Immunohistochemical staining with anti-PROX1 or anti-LYVE-1 antibodies consistently revealed increased number of lymphatic vessels in footpad tumors of mice treated with A549-EVcircTLCD4-RWDD3+ALIXWT compared with control group, while mutating ALIX SIM contributed to significant reduction in the number of EV-packaged circTLCD4-RWDD3-induced lymphatic vessels (Fig. 8e–g), indicating that lymphangiogenesis induced by EV-packaged circTLCD4-RWDD3 could be impaired by the mutation of SIM in ALIX in NSCLC cells. The gene discussed is PDCD6IP; the disease is non-small cell lung carcinoma.