secinh3 and Neoplasm-Metastasis

Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein-1 (ZO-1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.

Topics: ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Endothelial Cells; Female; Gene Knockout Techniques; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Nerve Tissue Proteins; Receptors, Cell Surface; Receptors, Immunologic; Signal Transduction; Triazoles; Vascular Endothelial Growth Factor A; Zonula Occludens-1 Protein

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients.

Topics: ADP-Ribosylation Factor 6; ADP-Ribosylation Factors; Adult; Aged; Aged, 80 and over; Amides; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Female; GTP-Binding Protein alpha Subunits, G12-G13; Guanine Nucleotide Exchange Factors; HEK293 Cells; Humans; Immunohistochemistry; Indoles; Isoxazoles; Kidney Neoplasms; Lysophospholipids; Male; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Nerve Tissue Proteins; Propionates; Pyridines; Pyrroles; Receptors, Lysophosphatidic Acid; Signal Transduction; Sirolimus; Sunitinib; Triazoles