美国维克森林大学医学院研究人员最近的研究发现,为开发一种能抑制肿瘤生长,而且具有帮助伤口愈合的作用的新药铺平了道路。这一发现是基于一项对血管生成的研究。发表在《美国国家科学院院刊》上的这项研究对血液中的一些蛋白如何参与并影响血管的生长作了探讨。
研究人员发现,血液中铁蛋白与另外一种叫HKa的蛋白结合可消弱其抑制血管生长的能力。由于新血管会为肿瘤不断提供生长所需的营养和氧气,因此这两种蛋白的结合实际上去除了HKa的作用,帮助了新血管的形成,因而也促进了肿瘤的生长。这一发现让研究人员推测,假如能防止铁蛋白和HKa的结合,将会使HKa抑制新血管生长,也就能阻止肿瘤的发展。研究结果还与伤口愈合有关。伤口愈合需要血管的生长,增加铁蛋白和HKa的结合有可能增加严重伤口愈合的机会。
“人们早就认识到,患有肿瘤的人的铁蛋白水平是升高的,但一直不清楚其中的原因。”生物化学副教授苏泽V﹒托蒂博士说。“铁蛋白在血管形成上起了重要作用。铁蛋白与HKa之间的互相作用提供了一个药物开发的新领域。”
研究人员给小鼠注射了前列腺癌细胞,用于铁蛋白和HKa如何影响新血管形成的研究。
这些注射癌细胞的小鼠会发生肿瘤。但与HKa一起注射时,HKa抑制了血管的形成。如果加入铁蛋白后,铁蛋白会恢复血管的形成,肿瘤重新又开始生长。
“血管既有帮助,如对伤口愈合,也会有害,如有利于肿瘤生长。”托蒂说。“我们新的发现是:铁蛋白和HKa相互作用会影响血管的形成。这一发现可以作为抑制或刺激血管生长的基本策略,开辟了一个治疗肿瘤或依赖新血管形成疾病的新领域。”(生物谷Bioon.com)
生物谷推荐原始出处:
PNAS January 6, 2009, doi: 10.1073/pnas.0812010106
Regulatory effects of ferritin on angiogenesis
Lan G. Coffmana, Derek Parsonageb, Ralph D'Agostino, Jr.cd, Frank M. Tortice and Suzy V. Tortibc1
aProgram in Molecular Medicine,
bDepartment of Biochemistry,
dDepartment of Public Health Sciences, Section on Biostatistics,
eDepartment of Cancer Biology, and
cComprehensive Cancer Center Wake Forest University School of Medicine, Winston Salem NC 27157
Abstract
Angiogenesis, the synthesis of new blood vessels from preexisting vessels, plays a critical role in normal wound healing and tumor growth. HKa (cleaved high molecular weight kininogen) is an endogenous inhibitor of angiogenesis formed by the cleavage of kininogen on endothelial cells. Ferritin is a protein principally known for its central role in iron storage. Here, we demonstrate that ferritin binds to HKa with high affinity (Kd 13 nM). Further, ferritin antagonizes the antiangiogenic effects of HKa, enhancing the migration, assembly, and survival of HKa-treated endothelial cells. Effects of ferritin were independent of its iron content. Peptide mapping revealed that ferritin binds to a 22-aa subdomain of HKa that is critical to its antiangiogenic activity. In vivo, ferritin opposed HKa's antiangiogenic effects in a human prostate cancer xenograft, restoring tumor-dependent vessel growth. Ferritin-mediated regulation of angiogenesis represents a new angiogenic regulatory pathway, and identifies a new role for ferritin in cell biology.