Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells.
Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells.
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癌细胞之间或与肿瘤微环境和/或转移前部位的健康细胞之间的细胞间通讯在癌症的进展和转移中起重要作用。除了配体-受体信号复合物外，细胞外囊泡（EVs）在组织稳态和癌症等疾病中都是细胞间通讯的新型介质。ev介导的影响形态特征和细胞运动的分子活动从高转移性SW620细胞转移到非转移性SW480细胞是一个很好的体外例子，可以说明结直肠癌恶性程度的增加导致其转化和侵袭行为。为了阻断由EVs促进的细胞间通讯，我们最近开发了一种针对人CD9 tetraspanin的单价Fab片段抗体，并显示其在阻断黑色素瘤细胞来源的EVs内化及其货物蛋白向受体细胞的核转移方面的有效性。本研究采用SW480/SW620模型研究抗cd9 Fab抗体的抗癌潜力。我们首先证明了大多数来自SW620细胞的ev含有CD9，使它们成为潜在的靶标。然后，我们发现抗cd9 Fab抗体，而不是相应的二价抗体，阻止EVs从SW620细胞内化到SW480细胞，从而抑制其表型转化，即从间质样形态转变为具有膜泡的圆形变形虫样形状，从而阻止细胞迁移增加。利用抗cd9 Fab抗体阻断ev介导的肿瘤生态位细胞间通讯，结合直接靶向癌细胞，可能会导致新的抗癌治疗策略的发展。
Intercellular communication between cancer cells themselves or with healthy cells in the tumor microenvironment and/or pre-metastatic sites plays an important role in cancer progression and metastasis. In addition to ligand–receptor signaling complexes, extracellular vesicles (EVs) are emerging as novel mediators of intercellular communication both in tissue homeostasis and in diseases such as cancer. EV-mediated transfer of molecular activities impacting morphological features and cell motility from highly metastatic SW620 cells to non-metastatic SW480 cells is a good in vitro example to illustrate the increased malignancy of colorectal cancer leading to its transformation and aggressive behavior. In an attempt to intercept the intercellular communication promoted by EVs, we recently developed a monovalent Fab fragment antibody directed against human CD9 tetraspanin and showed its effectiveness in blocking the internalization of melanoma cell-derived EVs and the nuclear transfer of their cargo proteins into recipient cells. Here, we employed the SW480/SW620 model to investigate the anti-cancer potential of the anti-CD9 Fab antibody. We first demonstrated that most EVs derived from SW620 cells contain CD9, making them potential targets. We then found that the anti-CD9 Fab antibody, but not the corresponding divalent antibody, prevented internalization of EVs from SW620 cells into SW480 cells, thereby inhibiting their phenotypic transformation, i.e., the change from a mesenchymal-like morphology to a rounded amoeboid-like shape with membrane blebbing, and thus preventing increased cell migration. Intercepting EV-mediated intercellular communication in the tumor niche with an anti-CD9 Fab antibody, combined with direct targeting of cancer cells, could lead to the development of new anti-cancer therapeutic strategies.
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DOI：
10.1083/jcb.200802081
发表时间：
2008-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fackler OT;Grosse R
通讯作者：
Grosse R
影响因子：
5.6
作者：
Depciuch, Joanna;Klebowski, Bartosz;Baran, Jarek
通讯作者：
Baran, Jarek
影响因子：
11.2
作者：
Bobrie, Angelique;Krumeich, Sophie;Thery, Clotilde
通讯作者：
Thery, Clotilde
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
影响因子：
50.3
作者：
Becker A;Thakur BK;Weiss JM;Kim HS;Peinado H;Lyden D
通讯作者：
Lyden D