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.