Inorganic phosphate induces cancer cell mediated angiogenesis dependent on forkhead box protein C2 (FOXC2) regulated osteopontin expression.
Inorganic phosphate induces cancer cell mediated angiogenesis dependent on forkhead box protein C2 (FOXC2) regulated osteopontin expression.
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DOI：
10.1002/mc.22153
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发表时间：
2015-09
影响因子：
4.6
通讯作者：
Beck, George R., Jr.
中科院分区：
文献类型：
--
作者：
Lin, Yiming;McKinnon, Kelly E.;Ha, Shin Woo;Beck, George R., Jr.
最近在啮齿动物和人类中的研究表明，在正常肾功能的情况下，血清磷升高会增强或加重与心血管疾病、骨代谢和癌症相关的病理。我们最近的微阵列研究确定了促血管生成基因的有效刺激，如Forkhead box蛋白C2（FOXC 2），骨桥蛋白和Vegfα，以及其他对无机磷酸盐（Pi）升高的反应。增加的血管生成和新血管形成是肿瘤生长和恶性进展中的重要事件，并且FOXC 2最近被鉴定为这些过程的潜在转录调节因子。在这项研究中，我们解决了高Pi环境通过需要FOXC 2的机制增加癌细胞血管生成潜力的可能性。我们的研究利用肺癌和乳腺癌细胞系与人脐血管内皮细胞（HUVEC）血管形成模型的组合，以更好地理解高Pi环境可能改变癌症进展的机制。癌细胞暴露于升高的Pi刺激FOXC 2的表达，并且来自Pi刺激的癌细胞的条件培养基刺激HUVEC模型中的迁移和管形成。从机制上讲，我们将FOXC 2对Pi诱导的OPN表达和癌细胞分泌的需求定义为血管生成反应所必需的。这些研究首次揭示了在高Pi环境中生长的癌细胞促进了内皮细胞的迁移和管形成，并由此确定了一种新的潜在治疗靶点以减少肿瘤进展。
Recent studies in both rodents and humans suggest that elevated serum phosphorus, in the context of normal renal function, potentiates or exacerbates pathologies associates with cardiovascular disease, bone metabolism, and cancer. Our recent microarray studies identified the potent stimulation of pro-angiogenic genes such as Forkhead box protein C2 (FOXC2), osteopontin, and Vegfα, among others in response to elevated inorganic phosphate (Pi). Increased angiogenesis and neovascularization are important events in tumor growth and the progression to malignancy and FOXC2 has recently been identified as a potential transcriptional regulator of these processes. In this study we addressed the possibility that a high Pi environment would increase the angiogenic potential of cancer cells through a mechanism requiring FOXC2. Our studies utilized lung and breast cancer cell lines in combination with the human umbilical vascular endothelial cell (HUVEC) vessel formation model to better understand the mechanism(s) by which a high Pi environment might alter cancer progression. Exposure of cancer cells to elevated Pi stimulated expression of FOXC2 and conditioned medium from the Pi-stimulated cancer cells stimulated migration and tube formation in the HUVEC model. Mechanistically, we define the requirement of FOXC2 for Pi-induced OPN expression and secretion from cancer cells as necessary for the angiogenic response. These studies reveal for the first time that cancer cells grown in a high Pi environment promote migration of endothelial cells and tube formation and in so doing identify a novel potential therapeutic target to reduce tumor progression.
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影响因子：
5.6
作者：
Camalier, Corinne E.;Yi, Ming;Yu, Li-Rong;Hood, Brian L.;Conrads, Kelly A.;Lee, Young Jae;Lin, Yiming;Garneys, Laura M.;Bouloux, Gary F.;Young, Matthew R.;Veenstra, Timothy D.;Stephens, Robert M.;Colburn, Nancy H.;Conrads, Thomas P.;Beck, George R., Jr.
通讯作者：
Beck, George R., Jr.
影响因子：
11.2
作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
通讯作者：
Mani SA
影响因子：
4.2
作者：
DRAPER, HH;BERGAN, JG;SIE, TL
通讯作者：
SIE, TL
影响因子：
6.2
作者：
Julien, Marion;Khoshniat, Solmaz;Guicheux, Jerome
通讯作者：
Guicheux, Jerome
影响因子：
6.2
作者：
Huttunen, Minna M.;Tillman, Ilse;Lamberg-Allardt, Christel J. E.
通讯作者：
Lamberg-Allardt, Christel J. E.