ANGPTL4 promotes the progression of cutaneous melanoma to brain metastasis.

Sivan Izraely,Dave S.B Hoon,Shlomit Ben-Menachem,Isaac P Witz,Orit Sagi-Assif,Tsipi Meshel,Metsada Pasmanik-Chor,Inna Zubrilov,Diego M Marzese,Shuichi Ohe

doi:10.18632/oncotarget.19018

Sivan Izraely, Dave S.B Hoon + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.19018

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Journal: Oncotarget	Publication Date: Jul 5, 2017
Citations: 23	License type: cc-by

Affiliation: Tel Aviv University, Saint John's Health Center

Abstract

In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such metastases.The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis.We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas from the same patients.In vitro experiments indicated that brain-derived soluble factors and transforming growth factor β1 (TGFβ1) up-regulated ANGPTL4 expression by melanoma cells.Forced over-expression of ANGPTL4 in cutaneous melanoma cells promoted their ability to adhere and transmigrate brain endothelial cells. Over-expressing ANGPTL4 in cells derived from brain metastases resulted in the opposite effects.In vivo data indicated that forced overexpression of ANGPTL4 promoted the tumorigenicity of cutaneous melanoma cells but did not increase their ability to form brain metastasis. This finding can be explained by inhibitory activities of brain-derived soluble factors.Taken together these findings indicate that ANGPTL4 promotes the malignancy phenotype of primary melanomas of risk to metastasize to the brain.

Highlights

Malignant melanoma has a high tendency to develop brain metastasis [1], conferring upon melanoma patients a very poor prognosis [2]
These findings were confirmed in three additional independent melanoma models: by using Western blot analysis, we assessed Angiopoietin-like 4 (ANGPTL4) expression in cutaneous and melanoma brain metastasis (MBM) cells of the parental human melanoma cells UCLA-SO-M12, UCLA-SO-M16, and DP-0574-Me
The expression of ANGPTL4 was measured in a cohort of 12 melanoma patients with paired primary melanoma (PRM), melanoma lymph node metastasis (LNM), and MBM

Summary

Introduction

Malignant melanoma has a high tendency to develop brain metastasis [1], conferring upon melanoma patients a very poor prognosis [2]. As disease management improves and the survival of melanoma patients is prolonged, the number of patients that eventually develop clinical brain metastasis increases. The brain microenvironment consists of several resident cell types: endothelial cells, astrocytes, microglia, and neurons. Melanoma cells must reach the brain vasculature, attach to endothelial cells covering the microvessel walls, extravasate the brain endothelium and invade the brain parenchyma, proliferate and induce angiogenesis [4]. Interactions with brain www.impactjournals.com/oncotarget microenvironmental cells facilitate metastasis formation. The molecules and mechanisms involved in the interactions between melanoma cells and normal brain microenvironment cells have not been fully characterized

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