Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

Publiverse Online S.R.L - 2013
Sonia L Hernandez1, Debarshi Banerjee1, Alejandro Garcia2, Thaned Kangsamaksin3, Wei-Yi Cheng4, Dimitris Anastassiou4, Yasuhiro Funahashi3, Angela Kadenhe-Chiweshe2, Carrie J Shawber3, Jan K Kitajewski5,3, Jessica J Kandel2, Darrell J Yamashiro5,2,1
1Department of Pediatrics, Columbia University Medical Center, New York, USA
2Department of Surgery, Columbia University Medical Center, New York, USA
3Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, USA
4Center for Computational Biology and Bioinformatics, Columbia University, New York, USA
5Department of Pathology and Cell Biology, Columbia University Medical Center New York, USA.

Tóm tắt

Anti-angiogenesis is a validated strategy to treat cancer, with efficacy in controlling both primary tumor growth and metastasis. The role of the Notch family of proteins in tumor angiogenesis is still emerging, but recent data suggest that Notch signaling may function in the physiologic response to loss of VEGF signaling, and thus participate in tumor adaptation to VEGF inhibitors. We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct, which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone.

Từ khóa


Tài liệu tham khảo

Glade Bender JL, Adamson PC, Reid JM, Xu L, Baruchel S, Shaked Y, Kerbel RS, Cooney-Qualter EM, Stempak D, Chen HX, et al: Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol. 2008, 26: 399-405. 10.1200/JCO.2007.11.9230.

Kim ES, Serur A, Huang J, Manley CA, McCrudden KW, Frischer JS, Soffer SZ, Ring L, New T, Zabski S, et al: Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci USA. 2002, 99: 11399-11404. 10.1073/pnas.172398399.

Zaghloul N, Hernandez SL, Bae JO, Huang J, Fisher JC, Lee A, Kadenhe-Chiweshe A, Kandel JJ, Yamashiro DJ: Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma. Int J Oncol. 2009, 34: 401-407.

Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993, 362: 841-844. 10.1038/362841a0.

Funahashi Y, Hernandez SL, Das I, Ahn A, Huang J, Vorontchikhina M, Sharma A, Kanamaru E, Borisenko V, Desilva DM, et al: A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 2008, 68: 4727-4735. 10.1158/0008-5472.CAN-07-6499.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005, 102: 15545-15550. 10.1073/pnas.0506580102.

Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM: Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003, 163: 1801-1815. 10.1016/S0002-9440(10)63540-7.

Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, et al: Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006, 444: 1083-1087. 10.1038/nature05313.

Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, Karsan A: Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol Cell Biol. 2004, 24: 8813-8822. 10.1128/MCB.24.20.8813-8822.2004.

Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M: Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol. 2003, 23: 14-25. 10.1128/MCB.23.1.14-25.2003.

Funahashi Y, Shawber CJ, Vorontchikhina M, Sharma A, Outtz HH, Kitajewski J: Notch regulates the angiogenic response via induction of VEGFR-1. J Angiogenes Res. 2010, 2: 3-10.1186/2040-2384-2-3.

Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, et al: Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest. 2007, 117: 3369-3382. 10.1172/JCI24311.

Taylor KL, Henderson AM, Hughes CC: Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res. 2002, 64: 372-383. 10.1006/mvre.2002.2443.

Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G: Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006, 444: 1032-1037. 10.1038/nature05355.

Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, et al: Therapeutic antibody targeting of individual Notch receptors. Nature. 2010, 464: 1052-1057. 10.1038/nature08878.

Soffer SZ, Moore JT, Kim E, Huang J, Yokoi A, Manley C, O’Toole K, Stolar C, Middlesworth W, Yamashiro DJ, Kandel JJ: Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor. Journal of pediatric surgery. 2001, 36: 1177-1181. 10.1053/jpsu.2001.25747.

Bergers G, Hanahan D: Modes of resistance to anti-angiogenic therapy. Nature reviews Cancer. 2008, 8: 592-603. 10.1038/nrc2442.

Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH: The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009, 137: 1124-1135. 10.1016/j.cell.2009.03.025.

Thông tin
Thông tin xuất bản

Publiverse Online S.R.L

Thông tin tác giả