Abstract
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.
Highlights
Angiogenesis is known as a hallmark of cancer progression for growth of solid tumors beyond 1–2 mm3 [1]
Cisplatin has been demonstrated to elicit antiangiogenic effects in solid tumors, and has recently been shown to be effective against xenografts of renal cell carcinoma [7], ovarian [8,9,10,11], gastric [12], and lung cancer cells [13,14,15], with the latter including tumors generated by the lung cancer cell line A549, which is used in the current study [14, 15]
The impact of cisplatin on the viability of A549 and H358 lung cancer cells was investigated following a 48-h incubation period. This treatment protocol was chosen based on recent findings that demonstrated a 48-h incubation to be sufficient for the induction of migration, viability, and tube formation of human umbilical vein endothelial cells (HUVECs) exposed to conditioned media (CM) from cancer cells [25]
Summary
Angiogenesis is known as a hallmark of cancer progression for growth of solid tumors beyond 1–2 mm3 [1]. Oxygen- and nutrition-starved tumors secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF), which target endothelial receptor tyrosine kinases on the surface of vessel cells to promote neovascularization [2]. Platinum-based chemotherapy is the recommended first-line treatment for the majority of advanced inoperable www.oncotarget.com lung cancers [4, 5], with the exception of inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase as the first-line therapy for patients with an activating EGFR mutation [5, 6]. One study further demonstrated the antiangiogenic properties of cisplatin in an in vivo alginate-encapsulated ovarian cancer cell assay [10]. None of these investigations have addressed a probable cisplatin-modulated tumor-toendothelial communication conferring antiangiogenesis
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