Hematogenous Metastasis: Roles of CD44v and Alternative Sialofucosylated Selectin Ligands
Hematogenous Metastasis: Roles of CD44v and Alternative Sialofucosylated Selectin Ligands
复制标题
DOI：
10.1007/978-1-4419-7877-6_32
复制
发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Thomas, Susan N.
中科院分区：
文献类型：
--
作者：
Konstantopoulos, Konstantinos;Thomas, Susan N.
P-选择素是一种跨膜糖蛋白，表达于活化的内皮细胞和血小板上，介导宿主细胞-肿瘤细胞粘附，与血行转移过程相关。P-选择素在转移过程中的直接作用的最令人信服的证据是在结肠癌细胞模型中，与野生型对照相比，P-选择素缺陷小鼠中的转移受到显著抑制[1-3]。沿着这些路线，从结肠癌细胞表面酶促去除P-选择素配体导致实验转移的显著减少[1]。尽管先前已在肿瘤细胞系中鉴定出结合P-选择素的分子[4-6]，但其功能作用和生物学意义尚未得到证实。正如文献[7]中所适当论证的，必须区分在体外静态条件下可以与P-选择素结合的分子和在体内流体动力学条件下与P-选择素相互作用的功能配体。通过鉴定结肠癌细胞上的功能性P-选择素配体，使用由生物工程工具和当代生物化学和分子生物学技术组成的综合方法，我们为工程设计选择性阻断肿瘤细胞配体结合功能从而干扰转移扩散的新型治疗剂提供了指南。这种策略可以提供特异性抗转移功效，而不损害其他重要的P-选择素介导的生理过程[8，9]。或者，这些分子可以用于靶向药物递送方法，其目标是选择性或优先从血管系统中根除结肠癌细胞。
P-selectin, expressed on activated endothelial cells and platelets, is a transmembrane glycoprotein (GP) that mediates, among others, host cell–tumor cell adhesion relevant to the process of hematogenous metastasis. The most compelling evidence for a direct role of P-selectin in the metastatic process is the pronounced inhibition of metastasis in P-selectin-deficient mice compared to wild-type controls in a colon carcinoma cell model [1–3]. Along these lines, enzymatic removal of P-selectin ligands from the colon carcinoma cell surface results in a pronounced reduction of experimental metastasis [1]. Although molecules that bind P-selectin have previously been identified in tumor cell lines [4–6], their functional roles and biological significance have not been substantiated. As has been appropriately argued in the literature [7], distinctions must be made between molecules that can bind to P-selectin under static conditions in vitro, and functional ligands that do interact with P-selectin under fluid dynamic conditions in vivo. By identifying the functional P-selectin ligand(s) on colon carcinoma cells, using an integrated approach consisting of bioengineering tools and contemporary biochemistry and molecular biology techniques, we provide guidelines for engineering novel therapeutic agents that selectively block tumor cell ligand binding function and thus interfere with metastatic spread. Such a strategy may offer specific antimetastatic efficacy without impairing other important P-selectin-mediated physiological processes [8, 9]. Alternatively, these molecules could be utilized in a targeted drug-delivery approach, which would aim at selectively or preferentially eradicating colon carcinoma cells from the vasculature.