A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis.
A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis.
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DOI：
10.1158/0008-5472.can-10-3151
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Lee AS
中科院分区：
文献类型：
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作者：
Dong D;Stapleton C;Luo B;Xiong S;Ye W;Zhang Y;Jhaveri N;Zhu G;Ye R;Liu Z;Bruhn KW;Craft N;Groshen S;Hofman FM;Lee AS
GRP 78/BiP是一种多功能蛋白，其在内质网（ER）蛋白加工、蛋白质质量控制、维持ER稳态以及控制细胞信号传导和活力中起主要作用。之前，使用转基因诱导的乳腺肿瘤模型，我们证明了Grp 78杂合性不仅通过抑制肿瘤细胞增殖和促进细胞凋亡来阻止癌症生长，Grp 78 +/−小鼠表现出内源性乳腺肿瘤微血管密度（MVD）的显著降低（70%），而对正常器官的MVD没有影响。这一观察结果表明，GRP 78可以关键地调节肿瘤微环境内宿主脉管系统的功能。在这份报告中，我们询问了GRP 78在肿瘤微环境中的作用。在小鼠肿瘤模型中，将野生型，同基因乳腺肿瘤细胞注射到宿主中，我们发现Grp 78 +/−小鼠在肿瘤生长的早期而不是晚期抑制肿瘤生长和血管生成。Grp 78 +/−小鼠中野生型、同基因黑色素瘤细胞的转移性病变的生长被有效抑制。我们在宿主内皮细胞中建立了GRP 78的条件性杂合敲除，并证明了肿瘤血管生成和转移生长的严重减少，对正常组织MVD的影响最小。此外，在永生化的人内皮细胞中GRP 78表达的敲低表明GRP 78是通过调节细胞增殖、存活和迁移的血管生成的关键介质。我们的研究结果表明，伴随使用目前的化疗药物和新的治疗GRP 78可能提供一个强大的双重方法来阻止癌症的发生，进展和转移。
GRP78/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we demonstrated that Grp78 heterozygosity not only impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis, the Grp78+/− mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this report, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models where wild-type, syngeneic mammary tumor cells were injected into the host, we showed that Grp78+/− mice suppressed tumor growth and angiogenesis during the early but not late phase of tumor growth. Growth of metastatic lesions of wild-type, syngeneic melanoma cells in the Grp78+/− mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and demonstrated severe reduction of tumor angiogenesis and metastatic growth with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells demonstrated that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression and metastasis.