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Δευτέρα 18 Σεπτεμβρίου 2017

Endothelial Rab7 GTPase Mediates Tumor Growth and Metastasis in Lysosomal Acid Lipase Deficient Mice [Cell Biology]

Tumors depend on their microenvironment for sustained growth, invasion and metastasis. In this environment, endothelial cells (ECs) are an important stromal cell type interacting with malignant cells to facilitate tumor angiogenesis and cancer cell extravasation. Of note, lysosomal acid lipase (LAL) deficiency facilitates melanoma growth and metastasis. ECs from LAL-deficient (lal-/-) mice possess enhanced proliferation, migration, and permeability of inflammatory cells by activating the mammalian target of rapamycin (mTOR) pathway. Here, we report that lal-/- ECs facilitated in vivo tumor angiogenesis, growth, and metastasis, largely by stimulating tumor cell proliferation, migration, adhesion and transendothelial migration via increased expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1). This prompted us to look for lysosomal proteins that are involved in lal-/- ECs dysfunctions. We found that lal-/- ECs displayed increased expression of Rab7, a late endosome-/lysosome-associated small GTPase. Moreover, Rab7 and mTOR were co-increased and co-localized to the lysosomes, and physically interacted in lal-/- ECs. Rab7 inhibition reversed lal-/- EC dysfunctions, including decreasing their enhanced migration and permeability of tumor-stimulatory myeloid cells, and suppressed EC-mediated stimulation of in vitro tumor cell transmigration, proliferation and migration, and in vivo tumor growth and metastasis. Finally, Rab7 inhibition reduced the over-production of reactive oxygen species and the increased IL-6 and MCP-1 secretion in lal-/- ECs. Our results indicate that metabolic reprogramming resulting from LAL deficiency enhances ECs ability to stimulate tumor cell proliferation and metastasis through stimulation of lysosomal-anchored Rab7 activity.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2ff1xE4
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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