Department of Hematology and Oncology with Sections BMT and Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Hamburg, Germany.
Clin Exp Metastasis. 2012 Dec;29(8):879-87. doi: 10.1007/s10585-012-9477-1. Epub 2012 Apr 8.
Blocking angiogenesis by inhibiting VEGF represents an established therapeutic strategy in many cancers. The role of placental growth factor (PlGF) and of its receptor VEGFR-1 in tumor biology remain more elusive. Currently, humanized monoclonal antibodies against PlGF are studied in early phase clinical trials because PlGF inhibition blocked murine tumor growth and angiogenesis. In contrast to mice exclusively expressing one PlGF isoform (PlGF-2), humans can produce four PlGF isoforms (PlGF1-4). Surprisingly nothing is yet known about expression of all four PlGF isoforms in human cancer, because until now mostly total PlGF levels or PlGF-1/2 were analyzed without discriminating further. In this study we determined mRNA expression levels of PlGF1-4 and of VEGFR-1 by QRT-PCR in human esophageal tumor tissue and investigated whether gene expression levels correlate with clinical data. PlGF-1 and -2 were expressed in virtually all analyzable tumors, whereas PlGF-3 and -4 were present in tumors of 59 and 74 % of patients, respectively. MRNA Expression levels of all four splice variants correlated with each other. In contrast, PlGF-1 and -2 mRNA expression was lower in esophageal control tissue and PlGF-3 and -4 mRNA were undetectable. VEGFR-1 was expressed by more than 80 % of patients. Interestingly, VEGFR-1 expression levels significantly correlate with presence of disseminated tumor cells (DTCs) in bone marrow. Patients with DTCs exhibit lower VEGFR-1 mRNA expression than patients without DTCs. Pending validation in other types of cancer, expression levels of VEGFR-1 might be useful as surrogate marker for DTCs.
通过抑制 VEGF 来阻断血管生成是许多癌症的一种既定治疗策略。胎盘生长因子 (PlGF) 及其受体 VEGFR-1 在肿瘤生物学中的作用仍然更加难以捉摸。目前，针对 PlGF 的人源化单克隆抗体正在进行早期临床试验，因为 PlGF 抑制可阻断鼠类肿瘤生长和血管生成。与仅表达一种 PlGF 同工型（PlGF-2）的小鼠不同，人类可以产生四种 PlGF 同工型（PlGF1-4）。令人惊讶的是，目前对于人类癌症中所有四种 PlGF 同工型的表达情况还一无所知，因为到目前为止，大多数研究主要分析了总 PlGF 水平或 PlGF-1/2，而没有进一步区分。在这项研究中，我们通过 QRT-PCR 测定了人食管肿瘤组织中 PlGF1-4 和 VEGFR-1 的 mRNA 表达水平，并研究了基因表达水平是否与临床数据相关。几乎所有可分析的肿瘤都表达 PlGF-1 和 -2，而 PlGF-3 和 -4 分别存在于 59%和 74%的患者的肿瘤中。所有四种剪接变体的 mRNA 表达水平相互相关。相比之下，食管对照组织中的 PlGF-1 和 -2 mRNA 表达水平较低，而 PlGF-3 和 -4 mRNA 则无法检测到。超过 80%的患者表达 VEGFR-1。有趣的是，VEGFR-1 表达水平与骨髓中播散性肿瘤细胞 (DTCs) 的存在显著相关。存在 DTC 的患者的 VEGFR-1 mRNA 表达水平低于不存在 DTC 的患者。在其他类型的癌症中进行验证之前，VEGFR-1 的表达水平可能作为 DTC 的替代标志物有用。
