Title : Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice - Zhao_2017_J.Biol.Chem_292_19198
Author(s) : Zhao T , Ding X , Yan C , Du H
Ref : Journal of Biological Chemistry , 292 :19198 , 2017
Abstract :

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(-/-) EC 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 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 overproduction of reactive oxygen species and increased IL-6 and MCP-1 secretion in lal(-/-) ECs. Our results indicate that metabolic reprogramming resulting from LAL deficiency enhances the ability of ECs to stimulate tumor cell proliferation and metastasis through stimulation of lysosome-anchored Rab7 activity.

PubMedSearch : Zhao_2017_J.Biol.Chem_292_19198
PubMedID: 28924047
Gene_locus related to this paper: mouse-1llip

Related information

Gene_locus mouse-1llip
Family Acidic_Lipase

Citations formats

Zhao T, Ding X, Yan C, Du H (2017)
Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice
Journal of Biological Chemistry 292 :19198

Zhao T, Ding X, Yan C, Du H (2017)
Journal of Biological Chemistry 292 :19198