Investigations into Tumor Angiogenesis

Angiogenesis (the recruitment and formation of new blood vessels) plays a fundamental role in vessel development in the embryo and placenta during pregnancy. In adults, it is confined mainly to the menstrual cycle and wound healing, and its occurrence otherwise often heralds pathologic states such as tumor development, atherosclerosis, endometriosis, ischemic injury, or macular degeneration. The late Dr. Judah Folkman, founder of the tumor angiogenesis field, demonstrated that tumors cannot grow beyond a minimal size without recruiting new blood vessels. His suggestion that inhibition of such tumor angiogenesis may be an effective and novel means to target tumors has led to a paradigm shift in cancer care. Hundreds of clinical trials worldwide are now testing anti-angiogenic therapeutic strategies.

Considerable basic and translational angiogenesis research has been conducted at the Center of Cancer Systems Biology. Several members of our team over the years had tight research collaborations with or trained under Dr. Folkman. Among these have been Lynn Hlatky, Philip Hahnfeldt, Amir Abdollahi, Giannoula Klement, Nava Almog, Clare Lamont, Abdo Abou-Slaybi, and Kashi Javaherian. Many of the angiogenic initiatives these researchers designed jointly with Dr. Folkman continued at the CCSB, dovetailing with two of our Center's primary interests: to investigate how intercellular interactions and tumor microenvironment modify tumor evolution, and to develop predictive quantitative models of carcinogenesis and metastasis.

Publications:

A strong body of work on the topic of tumor angiogenesis has been published by researchers at the CCSB:

• Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: an update. Radiat Prot Dosimetry. 2015 Sep;166(1-4):334-8. Epub 2015 Apr 20.
• Poleszczuk J, Hahnfeldt P, Enderling H. Therapeutic implications from sensitivity analysis of tumor angiogenesis models. PLoS One. 2015 Mar 18;10(3):e0120007. PMCID: PMC4364928.
• Shaked Y, McAllister S, Fainaru O, Almog N. Tumor dormancy and the angiogenic switch: possible implications of bone marrow-derived cells. Curr Pharm Des. 2014;20(30):4920-33. Epub 2013 Nov 25.
• Girdhani S, Lamont C, Peluso M, Sun M, Hlatky L. ⁵⁶Fe ion irradiation enhances angiogenesis and other inter-cellular determinants of carcinogenesis risk. J Radiat Res. 2014 Mar 1;55 Suppl 1:i124-i126. PMCID: PMC3941549.
• Piccioni A, Gaetani E, Neri V, Gatto I, Palladino M, Silver M, Smith RC, Giarretta I, Pola E, Hlatky L, Pola R. Sonic hedgehog therapy in a mouse model of age-associated impairment of skeletal muscle regeneration. J Gerontol A Biol Sci Med Sci. 2014 Mar;69(3):245-52. Epub 2013 Jun 18. PMCID: PMC3976139.   EDITOR'S CHOICE selection
• Benzekry S, Gandolfi A, Hahnfeldt P. Global dormancy of metastases due to systemic inhibition of angiogenesis. PLoS One. 2014 Jan 21;9(1):e84249. eCollection 2014 Jan 21. PMCID: PMC3897365.
• Palladino M, Gatto I, Neri V, Straino S, Smith RC, Silver M, Gaetani E, Marcantoni M, Giarretta I, Stigliano E, Capogrossi M, Hlatky L, Landolfi R, Pola R. Angiogenic impairment of the vascular endothelium: a novel mechanism and potential therapeutic target in muscular dystrophy. Arterioscler Thromb Vasc Biol 33(12):2867-76, 2013. Epub 2013 Sep 26.
• Wilkie KP, Hahnfeldt P. Mathematical models of immune-induced cancer dormancy and the emergence of immune evasion. Interface Focus 3(4):20130010, 2013. PMCID: PMC3915830.
• Pilatova K, Greplova K, Demlova R, Bencsikova B, Klement GL, Zdrazilova-Dubska L. Role of platelet chemokines, PF-4 and CTAP-III, in cancer biology. J Hematol Oncol 6: 42, 2013. PMCID: PMC3694472.
• Lignet F, Benzekry S, Wilson S, Billy F, Saut O, Tod M, You B, Adda Berkane A, Kassour S, Wei MX, Grenier E, Ribba B. Theoretical investigation of the efficacy of antiangiogenic drugs combined to chemotherapy in xenografted mice. J Theor Biol 320: 86-99, 2013. Epub 2012 Dec 21.
• Kareva I. Biological Stoichiometry in Tumor Micro-environments. PLoS One 8(1): e51844, 2013. Epub 2013 Jan 22. PMCID: PMC3551943.
• Almog N. Genes and Regulatory Pathways Involved in Persistence of Dormant Micro-tumors. Adv Exp Med Biol 734: 3-17, 2013. (also in Systems Biology of Tumor Dormancy. Enderling H, Almog N, Hlatky L, editors. New York: Springer; 2013, p. 3-17.)
• Hahnfeldt P. The host support niche as a control point for tumor dormancy: implications for tumor development and beyond. Adv Exp Med Biol 734: 19-35, 2013. (also in Systems Biology of Tumor Dormancy. Enderling H, Almog N, Hlatky L, editors. New York: Springer; 2013, p. 19-35.)
• Klement GL, Shai E, Varon D. Chapter 24 — The Role of Platelets in Angiogenesis. In: Michelson A (ed). Platelets. Third Edition. Waltham, MA: Academic Press (Elsevier Science), 2013:487-502.
• Palladino M, Gatto I, Neri V, Stigliano E, Smith RC, Pola E, Straino S, Gaetani E, Capogrossi M, Leone G, Hlatky L, Pola R. Combined therapy with sonic hedgehog gene transfer and bone marrow-derived endothelial progenitor cells enhances angiogenesis and myogenesis in the ischemic skeletal muscle. J Vasc Res 49(5): 425-31, 2012. Epub 2012 Jun 22.
• Girdhani S, Lamont C, Hahnfeldt P, Hlatky L. Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth. Radiat Res. 2012 Jul;178(1):31. Epub 2012 July 28. PMCID: PMC3499182.
• Enderling H, Hahnfeldt P, Hlatky L, Almog N. Systems biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy. Cancer Res 72(9): 2172-5, 2012. Epub 2012 Mar 13. PMCID: PMC3374524.
• Benzekry S. Mathematical and numerical analysis of a model for anti-angiogenic therapy in metastatic cancers. Esaim Math Model Numer Anal 46(2): 207-37, 2012. Epub 2011 Oct 6.
• Benzekry S. Passing to the limit 2D-1D in a model for metastatic growth. J Biol Dyn 6 Suppl 1: 19-30, 2012. Epub 2011 Jun 24.
• Benzekry S, André N, Benabdallah A, Ciccolini J, Faivre C, Hubert F, Barbolosi D. Modeling the impact of anticancer agents on metastatic spreading. Math Model Natl Phenom 7(1): 306-36, 2012. Epub 2012 Jan 25.
• Benzekry S, Chapuisat G, Ciccolini J, Erlinger A, Hubert F. A new mathematical model for optimizing the combination between antiangiogenic and cytotoxic drugs in oncology / Un nouveau modèle mathématique pour l'optimisation des combinaisons antiangiogéniques/cytotoxiques en cancérologie. Comptes Rendus Mathematique 350(1-2): 23-8, 2012. Epub 2011 Dec 16.
• Benzekry S. Mathematical analysis of a two-dimensional population model of metastatic growth including angiogenesis. J Evol Equ 11(1): 187-213, 2011. Epub 2010 Dec 23.
• Javaherian K, Lee TY, Tjin Tham Sjin RM, Parris GE, Hlatky L. Two endogenous antiangiogenic inhibitors, endostatin and angiostatin, demonstrate biphasic curves in their antitumor profiles. Dose Response 9(3): 369-76, 2011. Epub 2010 Oct 21. PMCID: PMC3186931.
• Klement GL. Platelet biomarkers in tumor growth. Curr Proteomics 8(3): 169-80, 2011.
• Almog N. Molecular mechanisms underlying tumor dormancy. Cancer Lett 294(2): 139-46, 2010. Epub 2010 Apr 2.
• Almog N, Klement G. Platelet proteome and tumor dormancy: can platelets content serve as predictive biomarkers for exit of tumors from dormancy? Cancers (Basel) 2(2): 842-58, 2010. PMCID: PMC3835108.
• Fainaru O, Almog N, Yung CW, Nakai K, Montoya-Zavala M, Abdollahi A, D'Amato R, Ingber DE. Tumor growth and angiogenesis are dependent on the presence of immature dendritic cells. FASEB J 24(5): 1411-8, 2010. Epub 2009 Dec 14. PMCID: PMC2879945.
• Lee TY, Folkman J, Javaherian K. HSPG-binding peptide corresponding to the exon 6a-encoded domain of VEGF inhibits tumor growth by blocking angiogenesis in murine model. PLoS One 5(4): e9945, 2010. PMCID: PMC2848586.
• Abdollahi A, Folkman J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat 13(1-2): 16-28, 2010. Epub 2010 Jan 12.
• Lee TY, Muschal S, Pravda EA, Folkman J, Abdollahi A, Javaherian K. Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins. Blood 114(9): 1987-98, 2009. Epub 2009 May 22. PMCID: PMC2738581.
• Klement GL, Yip TT, Cassiola F, Kikuchi L, Cervi D, Podust V, Italiano JE, Wheatley E, Abou-Slaybi A, Bender E, Almog N, Kieran MW, Folkman J. Platelets actively sequester angiogenesis regulators. Blood 113(12): 2835-42, 2009. Epub 2008 Nov 25. PMCID: PMC2661866.
• Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J, Abdollahi A. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res 69(3): 836-44, 2009. Epub 2009 Jan 27.   COVER ARTICLE
• Domhan S, Muschal S, Schwager C, Morath C, Wirkner U, Ansorge W, Maercker C, Zeier M, Huber PE, Abdollahi A. Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol Cancer Ther. 2009 Jun;7(6):1656-68.
• Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111(3): 1227-33, 2008. Epub 2007 Oct 25.
• Cervi D, Yip TT, Bhattacharya N, Podust VN, Peterson J, Abou-Slaybi A, Naumov GN, Bender E, Almog N, Italiano Jr. JE, Folkman J, Klement GL. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111(3): 1201-7, 2008. Epub 2007 Oct 3.
• Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, Hauser K, Hahnfeldt P, Hlatky L, Debus J, Peters JM, Friess H, Folkman J, Huber PE. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci U S A 104(31): 12890-5, 2007. Epub 2007 Jul 24. PMCID: PMC1931565.
• Almog N, Henke V, Flores L, Hlatky L, Kung AL, Wright RD, Berger R, Hutchinson L, Naumov GN, Bender E, Akslen LA, Achilles EG, Folkman J. Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J 20(7): 947-9, 2006. Epub 2006 Apr 25.
• Abdollahi A, Hlatky L, Huber PE. Endostatin: the logic of antiangiogenic therapy. Drug Resist Updat 8(1-2): 59-74, 2005. Epub 2005 Apr 7.
• Abdollahi A, Hahnfeldt P, Maercker C, Grone HJ, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE. Endostatin's antiangiogenic signaling network. Mol Cell 13(5): 649-63, 2004.
• Abdollahi A, Lipson KE, Sckell A, Zieher H, Klenke F, Poerschke D, Roth A, Han X, Krix M, Bischof M, Hahnfeldt P, Grone HJ, Debus J, Hlatky L, Huber PE. Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res 63(24): 8890-8, 2003.
• Abdollahi A, Lipson KE, Han X, Krempien R, Trinh T, Weber KJ, Hahnfeldt P, Hlatky L, Debus J, Howlett AR, Huber PE. SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Cancer Res 63(13): 3755-63, 2003.
• Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 220(4): 545-54, 2003.
• Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ, Moses MA, Kilroy S, Duensing S, Fletcher C, Fletcher JA, Hlatky L, Hahnfeldt P, Folkman J, Kaipainen A. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 110(7): 923-32, 2002.
• Browder T, Folkman J, Hahnfeldt P, Heymach J, Hlatky L, Kieran M, Rogers MS. Antiangiogenic therapy and p53. Science 297(5581): 471, 2002.
• Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst 94(12): 883-93, 2002.
• Sachs RK, Hlatky LR, Hahnfeldt P. Simple ODE models of tumor growth and anti-angiogenic or radiation treatment. Math Comp Modeling 33(12-13): 1297-305, 2001.
• Folkman J, Hahnfeldt P, Hlatky L. Cancer: looking outside the genome. Nat Rev Mol Cell Biol 1(1): 76-9, 2000.
• Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L. Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 59(19): 4770-5, 1999.
• Folkman J, Hahnfeldt P, Hlatky L. The logic of anti-angiogenic gene therapy. In: Friedmann T, editor. The Development of Gene Therapy, Ch. III. Target Tissues and Target Diseases - Cancer. New York: Cold Spring Harbor Laboratory Press, 1998: p1-17.
• Hlatky L, Hahnfeldt P, Tsionou C, Coleman CN. Vascular endothelial growth factor: environmental controls and effects in angiogenesis. Br J Cancer Suppl 27: S151-6, 1996.
• Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 54(23): 6083-6, 1994.