭示控制肝细胞癌侵袭的机制将有助于加强当前的肝癌治疗，并为患者提供更好的治疗选择。
