Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
[en] Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sennino, Barbara
Kuhnert, Frank
Tabruyn, Sébastien ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Mancuso, Michael R
Hu-Lowe, Dana D
Kuo, Calvin J
McDonald, Donald M
Language :
English
Title :
Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
Publication date :
2009
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
American Association for Cancer Research, Inc. (AACR), Baltimore, United States - Maryland
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353-364 (Pubitemid 26272076)
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967-974 (Pubitemid 43093963)
Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control 2007;14:285-294 (Pubitemid 47057799)
Crawford Y, Ferrara N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res 2009;335:261-269
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008;8:579-591
Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 2000;156:1363-1380 (Pubitemid 30660013)
Hirschi KK, D'Amore PA. Pericytes in the microvasculature. Cardiovasc Res 1996;32:687-698 (Pubitemid 26332308)
Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGFB-deficient mice. Science 1997;277:242-245 (Pubitemid 27446080)
von Tell D, Armulik A, Betsholtz C. Pericytes and vascular stability. Exp Cell Res 2006;312:623-629
Abramsson A, Berlin O, Papayan H, Paulin D, Shani M, Betsholtz C. Analysis of mural cell recruitment to tumor vessels. Circulation 2002;105:112-117 (Pubitemid 34049151)
Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 2002;160:985-1000. (Pubitemid 34224587)
Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 2005;97:512-523 (Pubitemid 41361741)
Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 2005;94:209-231
Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004;18:338-340
Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001;15:1239-1241
Darland DC, Massingham LJ, Smith SR, Piek E, Saint-Geniez M, D'Amore PA. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 2003;264:275-288 (Pubitemid 37393463)
Enge M, Bjarnegard M, Gerhardt H, et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J 2002;21:4307-4316
Hellstrom M, Kal n M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126:3047-3055
Bjarnegard M, Enge M, Norlin J, et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 2004;131:1847-1857 (Pubitemid 38559851)
Betsholtz C. Biology of platelet-derived growth factors in development. Birth Defects Res C Embryo Today 2003;69:272-285 (Pubitemid 38076452)
Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543-553 (Pubitemid 34280141)
Sennino B, Falcon BL, McCauley D, et al. Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 2007;67:7358-7367 (Pubitemid 47206566)
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111:1287-1295 (Pubitemid 36554699)
Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 2005;7:870-879
Miller KD, Sweeney CJ, Sledge GW, Jr. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 2001;19:1195-1206 (Pubitemid 32176298)
Fudge K, Wang CY, Stearns ME. Immunohistochemistry analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor α and β receptor expression in benign prostatic hyperplasias and Gleason-graded human prostate adenocarcinomas. Mod Pathol 1994;7:549-554
Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M, Oberg K. Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res 1993;53:4550-4554 (Pubitemid 23304378)
Potapova O, Laird AD, Nannini MA, et al. Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Mol Cancer Ther 2006;5:1280-1289 (Pubitemid 43881321)
Laird AD, Vajkoczy P, Shawver LK, et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000;60:4152-4160 (Pubitemid 30636598)
Druker BJ. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med 2002;8:S14-8.
Kuo CJ, Farnebo F, Yu EY, et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc Natl Acad Sci U S A 2001;98:4605-4610 (Pubitemid 32295023)
Kuhnert F, Tam BY, Sennino B, et al. Soluble receptor-mediated selective inhibition of VEGFR and PDGFRβ signaling during physiologic and tumor angiogenesis. Proc Natl Acad Sci U S A 2008;105:10185-10190
Hanahan D. Heritable formation of pancreatic β-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 1985;315:115-122 (Pubitemid 15064530)
Hu-Lowe D, Hallin M, Feeley R, et al. Characterization of potency and activity of the VEGF/PDGF receptor tyrosine kinase inhibitor AG013736. Proc Am Assoc Cancer Res 2002;43:A5357.
Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004;165:35-52. (Pubitemid 38821812)
Manley PW, Cowan-Jacob SW, Buchdunger E, et al. Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer 2002;38 Suppl 5:S19-27.
Chartier C, Degryse E, Gantzer M, Dieterle A, Pavirani A, Mehtali M. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol 1996;70:4805-4810 (Pubitemid 26187479)
Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008;14:7272-7283
Ono M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 2008;99:1501-1506
Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008;22:1276-1312
Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 2005;15:102-111 (Pubitemid 40127638)
Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-oncol 2005;7:452-464 (Pubitemid 41555617)
Sims DE. Diversity within pericytes. Clin Exp Pharmacol Physiol 2000;27:842-846
Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000;2:737-744
Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis. Cancer Cell 2002;1:193-202. (Pubitemid 41039165)
Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116:2610-2621 (Pubitemid 44511625)
Redmer DA, Doraiswamy V, Bortnem BJ, et al. Evidence for a role of capillary pericytes in vascular growth of the developing ovine corpus luteum. Biol Reprod 2001;65:879-889 (Pubitemid 32777376)