title: Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium.
abstract: It is well known that tumor-derived proangiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of "angiocrine" signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function, has been proposed, yet remains underinvestigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor data sets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal.
authors.affiliation: Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Dunaway
authors.forename: Meghana
authors.initials: M
authors.lastname: Rao
authors.forename: Sarah
authors.initials: S
authors.lastname: Short
authors.forename: Yoonha
authors.initials: Y
authors.lastname: Hwang
authors.forename: Yandong
authors.initials: Y
authors.lastname: Gao
authors.forename: Deyu
authors.initials: D
authors.lastname: Li
authors.forename: Aixiang
authors.initials: A
authors.lastname: Jiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D036104:Receptor, EphA2 / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D036104:Receptor, EphA2; D000098552:Slit Homolog 2 Protein