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CD146 as a potent target for anti-vascular therapies in lung cancer brain metastasis

ABSTRACT: Tumors in brain are hype-angiogenic and the anti-vascular therapies are important for the treatment of non-small cell lung carcinoma (NSCLC) derived brain metastasis (BM). Targeting vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is the most effective way of resisting angiogenesis. However, the most widely-used anti-vascular drug (Bevacizumab, Bev) has limited therapeutic effects on NSCLC BM. Here, we defined the overexpression of CD146 and its potent pro-angiogenesis role in NSCLC BM in clinical samples, animal models and ex vivo bionic microfluidic chips. Mechanistically, CD146 exerts a comprehensive and sustained reinforcing effect on the pro-angiogenic VEGF-VEGFR2 axis on the one hand by up-regulating tumoral VEGF transcription and on the other hand by amplifying and sensitizing the VEGFR on endothelial cell as a co-receptor. By revealing the underlying mechanism by which CD146 upregulated in BM that the reactive astrocyte-derived growth arrest specific 6 (GAS6) induces the transcription of CD146 by activating AXL signaling, we demonstrated Bemcentinib (R428/BGB324), an AXL inhibitor, effectively suppressed the CD146 expression in BM cells and exhibited superior anti-vascular efficacy against brain metastases when used alone and in combination with Bev in vivo, providing novel anti-vascular strategies in BM.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wenzhe Duan

PROVIDER: PXD047390 | iProX | Thu Nov 30 00:00:00 GMT 2023

REPOSITORIES: iProX

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Project description:Acquired neonatal brain lesions result from the co-incidence of environment deleterious factors occurring at a specific development stage. Hypoxia-ischemia and inflammation are the major triggers of brain damage in late pregnancy and early infancy, and result in a variety of damages depending on whether it affected fetuses, early or late preterm infants or at term neonates. Indeed brain responses to insults are different depending on age, since cerebral tissue presents a rapidly evolving cellular and biochemical substrate in this period. Clearly age-dependent etiology is largely documented; e.g. Intraventricular/intraparenchymal (IVH/IPH) brain hemorrhage in fetuses and extreme preterm (less than 28 gestation weeks; GW); focal or diffuse periventricular leucomalacia in preterm aged 28-34 GW or cortical necrosis in term infants. Definite periods of occurrence of preterm-encephalopathy are associated to particular vulnerability of distinct cell populations. Functional deficits remain in grown-up and represent a human and economical burden. IVH/IPH affects extreme preterm infants. It specific periventricular germinal matrix (GM) localization reveal vascular vulnerability at this site during a definite period. GM is the site of particularly intense metabolism due to neural cell precursor multiplication and angiogenesis. In addition, GM is at risk of hypoperfusion or perfusion arrest due to its watershed situation between centripetal and centrifugal vascular supplies, especially in very preterm infants otherwise subjected to fluctuant hemodynamics. Thus vascular bed in GM cumulates hypoxia-ischemia risks. The vulnerability of vasculature in this area was referred to be linked to intense angiogenesis and micro-vessels remodeling. Indeed endothelial support by pericytes and astrocytes end-feet is loose in these vessels and angiogenic factors also exhibit pro-hemorrhage potential. The blood to brain interface referred to as neurovascular unit is the multicellular structure shaping endothelial cells to regulate vascular permeability. The blood brain barrier (BBB) restrains pericellular diffusion and allows specific trans-endothelial transports. In previous studies in mice, we have observed structural and functional differences between young and adult brain microvascular endothelial cells (mvEC). Of note mvEC from neonates express the NMDA receptor and glutamate in these cells elicit protease secretions involved in vascular remodeling, while adult mvEC did not. Genetic inactivation of the t-PA inhibitor-1 allowed to mimick an age dependent IVH/IPH up to 5 days post-natal (P5) in mice. These observations (and others) support the hypothesis that mouse brain microvessels represent a heuristic paradigm in the study of vascular maturity as a favoring background for age dependent neonate brain hemorrhage. The present project was designed at studying constitutive protein contents of brain microvessels in a large scale, around the period of high disruption propensity (P5). We prepared enriched fractions of mouse forebrain microvessels (fMV) in order to insolating the neurovascular unit made of endothelial cells linked by blood brain barrier junctions, basal lamina including pericytes, astrocyte and neuritic end-feet from P5 (pro-hemorrhagic state), P10 (Immature hemorrhage resistant state) and P60 (Mature) mice, to study proteome onotogeny in fMV.

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CD146 as a potent target for anti-vascular therapies in lung cancer brain metastasis

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