A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth
A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth
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DOI：
10.1038/sj.onc.1207595
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发表时间：
2004-06-03
期刊：
影响因子：
8
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Martin, SS;Ridgeway, AG;Leder, P
许多小鼠乳腺癌模型形成很少转移的大的原发性肿瘤。侵袭性转移模型表达同时影响生长和凋亡途径的癌蛋白。为了确定凋亡抵抗的作用，并模拟肿瘤细胞在转移性播散过程中所面临的挑战，我们专注于细胞形状变化诱导的凋亡。在非致瘤性人10A-Ras乳腺上皮细胞中，用Latrunculin-A抑制肌动蛋白聚合导致细胞变圆并在数小时内死亡。相比之下，MDA-MB-231转移性乳腺肿瘤细胞抵抗LA诱导的死亡，并且尽管细胞变圆仍存活数天。用MDA-MB-231逆转录病毒表达文库感染10A-Ras细胞，并用Latrunculin-A筛选，反复鉴定Bcl-xL是细胞凋亡依赖性死亡的抑制因子。虽然Bcl-xL增强了转移性乳腺肿瘤细胞系的扩散，但尚未直接比较乳腺中和转移期间凋亡抗性对肿瘤生长的不同影响。我们发现Bcl-xL在小鼠乳腺上皮细胞中的过表达不会诱导原发性肿瘤形成或增强乳腺环境中MEK诱导的肿瘤发生。然而，它强烈增强了转移潜力。Bcl-xL的这些结果提供了新的证据，即孤立的凋亡抗性可以增加转移潜力，但仍然被基于乳腺肿瘤生长的测定所忽视。
Many mouse models of breast cancer form large primary tumors that rarely metastasize. Models with aggressive metastasis express oncoproteins that simultaneously affect growth and apoptosis pathways. To define the role of apoptotic resistance and to model a challenge faced by tumor cells during metastatic dissemination, we focused on apoptosis induced by cell shape change. Inhibiting actin polymerization with Latrunculin-A causes cell rounding and death within hours in nontumorigenic human 10A-Ras mammary epithelial cells. In contrast, MDA-MB-231 metastatic breast tumor cells resist LA-induced death, and survive for days despite cell rounding. Infecting 10A-Ras cells with a MDA-MB-231 retroviral expression library, and selecting with Latrunculin-A repeatedly identified Bcl-xL as a suppressor of cytoskeleton-dependent death. Although Bcl-xL enhances the spread of metastatic breast tumor cell lines, the distinct effects of apoptotic resistance on tumor growth in the mammary gland and during metastasis have not been compared directly. We find that Bcl-xL overexpression in mouse mammary epithelial cells does not induce primary tumor formation or enhance MEK-induced tumorigenesis within the mammary gland environment. However, it strongly enhances metastatic potential. These results with Bcl-xL provide novel evidence that isolated apoptotic resistance can increase metastatic potential, but remain overlooked by assays based on breast tumor growth.