Neuropeptide substance P (SP) has been implicated in
inflammation,
pain, depression and
breast cancer cell (BCC) growth. Here, we examined the role of SP in trafficking of BCCs (human MDA-MB-231 and MDA-MB-231BrM2 cells) across the blood-brain barrier (BBB) and brain microvascular endothelial cells (BMECs) using in vitro and in vivo models. SP was secreted from BCCs and mediated adhesion and transmigration of BCCs across human BMECs (HBMECs) in vitro. SP induced activation of HBMECs, leading to secretion of
Tumor Necrosis Factor alpha (TNF-α) and
angiopoietin-2 (Ang-2) from HBMECs, resulting in changes in localization and distribution of tight junction (TJ) ZO-1 (
tight junction protein zonula
occludins-1) and
claudin-5 structures as well as increased permeability of HBMECs. Using spontaneous
breast cancer metastasis mouse model (syngeneic) of GFP-4T1-BrM5 mammary
tumor cells administered into mammary fat pads of Balb/c mice, SP inhibitor
spantide III inhibited in vivo changes in permeability of the BBB and BMEC-TJs ZO-1 and
claudin-5 structures as well as decreased
tumor cell colonization in brain. Thus, SP secreted from BCCs induces transmigration of BCCs across the BBB, leading to activation of BMECs and secretion of TNF-α and Ang-2, resulting in BBB impairment and colonization of
tumor cells in brain. Therefore,
therapies based on SP inhibition in combination with other
therapies may prevent breaching of the BBB by BCCs and their colonization in brain.