Endothelial Rab7 GTPase mediates tumor growth and metastasis in lysosomal acid lipase-deficient mice.

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.

• Authors: Ting Zhao, Xinchun Ding, Cong Yan, Hong Du
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 47 Pg. 19198-19208 (11 24 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28924047 (Publication Type: Journal Article)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Reactive Oxygen Species
• rab7 GTP-Binding Proteins
• rab7 GTP-binding proteins, mouse
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• Sterol Esterase
• lysosomal acid lipase, mouse
• rab GTP-Binding Proteins

Topics

• Animals
• Apoptosis
• Carcinoma, Lewis Lung (genetics, metabolism, secondary)
• Cell Movement
• Cell Proliferation
• Endothelium, Vascular (enzymology, pathology)
• Lysosomes (enzymology)
• Melanoma, Experimental (genetics, metabolism, secondary)
• Mice
• Mice, Knockout
• Myeloid Cells (metabolism, pathology)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Reactive Oxygen Species
• Signal Transduction
• Sterol Esterase (physiology)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transendothelial and Transepithelial Migration
• Tumor Cells, Cultured
• Wolman Disease (complications, physiopathology)
• rab GTP-Binding Proteins (genetics, metabolism)
• rab7 GTP-Binding Proteins
• Wolman Disease