Oncostatin M stimulates VEGF-mediated angiogenesis

描述（由申请人提供）：Oncostatin M （OSM）是多种细胞类型产生的多效细胞因子，包括中性粒细胞和肿瘤相关巨噬细胞。OSM在体外抑制乳腺癌细胞的增殖，因此被评估为一种潜在的癌症治疗方法。然而，文献中的间接证据表明，OSM可以促进肿瘤微环境中的血管生成。我们的数据表明，OSM在肿瘤相关的中性粒细胞和乳腺癌上皮细胞中表达，但在正常乳腺组织中不表达。此外，我们已经证明OSM能从乳腺癌细胞中诱导促血管生成分子血管内皮生长因子（VEGF），并且OSM处理的乳腺癌细胞产生的VEGF会诱导内皮细胞增殖并刺激管的形成。因此，虽然OSM可能在体外引起乳腺癌细胞的生长停滞，但没有研究表明OSM在更复杂的体内环境中诱导乳腺癌细胞的VEGF或诱导血管生成依赖性乳腺癌进展的能力。我们的目的是表征osm诱导的VEGF在血管生成和乳腺癌进展中的作用。我们假设osm治疗的乳腺癌细胞在体内和体外都会刺激血管生成。此外，我们预测OSM实际上会通过启动或增强vegf依赖性血管生成来促进肿瘤进展，尽管它具有生长抑制特性。这一结果不仅表明OSM不适合作为潜在的乳腺癌治疗方法，而且表明OSM本身是一个有效的治疗靶点。为了研究OSM在血管生成和肿瘤进展中的作用，我们建议：1)确定OSM诱导VEGF的受体和信号通路；2)证实经osm处理的乳腺癌细胞产生的VEGF会在培养的内皮细胞中诱导血管生成表型；3)建立过表达OSM的乳腺癌细胞系，在体内研究OSM刺激血管生成和促进乳腺癌进展的能力。本研究为OSM不适合作为一种潜在的乳腺癌治疗方法提供了证据，并为合理设计基于OSM的实验性抗血管生成疗法奠定了基础。

DESCRIPTION (provided by applicant): Oncostatin M (OSM) is a pleiotropic cytokine produced by many cell types, including neutrophils and tumor-associated macrophages. OSM inhibits the proliferation of breast cancer cells in vitro, and is therefore being evaluated as a potential cancer therapy. Circumstantial evidence in the literature, however, suggests that OSM could promote angiogenesis in a tumor microenvironment. Our data demonstrates that OSM is expressed by tumor-associated neutrophils and by breast cancer epithelial cells, but not by normal breast tissue. In addition, we have shown that OSM potently induces the pro-angiogenic molecule vascular endothelial growth factor (VEGF) from breast cancer cells, and that VEGF produced by OSM-treated breast cancer cells will induce endothelial cell proliferation and stimulate tube formation. Thus, while OSM may cause growth-arrest in breast cancer cells in vitro, no studies have addressed OSM's ability to induce VEGF from breast cancer cells or to induce angiogenesis-dependent breast cancer progression in the more complex in vivo environment. Our objective is to characterize the role of OSM-induced VEGF in angiogenesis and breast cancer progression. We hypothesize that OSM-treated breast cancer cells will stimulate angiogenesis in vitro and in vivo. Furthermore, we predict that OSM will actually promote tumor progression by initiating or enhancing VEGF-dependent angiogenesis, in spite of its growth-inhibitory properties. Results to this end will not only render OSM unsuitable as a potential breast cancer therapy, but will suggest that OSM itself is a valid therapeutic target. To examine the role of OSM in angiogenesis and tumor progression, we propose to: 1) determine the receptor and signaling pathway utilized by OSM to induce VEGF; 2) demonstrate that VEGF produced by OSM-treated breast cancer cells will induce an angiogenic phenotype in cultured endothelial cells; and 3) establish breast cancer cell lines that overexpress OSM to investigate the ability of OSM to stimulate angiogenesis and promote breast carcinoma progression in vivo. This work could provide evidence that OSM is unsuitable as a potential breast cancer therapy, and establish a foundation for the rational design of experimental, OSM-based anti-angiogenic therapeutics.