Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. Ó2016 AACR.

LncRNA NKX2-1-AS1 As ceRNA Promotes Tumor Progression and Angiogenesis by Upregulating SERPINE1 Expression and Activating VEGFR-2 Signaling Pathway in Gastric Cancer

“…Conversely, miRNA-145 was shown to inhibit GC cell invasion, metastasis and angiogenesis by targeting v-ets erythroblastosis virus E26 oncogene homolog 1 (39). Additionally, inhibition of miRNA-mediated SERPINE1 limits tumor angiogenesis, regardless of the angiogenic stimuli, in malignant pleural mesothelioma (40). In the present study, it is found that SERPINE1 is a direct target of miR-145-5p.…”

Inhibition of PAI‐1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer‐associated fibroblasts

“…PAI‐1 has been also reported to be involved in resistance to chemotherapy and tumourigenesis in various types of cancers . In vivo studies revealed the significance of PAI‐1 in regulating tumour angiogenesis . Furthermore, several in vitro studies have shown that PAI‐1 has a direct pro‐proliferative and anti‐apoptotic effect on the cancer cells.…”

Global secretome analysis of resident cardiac progenitor cells from wild‐type and transgenic heart failure mice: Why ambience matters

“…In addition, the Sca-1 + cell secretome is composed of a variety of cytoprotective molecules that were comparably secreted in both conditions such as inhibitors of apoptosis like IGF1 and SRPF2 (Vinciguerra, Santini, Claycomb, Ladurner, & Rosenthal, 2009;Zhang et al, 2009), WISP2 known to induce proliferation (Chowdhury et al, 2014) and the proangiogenic VEGFD (Jauhiainen et al, 2011) Angiogenesis is a dynamic process, which is tightly regulated by pro-and anti-angiogenic factors. Our data show a higher secretion of several angiogenic promoters namely MFGM, MYDGF, ANGP2, and PAI1 (Leblond et al, 2015;Mazzieri et al, 2011;Takayama et al, 2016;Uchiyama et al, 2014), as well as of inhibitors such as PEDF and TSP2 (Cai, Jiang, Grant, & Boulton, 2006;Krady et al, 2008) in Cyc cells than in Wt cells. Beside we observed no remarkable difference in the relative abundance of positive versus negative regulators in either CM.…”