Decaussin M, Sartelet H, Robert C, Moro D, Claraz C, Brambilla C, Brambilla E
Laboratoire de Pathologie Cellulaire, Hôpital Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France.
J Pathol. 1999 Aug;188(4):369-77. doi: 10.1002/(SICI)1096-9896(199908)188:4<369::AID-PATH381>3.0.CO;2-X.
The formation of new vessels (angiogenesis) is essential for primary tumour growth and metastasis and is induced by several angiogenic factors, including vascular endothelial growth factor (VEGF). The microvascular density (MVD) in tumours was assessed and the expression of VEGF and its receptors VEGF-R1-Flt1 and VEGF-R2-KDR/Flk1 was investigated in the different cellular compartments in vivo, in order to establish their interrelationship and their prognostic influence. Immunohistochemical study of 69 stage I-II non-small cell lung carcinomas (NSCLCs) was performed on paraffin sections with CD34 antibody to estimate MVD, using a Chalkley eye-piece graticule and VEGF, VEGF-R1, and VEGF-R2 antibodies. There was strong expression of VEGF and its receptors in tumour cells, endothelial cells, and stromal fibroblasts. In tumour cells, the level of VEGF was correlated with that of VEGF-R1 ( p = 0. 018) but not that of VEGF-R2. In fibroblasts, high expression of VEGF was correlated with that of VEGF-R1 ( p = 0.0001) and VEGF-R2 ( p = 0.0001). In endothelial cells, expression of VEGF was correlated with that of VEGF-R1 ( p < 0.0001) and VEGF-R2 ( p = 0.04). The level of VEGF in fibroblasts was correlated with that of VEGF-R1 ( p = 0.0028) and VEGF-R2 ( p = 0.01) in endothelial cells. There was no correlation between the level of MVD and that of VEGF or VEGF-R1 or VEGF-R2. Neither the level of MVD, nor the level of expression of VEGF and VEGF receptors in any compartment influenced the patient's survival. In conclusion, although angiogenesis is essential for tumour growth, this study failed to demonstrate that MVD, VEGF, VEGF-R1, and VEGF-R2 are prognostic markers for stage I-II NSCLC. VEGF, however, might act as a direct autocrine growth factor for tumour cells via VEGF-R1 and angiogenesis could be promoted in a paracrine loop, where VEGF is produced by fibroblasts and tumour cells and then binds to endothelial cells via induced VEGF receptors. VEGF and its receptors thus appear as relevant therapeutic targets in NSCLC.
新血管形成（血管生成）对于原发性肿瘤的生长和转移至关重要，并且由包括血管内皮生长因子（VEGF）在内的多种血管生成因子诱导。评估肿瘤中的微血管密度（MVD），并在体内不同细胞区室中研究VEGF及其受体VEGF-R1-Flt1和VEGF-R2-KDR/Flk1的表达，以确定它们之间的相互关系及其预后影响。对69例I-II期非小细胞肺癌（NSCLC）进行免疫组织化学研究，在石蜡切片上使用CD34抗体估计MVD，使用Chalkley目镜测微计以及VEGF、VEGF-R1和VEGF-R2抗体。VEGF及其受体在肿瘤细胞、内皮细胞和基质成纤维细胞中有强表达。在肿瘤细胞中，VEGF水平与VEGF-R1水平相关（p = 0.018），但与VEGF-R2水平无关。在成纤维细胞中，VEGF的高表达与VEGF-R1（p = 0.0001）和VEGF-R2（p = 0.0001）的高表达相关。在内皮细胞中，VEGF的表达与VEGF-R1（p < 0.0001）和VEGF-R2（p = 0.04）的表达相关。成纤维细胞中VEGF水平与内皮细胞中VEGF-R1（p = 0.0028）和VEGF-R2（p = 0.01）水平相关。MVD水平与VEGF、VEGF-R1或VEGF-R2水平之间无相关性。MVD水平以及任何区室中VEGF和VEGF受体的表达水平均未影响患者的生存。总之，尽管血管生成对于肿瘤生长至关重要，但本研究未能证明MVD、VEGF、VEGF-R1和VEGF-R2是I-II期NSCLC的预后标志物。然而，VEGF可能通过VEGF-R1作为肿瘤细胞的直接自分泌生长因子，并且血管生成可能在旁分泌环中被促进，其中VEGF由成纤维细胞和肿瘤细胞产生，然后通过诱导的VEGF受体与内皮细胞结合。因此，VEGF及其受体似乎是NSCLC中相关的治疗靶点。
