Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors
Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors
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DOI：
10.1172/jci200318549
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发表时间：
2003-10-01
影响因子：
15.9
通讯作者：
Betsholtz, C
中科院分区：
文献类型：
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作者：
Abramsson, A;Lindblom, P;Betsholtz, C
肿瘤浸润性血管在形态和生化上偏离正常血管，增加了选择性药物靶向的前景。目前的抗血管生成方法主要集中在内皮细胞，但最近的数据表明，靶向周细胞可能会提供额外的好处。这些概念的进一步发展将需要对周细胞在肿瘤中的招募和功能的机制有更深入的了解。在这里，我们应用遗传工具来破译PDGF-B和PDGF-Rbeta在小鼠纤维肉瘤模型中周细胞募集中的功能。在移植到PDGF-B保留基序缺陷(PDGF-b(ret/ret))小鼠的肿瘤中，周细胞较少，部分从血管壁分离，与肿瘤血管直径增加和出血相吻合。转基因PDGF-B在肿瘤细胞中的表达能够增加WT和PDGF-b(ret/ret)小鼠的周细胞密度，但不能纠正PDGF-b(ret/ret)小鼠的周细胞脱离。外源性周细胞和肿瘤细胞共注射表明周细胞需要PDGF-Rbeta才能募集到肿瘤血管，而内皮PDGF-B的滞留是周细胞在血管壁正确整合所必需的。我们的数据支持周细胞在肿瘤血管中发挥重要作用的观点，并强调PDGF-B和PDGF-Rbeta是治疗干预的有希望的分子靶点。
Tumor-infiltrating blood vessels deviate morphologically and biochemically from normal vessels, raising the prospect of selective pharmacological targeting. Current antiangiogenic approaches focus mainly on endothelial cells, but recent data imply that targeting pericytes may provide additional benefits. Further development of these concepts will require deeper insight into mechanisms of pericyte recruitment and function in tumors. Here, we applied genetic tools to decipher the function of PDGF-B and PDGF-Rbeta in pericyte recruitment in a mouse fibrosarcoma model. In tumors transplanted into PDGF-B retention motif-deficient (pdgf-b(ret/ret)) mice, pericytes were fewer and were partially detached from the vessel wall, coinciding with increased tumor vessel diameter and hemorrhaging. Transgenic PDGF-B expression in tumor cells was able to increase the pericyte density in both WT and pdgf-b(ret/ret) mice but failed to correct the pericyte detachment in pdgf-b(ret/ret) mice. Coinjection of exogenous pericytes and tumor cells showed that pericytes require PDGF-Rbeta for recruitment to tumor vessels, whereas endothelial PDGF-B retention is indispensable for proper integration of pericytes in the vessel wall. Our data support the notion that pericytes serve an important function in tumor vessels and highlight PDGF-B and PDGF-Rbeta as promising molecular targets for therapeutic intervention.