of snail and N-cadherin was reduced in tumors with PAR-1 deficiency and E-cadherin expression was increased (Fig. [5i](#Fig5){ref-type="fig"}). Together with the in-vitro experiments, these results allowed us to conclude that PAR-1 plays an important role in thrombin-induced VM formation in NSCLC.

Combination therapy with DTIP and an EGFR inhibitor resulted in improved antitumor efficacy {#Sec8}
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EGFR-TKIs, including gefitinib, erlotinib, and so on, as angiogenesis inhibitors have significantly improved clinical outcomes. However, most NSCLC patients do not respond (primary resistance) and those who initially respond eventually progress (acquired resistance). There is an urgent need to develop a combination therapy of TKIs with other reagents to enhance antitumor activity and overcome drug resistance. Van der Schaft et al.^[@CR41]^ reported that angiogenesis inhibitors had no effect on VM and Naumov et al.^[@CR42]^ reported that EGFR inhibitors could induce a rise in both host and tumor-derived vascular endothelial growth factor (VEGF), which is associated with resistance. One week after LLC inoculation, mice were randomly divided into four groups: normal saline, DTIP (1 mg/kg per day, s.c.), gefitinib (100 mg/kg per day, intragastric), and combination DTIP with gefitinib treatment groups. Next, the mice were administered DTIP, gefitinib, or normal saline for 21 consecutive days. The tumor volume and tumor weight in the combination treatment group were significantly lower than those in the groups administered DTIP alone or gefitinib alone (Fig. [6a--c](#Fig6){ref-type="fig"}). The number of mice with lung metastases was largely reduced in the combination treatment group compared with that in the single-treatment groups (Fig. [6d, e](#Fig6){ref-type="fig"}). Consistent with previous reports,^[@CR41],[@CR42]^ we found that gefitinib had no effect on VM formation (Fig. [6f, g](#Fig6){ref-type="fig"}), and after gefitinib