Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.
Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.
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DOI：
10.1158/0008-5472.can-10-0412
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Kohgo Y
中科院分区：
文献类型：
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作者：
Sasajima J;Mizukami Y;Sugiyama Y;Nakamura K;Kawamoto T;Koizumi K;Fujii R;Motomura W;Sato K;Suzuki Y;Tanno S;Fujiya M;Sasaki K;Shimizu N;Karasaki H;Kono T;Kawabe J;Ii M;Yoshiara H;Kamiyama N;Ashida T;Bardeesy N;Chung DC;Kohgo Y
血管向组织输送氧气和营养物，并且血管网络在空间上被组织以满足维持体内平衡的代谢需要。相比之下，肿瘤的脉管系统是不成熟和渗漏的，导致营养和氧气的输送不足。血管生成过程通常发生在成人组织中，以修复“受伤”的血管，这使我们假设骨髓单核细胞（BMMNC）可能能够恢复肿瘤血管系统中适当的血管功能。用内皮生长培养基培养BMMNC导致早期生长的梭形贴壁细胞表达具有促血管生成活性的CD 11b/Flt 1/Tie 2/c-Kit/CXCR 4。将这些培养的血管促血管生成细胞（VPC）静脉内给予携带胰腺癌异种移植物的裸鼠和发展胰腺导管腺癌的Pdx 1-Cre; LSL-KrasG 12 D; p53 lox/+基因工程小鼠，显著减少缺氧面积，而不促进肿瘤生长。由此产生的脉管系统在结构上模仿具有密集周细胞覆盖的正常血管。在注射基于微泡的造影剂（Sonazoid）期间，使用超声诊断系统可视化VPC注射的异种移植物内的血管化区域的增加，表明肿瘤血管系统的功能“正常化”。此外，VPC移植的异种移植物的基因表达谱显示，参与耐药性和癌细胞“干性”的主要因素显著减少。总之，我们的研究结果确定了一种新的替代方法来调节异常的肿瘤血管，提供了改善抗癌药物对缺氧肿瘤的递送和疗效的潜力。
Blood vessels deliver oxygen and nutrients to tissues and vascular networks are spatially organized to meet metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair “injured” blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in tumor vasculature. Culturing BMMNC with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with pro-angiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-KrasG12D;p53lox/+ genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in the vascularized area within VPC-injected xenografts were visualized with the ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional “normalization” of the tumor vasculature. In addition, gene expression profiles on the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and “stemness” of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve delivery and efficacy of anti-cancer drugs to hypoxic tumors.