Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, 350116, China; Institute of Oceanography, Minjiang University, Fuzhou, 350108, China.
Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, 350116, China.
Pharmacol Res. 2019 Jan;139:535-549. doi: 10.1016/j.phrs.2018.10.020. Epub 2018 Oct 23.
A perfect microenvironment facilitates the activated circulating tumor cells (CTCs) to spark the adhesion-invasion-extravasation metastatic cascade in their premetastatic niche. Platelet-CTC interaction contributes to the progression of tumor malignancy by protecting CTCs from shear stress and immunological assault, aiding CTCs entrapment in the capillary bed, enabling CTCs to successfully exit the bloodstream and enter the tissue, inducing epithelial-mesenchymal-like transition (EMT), and assisting in the establishment of metastatic foci. To prevent the cascade from sparking, we show that, the multifunctional S-nitrosocaptopril (CapNO) acts on both CTCs and platelets to interrupt platelet/CTCs interplay and adhesion to endothelium, thus inhibiting CTC-based pulmonary metastasis in vivo. The activated platelets cloak cancer HT29 cells, resulting in HT29-exhibiting platelet biomarkers CD61 and P-selectin positive. CapNO inhibits both sialyl Lewis (Slex) expression on HT29 and ADP-induced activation of platelets through P-selectin- and GPIIb/IIIa-dependent mechanisms, confirmed by the corresponding antibody assay. CapNO inhibits platelet- or interleukin (IL)-1β-mediated adhesion between HT29 and endothelial cells, and micrometastatic formation in the lungs of immunocompetent syngeneic mouse models. CapNO have also shown the effects of vasodilation, anticoagulation, inhibition of matrix metalloproteinase-2 (MMP2) expression on cancer cells, and inhibition of cell adhesion molecules (CAMs) expression on vascular endothelium. Due to a series of the beneficial effects of CapNO, CTCs remain exposed to the hostile bloodstream environment and are vulnerable to death induced by shear stress and immune elimination. This new discovery provides a basis for CapNO used for cancer metastatic chemoprevention, and might suggest regulation of the CTCs bloodstream microenvironment as a new avenue for cancer metastatic prevention.
一个理想的微环境有利于激活的循环肿瘤细胞（CTCs）在其转移前生态位中引发黏附-侵袭-外渗转移级联反应。血小板与 CTC 的相互作用通过保护 CTC 免受切应力和免疫攻击、帮助 CTC 被困在毛细血管床中、使 CTC 能够成功地离开血液进入组织、诱导上皮-间充质转化（EMT）以及协助转移灶的建立，促进肿瘤恶性进展。为了防止级联反应的发生，我们表明，多功能 S-亚硝基巯基丙酰基半胱氨酸（CapNO）作用于 CTC 和血小板，中断血小板/CTCs 的相互作用和与内皮的黏附，从而抑制体内 CTC 诱导的肺转移。激活的血小板掩盖了癌症 HT29 细胞，导致 HT29 表现出血小板生物标志物 CD61 和 P-选择素阳性。CapNO 通过 P-选择素和 GPIIb/IIIa 依赖性机制抑制 HT29 上的唾液酸化 Lewis（Slex）表达和 ADP 诱导的血小板激活，这通过相应的抗体检测得到证实。CapNO 抑制血小板或白细胞介素（IL）-1β介导的 HT29 与内皮细胞之间的黏附，以及免疫活性同基因小鼠模型肺部的微转移形成。CapNO 还显示出血管舒张、抗凝、抑制基质金属蛋白酶-2（MMP2）表达对癌细胞的作用，以及抑制血管内皮细胞上细胞黏附分子（CAM）的表达。由于 CapNO 的一系列有益作用，CTCs 仍然暴露于恶劣的血流环境中，容易受到剪切应力和免疫消除诱导的死亡。这一新发现为 CapNO 用于癌症转移化学预防提供了依据，并可能提示调节 CTCs 血流微环境作为癌症转移预防的新途径。
