Medical Research Council (MRC) Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hepatology. 2011 Apr;53(4):1192-205. doi: 10.1002/hep.24108.
There is increasing evidence that the physical environment is a critical mediator of tumor behavior. Hepatocellular carcinoma (HCC) develops within an altered biomechanical environment, and increasing matrix stiffness is a strong predictor of HCC development. The aim of this study was to establish whether changes in matrix stiffness, which are characteristic of inflammation and fibrosis, regulate HCC cell proliferation and chemotherapeutic response. Using an in vitro system of "mechanically tunable" matrix-coated polyacrylamide gels, matrix stiffness was modeled across a pathophysiologically relevant range, corresponding to values encountered in normal and fibrotic livers. Increasing matrix stiffness was found to promote HCC cell proliferation. The proliferative index (assessed by Ki67 staining) of Huh7 and HepG2 cells was 2.7-fold and 12.2-fold higher, respectively, when the cells were cultured on stiff (12 kPa) versus soft (1 kPa) supports. This was associated with stiffness-dependent regulation of basal and hepatocyte growth factor-stimulated mitogenic signaling through extracellular signal-regulated kinase, protein kinase B (PKB/Akt), and signal transducer and activator of transcription 3. β1-Integrin and focal adhesion kinase were found to modulate stiffness-dependent HCC cell proliferation. Following treatment with cisplatin, we observed reduced apoptosis in HCC cells cultured on stiff versus soft (physiological) supports. Interestingly, however, surviving cells from soft supports had significantly higher clonogenic capacity than surviving cells from a stiff microenvironment. This was associated with enhanced expression of cancer stem cell markers, including clusters of differentiation 44 (CD44), CD133, c-kit, cysteine-X-cysteine receptor 4, octamer-4 (CXCR4), and NANOG.
Increasing matrix stiffness promotes proliferation and chemotherapeutic resistance, whereas a soft environment induces reversible cellular dormancy and stem cell characteristics in HCC. This has implications for both the treatment of primary HCC and the prevention of tumor outgrowth from disseminated tumor cells. (HEPATOLOGY 2011;).
越来越多的证据表明，物理环境是肿瘤行为的一个关键介质。肝细胞癌（HCC）在改变的生物力学环境中发展，基质硬度增加是 HCC 发展的一个强有力的预测指标。本研究的目的是确定基质硬度的变化是否调节 HCC 细胞的增殖和化疗反应，这些变化是炎症和纤维化的特征。通过使用体外的“力学可调”基质涂覆聚丙烯酰胺凝胶系统，在生理相关的范围内模拟基质硬度，对应于正常和纤维化肝脏中遇到的硬度值。研究发现，基质硬度的增加促进了 HCC 细胞的增殖。 Huh7 和 HepG2 细胞的增殖指数（通过 Ki67 染色评估）在硬（12kPa）和软（1kPa）支撑物上分别增加了 2.7 倍和 12.2 倍。这与细胞外信号调节激酶（ERK）、蛋白激酶 B（PKB/Akt）和信号转导和转录激活因子 3（STAT3）的基础和肝细胞生长因子刺激有丝分裂信号的刚度依赖性调节有关。β1-整合素和粘着斑激酶被发现调节 HCC 细胞增殖的硬度依赖性。在用顺铂治疗后，我们观察到在硬支撑物（生理）上培养的 HCC 细胞的凋亡减少。然而，有趣的是，与硬微环境中的存活细胞相比，来自软支撑物的存活细胞的集落形成能力显著提高。这与癌症干细胞标志物的表达增强有关，包括分化群 44（CD44）、CD133、c-kit、半胱氨酸-X-半胱氨酸受体 4、八聚体-4（CXCR4）和 NANOG。
基质硬度的增加促进了增殖和化疗耐药性，而软环境则在 HCC 中诱导可逆的细胞休眠和干细胞特征。这对原发性 HCC 的治疗和预防播散性肿瘤细胞的肿瘤生长都有影响。（HEPATOLOGY 2011；）。
