Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Oncogene. 2011 Sep 29;30(39):4075-86. doi: 10.1038/onc.2011.122. Epub 2011 Apr 18.
Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.
Notch 信号通路在肿瘤进展过程中经常被缺氧异常激活；然而，缺氧诱导的 Notch 信号通路在肿瘤转移中的具体病理作用仍知之甚少。在这项研究中，我们旨在确定缺氧在原发性肿瘤和转移灶基质细胞中激活 Notch 配体的机制，并阐明它们在肿瘤进展中的作用。我们分析了 GEO 数据库中 779 例乳腺癌患者的各种 Notch 配体的表达谱，发现五种配体中 Jagged2 的表达与乳腺癌患者的总生存和无转移生存最显著相关。我们对 61 例临床样本 Jagged2 的免疫组化（IHC）分析结果也表明，Jagged2 和 Notch 信号通路在缺氧侵袭前沿均强烈上调。肿瘤细胞中缺氧诱导的 Jagged2 激活诱导 EMT，并在体外促进细胞存活。值得注意的是，γ-分泌酶抑制剂通过促进 E-钙粘蛋白的表达和抑制 Akt 磷酸化，显著阻断了 Notch 介导的缺氧下的侵袭和存活。重要的是，在缺氧下，骨髓基质中也发现 Jagged2 上调，并通过激活其 Notch 信号通路促进癌症干细胞样细胞的生长。因此，缺氧诱导的肿瘤侵袭前沿和正常骨基质中 Jagged2 的激活在肿瘤进展和转移中具有关键作用，Jagged2 被认为是一种有价值的预后标志物，并可能成为转移性乳腺癌的新治疗靶点。
