Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia.
Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide 5001, SA, Australia.
Int J Mol Sci. 2017 Nov 1;18(11):2293. doi: 10.3390/ijms18112293.
Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes, with poor overall survival and quality of life. Limited targeted treatment strategies exist due to restricted knowledge of pathogenic pathways. Vasculogenic mimicry (VM) is a newly described phenomenon associated with increased aggressiveness in other malignancies, and has been characterized in MM. Normal mesothelium expresses aquaporin 1 (AQP1) and retained expression has been associated with improved survival in MM. AQP1 is expressed by normal vascular endothelium and is involved in mediating MM cell motility and proliferation. We investigated the role of AQP1 in VM, and its interaction with the pro-angiogenic factor vascular endothelial growth factor A (VEGFA), which is variably expressed in MM. Matrigel VM assays were performed using NCI-H226 and NCI-H28 MM cell lines and primary cells in hypoxia and normoxia. The synthetic blocker AqB050 and siRNA were used to inhibit AQP1, and bevacizumab was used to inhibit VEGF. Inhibition of AQP1 resulted in increased VEGFA secretion by MM cells and reduced VM in MM cell lines in hypoxia but not normoxia. No change in VM was seen in MM primary cells. Combined inhibition of AQP1 and VEGF had no effect on VM in normoxia. In a heterotopic xenograft mouse model, AqB050 treatment did not alter vessel formation. AQP1 may interact with VEGFA and play a role in VM, especially under hypoxic conditions, but the heterogeneity of MM cells may result in different dominant pathways between patients.
恶性间皮瘤（MM）是一种侵袭性的浆膜恶性肿瘤，整体存活率和生活质量都很差。由于对发病途径的了解有限，目前只有有限的靶向治疗策略。脉管生成拟态（VM）是一种与其他恶性肿瘤侵袭性增加相关的新描述现象，已在 MM 中得到了描述。正常间皮表达水通道蛋白 1（AQP1），并且保留表达与 MM 中的存活率提高有关。AQP1 由正常血管内皮表达，并参与调节 MM 细胞的运动和增殖。我们研究了 AQP1 在 VM 中的作用，以及它与血管内皮生长因子 A（VEGFA）的相互作用，VEGFA 在 MM 中表达情况不同。使用 NCI-H226 和 NCI-H28 MM 细胞系和低氧和常氧条件下的原代细胞进行了 Matrigel VM 测定。使用合成抑制剂 AqB050 和 siRNA 抑制 AQP1，并用 bevacizumab 抑制 VEGF。抑制 AQP1 导致 MM 细胞中 VEGFA 分泌增加，并降低了 MM 细胞系在低氧但非常氧条件下的 VM，但在 MM 原代细胞中未观察到 VM 变化。在常氧条件下，AQP1 和 VEGF 的联合抑制对 VM 没有影响。在异位异种移植小鼠模型中，AqB050 治疗未改变血管形成。AQP1 可能与 VEGFA 相互作用，在 VM 中发挥作用，特别是在低氧条件下，但 MM 细胞的异质性可能导致不同患者之间存在不同的优势途径。
