Autoantibodies against cell surface GRP78 promote tumor growth in a murine model of melanoma.
Autoantibodies against cell surface GRP78 promote tumor growth in a murine model of melanoma.
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DOI：
10.1097/cmr.0b013e3283426805
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发表时间：
2011-02
影响因子：
2.2
通讯作者：
Pizzo SV
中科院分区：
文献类型：
--
作者：
de Ridder GG;Gonzalez-Gronow M;Ray R;Pizzo SV
前列腺癌、黑色素瘤和卵巢癌患者的血清中存在与许多肿瘤细胞系细胞表面表达的GRP 78反应的自身抗体。这些自身抗体是前列腺癌的一个负面预后因素，当纯化后，刺激肿瘤细胞在体外增殖。然而，目前还不清楚这些IgG是否仅仅是一种生物标志物，或者它们是否真的促进了体内肿瘤的生长。我们用重组GRP 78免疫C57 B16小鼠，然后植入B16 F1鼠黑素瘤细胞系作为侧腹肿瘤。我们采用来自这些小鼠的抗血清进行体外细胞信号传导和增殖测定。这些免疫小鼠的抗体库中充分代表了人类癌症患者的免疫显性表位。与对照组相比，我们观察到GRP 78免疫小鼠的肿瘤生长显著加速，存活期缩短。此外，来自这些小鼠的抗血清以及来自类似免疫小鼠的纯化抗GRP 78 IgG刺激培养物中B16 F1和人DM 6黑色素瘤细胞的Akt磷酸化和增殖。这些研究证明了在鼠黑素瘤模型中对GRP 78的体液应答与癌症进展之间的因果关系。他们支持这样的假设，即这种自身抗体参与了人类癌症的进展，而不仅仅是一种生物标志物。由于GRP 78存在于许多类型的癌细胞表面，因此这一假设具有广泛的临床和治疗意义。
Autoantibodies that react with GRP78 expressed on the cell-surface of many tumor cell lines occur in the sera of patients with prostate cancer, melanoma, and ovarian cancer. These autoantibodies are a negative prognostic factor in prostate cancer, and when purified, stimulate tumor cell proliferation in vitro. It is unclear, however, whether these IgGs are merely a biomarker, or if they actually promote tumor growth in vivo. We immunized C57Bl/6 mice with recombinant GRP78 and then implanted the B16F1 murine melanoma cell line as flank tumors. We employed the antisera from these mice for in vitro cell signaling and proliferation assays. The immunodominant epitope in human cancer patients was well represented in the antibody repertoire of these immunized mice. We observed significantly accelerated tumor growth, as well as shortened survival in GRP78-immunized mice as compared to controls. Furthermore, antisera from these mice, as well as purified anti-GRP78 IgG from similarly immunized mice, stimulate Akt phosphorylation and proliferation in B16F1 and human DM6 melanoma cells in culture. These studies demonstrate a causal link between a humoral response to GRP78 and the progression of cancer in a murine melanoma model. They support the hypothesis that such autoantibodies are involved in the progression of human cancers and are not simply a biomarker. Because GRP78 is present on the surface of many types of cancer cells, this hypothesis has broad clinical and therapeutic implications.