Low density lipoprotein receptor mediates anti-VEGF effect of lymphocyte T-derived microparticles in Lewis lung carcinoma cells.
Nonstop proliferation and vigorous neovascularization are two prominent characteristics of cancer. Antiangiogenic therapy has emerged as an important modality in treatment of solid tumors. Our previous work demonstrated that microparticles derived from apoptotic T-lymphocytes (LMPs) not only reduced the viabilities of high-proliferating cells, but also exhibited potent antiangiogenic effects through inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor 2 signalling pathway. In the present study, we extended these studies to explore the anticancer potential of LMPs using a murine model of Lewis lung carcinoma (LLC). Results show that intratumoral injection of LMPs (2.5 mg/kg) decreased tumor size by more than 50% relative to control. Tumor microvessel density and VEGF-A levels were also markedly reduced upon LMPs treatment. To elucidate the underlying mechanisms of LMPs-mediated antitumor activity, LLC cells were utilized in in vitro experiments. LMPs suppressed VEGF-A protein levels in LLC cells and led to inhibition of LLC cell viability and proliferation. In addition, knockdown of the low-density lipoprotein receptor (LDLR) expression reduced the uptake of LMPs into LLC cells and attenuated the inhibitory effects of LMPs on cell growth and VEGF-A expression. Our findings demonstrate that LMPs exert antiangiogenic and proapoptotic effects that lead to inhibition of lung carcinoma by reducing VEGF-A levels and LDLR mediates the anti-VEGF effect of LMPs through translocating LMPs into LLC cells. These results suggest that LMPs are promising antiangiogenic therapeutic agent and represent a new therapeutic strategy for treating lung carcinomas.
Yang
Chun
C
Department of Paediatrics and Pharmacology, Research Center of CHU Sainte-Justine, Montréal, Québec, Canada.
Gagnon
Carmen
C
Hou
Xin
X
Hardy
Pierre
P
D020533:Angiogenesis Inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D055252:Cell-Derived Microparticles / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000628:therapy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D042461:Vascular Endothelial Growth Factor A