The antiangiogenic action of cisplatin on endothelial cells is mediated through the release of tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells

In addition to suppressing cancer cell proliferation and tumor growth, cisplatin has been shown to inhibit tumor angiogenesis. However, the underlying mechanism remains a matter of debate. The present study addressed the impact of cisplatin on potential tumor-to-endothelial cell communication conferring an antiangiogenic effect. For this purpose, migration and tube formation of human umbilical vein endothelial cells (HUVECs) exposed to conditioned media (CM) from vehicle- or cisplatin-treated A549 and H358 lung cancer cells were quantified. Cancer cells were exposed to non-toxic concentrations of cisplatin to mimic low-dose treatment conditions. CM from cancer cells exposed to cisplatin at concentrations of 0.01 to 1 µM elicited a concentration-dependent decrease in HUVEC migration and tube formation as compared with CM from vehicle-treated cells. The viability of HUVECs was virtually unaltered under these conditions. siRNA approaches revealed cisplatin-induced expression and subsequent release of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) by lung cancer cells to be causally linked to a decrease in HUVEC migration and tube formation. Moreover, TIMP-1 upregulation and consequent inhibition of HUVEC migration by cisplatin was shown to be dependent on activation of p38 and p42/44 mitogen-activated protein kinases. Inhibition of angiogenic features was not observed when HUVECs were directly exposed to cisplatin. Similarly, antiangiogenic effects were not detectable in HUVECs exposed to CM from the cisplatin-challenged bronchial non-cancer cell line BEAS-2B. Collectively, the present data suggest a pivotal role of cisplatin-induced TIMP-1 release from lung cancer cells in tumor-to-endothelial cell communication resulting in a reduced cancer-associated angiogenic impact on endothelial cells.