[en] Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies.
Disciplines :
Biotechnology
Author, co-author :
Prats, A. C.
Van den Berghe, L.
Rayssac, A.
Ainaoui, N.
Morfoisse, Florent ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Pujol, F.
Legonidec, S.
Bikfalvi, A.
Prats, H.
Pyronnet, S.
Garmy-Susini, B.
Language :
English
Title :
CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.
Publication date :
2013
Journal title :
Microvascular Research
ISSN :
0026-2862
eISSN :
1095-9319
Publisher :
Elsevier, Atlanta, Georgia
Volume :
89
Pages :
25-33
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2013 Elsevier Inc. All rights reserved.
Avraamides C.J., Garmy-Susini B., et al. Integrins in angiogenesis and lymphangiogenesis. Nat. Rev. Cancer 2008, 8(8):604-617.
Bossard C., Van Den Berghe L., et al. Antiangiogenic properties of fibstatin, an extracellular FGF-2-binding polypeptide. Cancer Res. 2004, 64(20):7507-7512.
Brideau G., Makinen M.J., et al. Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res. 2007, 67(24):11528-11535.
Byers L.A., Heymach J.V. Dual targeting of the vascular endothelial growth factor and epidermal growth factor receptor pathways: rationale and clinical applications for non-small-cell lung cancer. Clin. Lung Cancer 2007, 8(Suppl. 2):S79-S85.
Campochiaro P.A. Gene transfer for neovascular age-related macular degeneration. Hum. Gene Ther. 2011, 22(5):523-529.
Campochiaro P.A. Gene transfer for ocular neovascularization and macular edema. Gene Ther. 2012, 19(2):121-126. (Epub 2011 Nov 10) (Feb). 10.1038/gt.2011.164.
Cui K., Zhao W., et al. The CXCR4-CXCL12 pathway facilitates the progression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis. J. Surg. Res. 2011, 171(1):143-150.
Delluc-Clavieres A., Le Bec C., et al. Efficient gene transfer in skeletal muscle with AAV-derived bicistronic vector using the FGF-1 IRES. Gene Ther. 2008, 15(15):1090-1098.
Dubrac A., Quemener C., et al. Functional divergence between 2 chemokines is conferred by single amino acid change. Blood 2010, 116(22):4703-4711.
Foy K.C., Liu Z., et al. Combination treatment with HER-2 and VEGF peptide mimics induces potent anti-tumor and anti-angiogenic responses in vitro and in vivo. J. Biol. Chem. 2011, 286(15):13626-13637.
Garmy-Susini B., Makale M., et al. Methods to study lymphatic vessel integrins. Methods Enzymol. 2007, 426:415-438.
Garmy-Susini B., Avraamides C.J., et al. Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res. 2010, 70(8):3042-3051.
Gordis L., Gold E.B. Epidemiology of pancreatic cancer. World J. Surg. 1984, 8(6):808-821.
Kerbel R., Folkman J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2002, 2(10):727-739.
Kim K.S., Park Y.S. Antitumor effects of angiostatin K1-3 and endostatin genes coadministered by the hydrodynamics-based transfection method. Oncol. Res. 2005, 15(7-8):343-350.
Liu Y., Thor A., et al. Systemic gene delivery expands the repertoire of effective antiangiogenic agents. J. Biol. Chem. 1999, 274(19):13338-13344.
Mulder K., Koski S., et al. Antiangiogenic agents in advanced gastrointestinal malignancies: past, present and a novel future. Oncotarget 2010, 1(7):515-529.
Mumprecht V., Detmar M. Lymphangiogenesis and cancer metastasis. J. Cell. Mol. Med. 2009, 13(8A):1405-1416.
Nagy J.A., Vasile E., et al. VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harb. Symp. Quant. Biol. 2002, 67:227-237.
Nierodzik M.L., Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 2006, 10(5):355-362.
O'Reilly M.S., Boehm T., et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997, 88(2):277-285.
Ou J., Li J., et al. Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9. J. Cell. Biochem. 2011, 112(8):2106-2114.
Paez-Ribes M., Allen E., et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009, 15(3):220-231.
Ponnazhagan S., Mahendra G., et al. Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor. Cancer Res. 2004, 64(5):1781-1787.
Rayssac A., Neveu C., et al. IRES-based vector coexpressing FGF2 and Cyr61 provides synergistic and safe therapeutics of lower limb ischemia. Mol. Ther. 2009, 17(12):2010-2019.
Renyi-Vamos F., Tovari J., et al. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin. Cancer Res. 2005, 11(20):7344-7353.
Rupp C.C., Linehan D.C. Extended lymphadenectomy in the surgery of pancreatic adenocarcinoma and its relation to quality improvement issues. J. Surg. Oncol. 2009, 99(4):207-214.
Sirven A., Ravet E., et al. Enhanced transgene expression in cord blood CD34(+)-derived hematopoietic cells, including developing T cells and NOD/SCID mouse repopulating cells, following transduction with modified trip lentiviral vectors. Mol. Ther. 2001, 3(4):438-448.
Skobe M., Hawighorst T., et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 2001, 7(2):192-198.
Stacker S.A., Caesar C., et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat. Med. 2001, 7(2):186-191.
Struyf S., Burdick M.D., et al. Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis. Cancer Res. 2007, 67(12):5940-5948.
Tammela T., Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 2010, 140(4):460-476.