CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance
CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance
复制标题
DOI：
10.1158/1541-7786.mcr-08-0207
复制
发表时间：
2009-02-01
影响因子：
5.2
通讯作者：
Zoeller, Margot
中科院分区：
文献类型：
--
作者：
Klingbeil, Pamela;Marhaba, Rachid;Zoeller, Margot
CD 44是由一个基因通过选择性剪接产生的具有相当大的结构和功能多样性的蛋白质大家族。因此，CD 44变体同种型（CD 44 v）的过表达与癌细胞的转移扩散有因果关系。为了研究潜在的机制，建立了含有高转移性大鼠腺癌细胞系BSp 73 ASML（ASML（wt））的CD 44亚型（CD 44 V（kd））的外显子v7缺失的稳定敲低克隆。ASML-CD 44 v（kd）克隆在足垫内应用后几乎不形成肺转移，并且淋巴结中的转移负荷显著降低。虽然在降低的水平下，但在ASML-CD 44 v（kd）细胞（ASML-CD 44 v（rsc））中拯救CD 44 v表达恢复了转移潜力。观察到ASML（wt）、ASML-CD 44 v（kd）和ASML-CD 44 vrsc克隆的以下主要差异：（a）ASML（wt）细胞以CD 44 v依赖性方式产生和组装基质，其支持整联蛋白介导的粘附并有利于存活。ASML-CD 44 v（kd）细胞中丢失了该特征。(b)CD 44 v交联引发ASML（wt）细胞中的磷脂酰肌醇3-激酶/Akt活化。因此，ASML-CD 44 v（kd）细胞的凋亡抗性显著降低。ASML-CD 44 vrsc细胞恢复产生粘附基质但不产生凋亡抗性的能力。这些数据证明了CD 44 v对转移形成的2倍效应：CD 44 v介导的基质形成对于继发部位的沉降和生长至关重要，而细胞凋亡抗性支持转移形成的功效。(Mol Cancer Res 2009;7（2）：168-79）
CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44V(kd)) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML(wt)) were established. ASML-CD44v(kd) clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44v(kd) cells (ASML-CD44v(rsc)) restores the metastatic potential. The following major differences in ASML(wt), ASML-CD44v(kd), and ASML-CD44vrsc clones were observed: (a) ASML(wt) cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44v(kd) cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASML(wt) cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44v(kd) cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44vrsc cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation. (Mol Cancer Res 2009;7(2):168-79)