An important step in the process of
metastasis from the primary
tumor is invasive spread into the surrounding stroma. Using an in vivo invasion assay, we have previously shown that imposed gradients of
epidermal growth factor (
EGF) or colony-stimulating factor-1 (CSF-1) can induce invasion through an
EGF/CSF-1 paracrine loop between
cancer cells and macrophages. We now report that invasion induced by other
ligands also relies on this
EGF/CSF-1 paracrine invasive loop. Using an in vivo invasion assay, we show that MTLn3
breast cancer cells overexpressing ErbB3 exhibit enhanced invasion compared with control MTLn3 cells in response to the ErbB3
ligand HRG-beta1. The invasive response of both MTLn3-ErbB3 and transgenic MMTV-Neu
tumors to HRG-beta1 is inhibited by blocking
EGF receptor,
CSF-1 receptor, or macrophage function, indicating that invasiveness to HRG-beta1 is dependent on the
EGF/CSF-1 paracrine loop. Furthermore, we show that CXCL12 also triggers in vivo invasion of transgenic MMTV-PyMT
tumors in an
EGF/CSF-1-dependent manner. Although the invasion induced by HRG-beta1 or CXCL12 is dependent on the
EGF/CSF-1 paracrine loop, invasion induced by
EGF is not dependent on HRG-beta1 or CXCL12 signaling, showing an asymmetrical relationship between different
ligand/receptor systems in driving invasion. Our results identify a stromal/
tumor interaction that acts as an engine underlying invasion induced by multiple
ligands.