Oncostatin M stimulates VEGF-mediated angiogenesis

描述(申请人提供)：OSM是一种多效性细胞因子，由多种细胞类型产生，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，因此正在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由肿瘤相关的中性粒细胞和乳腺癌上皮细胞表达，而不是由正常乳腺组织表达。此外，我们还发现OSM能有效地诱导乳腺癌细胞产生促血管生成分子血管内皮生长因子(VEGF)，并且经OSM处理的乳腺癌细胞产生的血管内皮生长因子将诱导内皮细胞增殖并刺激管状细胞的形成。因此，虽然OSM在体外可能导致乳腺癌细胞生长停滞，但还没有研究表明OSM在更复杂的体内环境中诱导乳腺癌细胞产生血管内皮生长因子或诱导血管生成依赖型乳腺癌进展的能力。我们的目标是研究OSM诱导的血管内皮生长因子在血管生成和乳腺癌进展中的作用。我们假设，经OSM处理的乳腺癌细胞将在体外和体内刺激血管生成。此外，我们预测，尽管OSM具有抑制生长的特性，但它实际上会通过启动或促进血管内皮生长因子依赖的血管生成来促进肿瘤进展。这一结果不仅会使OSM不适合作为潜在的乳腺癌治疗方法，而且将表明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诱导血管生成的受体和信号通路；2)证明OSM处理的乳腺癌细胞产生的VEGF将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，以研究OSM在体内刺激血管生成和促进乳腺癌进展的能力。这项工作可能为OSM不适合作为潜在的乳腺癌治疗方法提供证据，并为合理设计以OSM为基础的实验性抗血管生成药物奠定基础。

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.