用一个小鼠皮肤乳头状瘤模型所做的实验表明，肿瘤血管系统不仅供血，而且起一个支持癌症干细胞的血管小环境的作用。肿瘤细胞对“血管内皮生长因子”（VEGF）的表达对于血管生成很重要，而且通过其受体以“自分泌”方式发挥作用，以促进癌症干细胞的自我更新性的细胞分裂。Nrp1的删除阻断VEGF促进肿瘤生成的能力，并且可能是皮肤癌的一个可行的治疗目标。(生物谷 Bioon.com)
doi:10.1038/nature10525
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A vascular niche and a VEGF–Nrp1 loop regulate the initiation and stemness of skin tumours
Benjamin Beck,1 Gregory Driessens, Steven Goossens, Khalil Kass Youssef,1 Anna Kuchnio, Amélie Caauwe,Panagiota A. Sotiropoulou,Sonja Loges,Gaelle Lapouge, Aurélie Candi,Guilhem Mascre, Benjamin Drogat, Sophie Dekoninck,Jody J. Haigh,Peter Carmeliet & Cédric Blanpain
Angiogenesis is critical during tumour initiation and malignant progression1. Different strategies aimed at blocking vascular endothelial growth factor (VEGF) and its receptors have been developed to inhibit angiogenesis in cancer patients2. It has become increasingly clear that in addition to its effect on angiogenesis, other mechanisms including a direct effect of VEGF on tumour cells may account for the efficiency of VEGF-blockade therapies3. Cancer stem cells (CSCs) have been described in various cancers including squamous tumours of the skin4, 5. Here we use a mouse model of skin tumours to investigate the impact of the vascular niche and VEGF signalling on controlling the stemness (the ability to self renew and differentiate) of squamous skin tumours during the early stages of tumour progression. We show that CSCs of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking VEGFR2 caused tumour regression not only by decreasing the microvascular density, but also by reducing CSC pool size and impairing CSC renewal properties. Conditional deletion of Vegfa in tumour epithelial cells caused tumours to regress, whereas VEGF overexpression by tumour epithelial cells accelerated tumour growth. In addition to its well-known effect on angiogenesis, VEGF affected skin tumour growth by promoting cancer stemness and symmetric CSC division, leading to CSC expansion. Moreover, deletion of neuropilin-1 (Nrp1), a VEGF co-receptor expressed in cutaneous CSCs, blocked VEGF’s ability to promote cancer stemness and renewal. Our results identify a dual role for tumour-cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for CSCs, and by directly affecting CSCs through Nrp1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumour initiation. These results may have important implications for the prevention and treatment of skin cancers.
