Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor anglogenesis in transgene-induced mammary tumor development
Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor anglogenesis in transgene-induced mammary tumor development
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DOI：
10.1158/0008-5472.can-07-2950
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发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Dong, Dezheng;Ni, Min;Lee, Amy S.
未折叠蛋白反应（unfolded protein response，UPR）是一种进化上保守的机制，能够激活促凋亡和存活途径，使真核细胞适应内质网（endoplasmic reticulum，ER）应激。尽管UPR与肿瘤发生有关，但其在内源性癌症中的确切作用仍不清楚。一个主要的UPR保护性反应是ER伴侣GRP 78/BiP的诱导，其在多种肿瘤中以高水平表达，并在增殖和休眠癌细胞中赋予耐药性。为了确定GRP 78在原位产生的肿瘤中的生理作用及其对正常器官的抑制的后果，我们在GRP 78杂合小鼠中使用乳腺癌的遗传模型，其中GRP 78表达水平降低约一半，模拟实现GRP 78表达的部分抑制的抗GRP 78剂。在这里，我们报告Grp 78杂合性对器官发育或抗体产生没有影响，但延长了潜伏期，并显着阻碍肿瘤生长。我们的研究结果揭示了GRP 78介导的肿瘤进展的三个主要机制：增强肿瘤细胞增殖，保护细胞凋亡和促进肿瘤血管生成。重要的是，尽管Grp 78杂合小鼠中GRP 78的部分减少显著降低了肿瘤微血管密度，但它对正常器官的血管系统没有影响。我们的研究结果表明，一个关键的UPR目标GRP 78是最好的病理生理条件，如肿瘤增殖，生存和血管生成，强调其作为一个新的治疗目标的双重抗肿瘤和抗血管生成活性的潜在价值。
The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.