The Mechanisms of GM-CSF Inhibition of Breast Cancer Growth and Metastasis

GM-CSF抑制乳腺癌生长和转移的机制

• 批准号: 7923523
• 负责人: Timothy D Eubank
• 金额: $ 4.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923523
• 关键词: Address; Angiogenic Switch; Binding; Biological; Biological Assay; Blood; Breast Cancer Model; Breast Cancer Treatment; Cell Death; Cell Line; Cell Survival; Cells; Data; Dose; Effectiveness; Endothelial Cells; Endothelium; Environment; Epithelial Cells; Fatty acid glycerol esters; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Human; Immune; Injection of therapeutic agent; Laboratories; Leukocytes; Mammary Neoplasms; Mammary gland; Membrane; Metastatic Neoplasm to the Lung; Mononuclear; Mus; Necrosis; Neoplasm Metastasis; Nude Mice; Oxygen; Pattern; Phagocytes; Phenotype; Physiological; Primary Neoplasm; Production; Publishing; RNA Splicing; Research Personnel; Role; Scheme; Translating; Tumor Cell Line; Variant; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Woman; Work; angiogenesis; chemotherapy; effective therapy; in vivo; insight; killings; macrophage; malignant breast neoplasm; matrigel; meetings; monocyte; neoplastic cell; novel; outcome forecast; receptor; response; success; tumor; tumor growth; tumorigenic; vascular bed

DESCRIPTION (provided by applicant): This proposal focuses on understanding the mechanism of GM-CSF-induced sVEGFR-1 production from mononuclear phagocytes and the resulting anti-tumor activity therein. Our data indicates when normal FVB/N female mice are injected with PyMT tumor cells and form a tumor, local injection of rmGM-CSF significantly inhibits tumor growth, metastases to the lung, oxygen within the tumors, as well as increases overall survival of the mouse. Our hypothesis is that GM-CSF will induce the monocytes and macrophages, which reside in mammary tumors, to produce and release the soluble form of the VEGF receptor-1 (sVEGFR-1). This decoy receptor is an alternately-spliced variant of the membrane-bound VEGFR-1 that binds and sequesters VEGF from biological activity. With reduced VEGF in the tumor environment, which is essential in maintaining endothelial cell survival and normal blood vascular beds, the tumor vasculature will break down and result in patterned necrosis within the tumor and eventual tumor cell death. We have published these effects in vivo in a Matrigel plug assay and show reduced angiogenesis within these plugs. Preliminary data in this proposal suggest that GM-CSF significantly reduces tumor growth and metastases in a murine model of breast cancer, in part, by inhibiting the available oxygen to the tumor. It is essential to further these findings by evaluating the effects of GM-CSF in a human tumor environment. We will be using immunodeficient, athymic nude female mice in conjunction with MCF10A, MCF10AT1k, MCF10CA1h and MCF10CA1a human tumor cell lines to see these effects. These cell lines, tumorigenic when injected into the mammary fat pad of nude mice, are immortalized mammary epithelial cells and vary in metastatic aggressiveness. Thus the Specific Aims will address the following questions: Aim 1. To determine the effect of GM-CSF-induced sVEGFR-1 on angiogenesis and metastases in breast tumors. Aim 2. To determine the cells responsible for sVEGFR-1 production in response to GM-CSF. Aim 3. Does GM-CSF inhibit tumor growth, angiogenesis, and metastases of human tumors in nude mice? We anticipate the findings from these studies will provide novel insight in the mechanisms of tumorassociated cells, in this case mononuclear phagocytes, and the potential to change their phenotype from that of tumor-supporting to that of tumor-suppressive.

描述（由申请人提供）：该提案的重点是了解GM-CSF诱导的SVEGFR-1从单核吞噬细胞和所得的抗肿瘤活性的机理。我们的数据表明，何时将正常的FVB/N雌性小鼠注射PYMT肿瘤细胞并形成肿瘤时，局部注射RMGM-CSF会显着抑制肿瘤的生长，转移到肺中，肿瘤内的氧气，并增加小鼠的整体存活。我们的假设是，GM-CSF将诱导驻留在乳腺肿瘤中的单核细胞和巨噬细胞，以产生和释放VEGF受体1的可溶形式（SVEGFR-1）。该诱饵受体是膜结合的VEGFR-1的交替绘制的变体，它结合并从生物学活性结合VEGF。随着肿瘤环境中VEGF的减少，这对于维持内皮细胞存活和正常血管床至关重要，肿瘤血管会分解并导致肿瘤内的模式坏死和最终的肿瘤细胞死亡。我们已经在Matrigel插头测定中在体内发表了这些效果，并显示了这些塞子中的血管生成减少。该提案中的初步数据表明，在乳腺癌的鼠模型中，GM-CSF显着降低了肿瘤的生长和转移，部分原因是抑制对肿瘤的可用氧气。通过评估GM-CSF在人类肿瘤环境中的影响来进一步进一步进一步。我们将与MCF10A，MCF10AT1K，MCF10CA1H和MCF10CA1A和MCF10CA1A人类肿瘤细胞系一起使用免疫缺陷的裸雌性小鼠，以查看这些作用。这些细胞系，当注射到裸鼠的乳腺脂肪垫中时，是永生的乳腺上皮细胞，并且在转移性攻击性中有所不同。 因此，具体目的将解决以下问题：目的1。确定GM-CSF诱导的SVEGFR-1对乳腺肿瘤中血管生成和转移的影响。目标2。确定负责响应GM-CSF的SVEGFR-1产生的细胞。 AIM 3。GM-CSF是否抑制裸鼠的人类肿瘤的肿瘤生长，血管生成和转移？ 我们预计这些研究的发现将提供有关肿瘤相关细胞的机制，单核吞噬细胞的新见解，以及将其表型从肿瘤支持到肿瘤抑制的潜力。

项目成果

Stabilization of HIF-2α induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model.

HIF-2α 的稳定诱导肿瘤相关巨噬细胞产生 sVEGFR-1，并减少小鼠黑色素瘤模型中的肿瘤生长。

• DOI: 10.4049/jimmunol.1103817
• 发表时间: 2012
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Roda,JulieM;Wang,Yijie;Sumner,LauraA;Phillips,GaryS;Marsh,ClayB;Eubank,TimothyD
• 通讯作者: Eubank,TimothyD