1] INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière, BP 23194, 06204 Nice, France [2] Université de Nice Sophia Antipolis, Faculté de Médecine, 06107 Nice, France.
1] Université de Nice Sophia Antipolis, Faculté de Médecine, 06107 Nice, France [2] Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Laboratoire Central d'Anatomo Pathologie, 06002 Nice, France.
Nat Commun. 2015 Apr 30;6:6993. doi: 10.1038/ncomms7993.
Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.
肿瘤衍生的分泌因子破坏血管内皮屏障是癌细胞渗出和转移的关键步骤。在这里，我们通过黑色素瘤分泌组的比较蛋白质组学分析，鉴定出细胞外基质蛋白 SPARC 是一种新型的肿瘤衍生的血管通透性因子。SPARC 缺陷可消除肿瘤引发的肺毛细血管通透性，并防止渗出；而 SPARC 过表达则增强血管通透性、渗出和肺转移。SPARC 诱导的细胞旁通透性依赖于内皮 VCAM1 受体和 p38 MAPK 信号通路。阻断 VCAM1 可阻碍黑色素瘤诱导的内皮通透性和渗出。我们的研究发现肿瘤中检测到高水平的 SPARC，这突出了我们研究结果的临床相关性，来自人类肺黑色素瘤病变的肿瘤。我们的研究确立了肿瘤产生的 SPARC 和 VCAM1 是癌症渗出的调节剂，揭示了一种可靶向的新的预防转移的作用靶点。
