Skip to main content
SpringerLink
Log in
Book cover

mTOR Pathway and mTOR Inhibitors in Cancer Therapy pp 49–74Cite as

mTOR Signaling in Angiogenesis

  • Chapter
  • First Online:

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

An important feature of tumor blood vessels is that they are in a state of constant new tumor blood vessel growth. In endothelial cells, the PI3K/Akt pathway has been shown to play an important role in mediating cell survival, proliferation, and migration. The serine/threonine kinase, mammalian target of rapamycin (mTOR), an important downstream target of PI3K/Akt and mTOR signaling, has been shown to be involved in the control of cell growth and proliferation. To grow beyond a certain size primary tumor and metastases are dependent on the formation of new blood vessels or angiogenesis. In angiogenesis mTOR serves as a central regulator. There is growing evidence in support of the hypothesis that mTOR acts as a critical switch for endothelial cellular catabolism and anabolism, thus determining whether these cells grow and proliferate. This is especially critical in cancer cells bearing disturbances in the TOR pathway. There are several human cancers whereby the PI3K/Akt pathway is dysregulated. Gain or loss mutations of this pathway lead to neoplastic transformation. mTOR inhibitors downregulate hypoxia-inducible factor 1α (HIF1α)-mediated production of pro-angiogenic cytokine, vascular endothelial growth factor (VEGF), by tumor cells and the resulting activation of vascular endothelial growth factor receptors (VEGF-Rs) on endothelial and lymphatic precursor cells inhibiting survival and growth-promoting signals that support tumor vascularization and tumorigenesis. The antiangiogenic and antilymphangiogenic effects of mTOR inhibition may well translate into a reduced incidence of clinically apparent malignancies through reduced tumor growth and lymphatic metastasis, respectively.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

AMPK:

AMP-dependent protein kinase

ANG:

angiopoietin

bFGF:

basic fibroblast growth factor

CNI:

calcinurin inhibitor

EGF:

epidermal growth factor

eIF-4E:

eukaryotic translation factor 4E

ECM:

extracellular matrix

ERK1/2:

extracellular signal-regulated kinase

FGFs:

fibroblast growth factors

Flk-1/KDR:

fetal liver kinase receptor

GβL:

G protein β-subunit-like protein

GSK 3β:

glucagen synthase kinase -3β

HUVEC:

human umbilical cord vein endothelial cell

HIFs:

hypoxia-inducible transcription factors

IKKβ :

I kappa B kinase β

IGF:

insulin like growth factor

IL-8:

interleukin-8

KS:

Kaposi’s sarcoma

LPA:

lysophosphatic acid

mTORC:

mammalian target of rapamycin complex

mTOR:

mammalian target of rapamycin

mSin1:

mitogen-activated protein kinase-associated protein 1

MAPK:

mitogen-activated protein kinase

NF1:

neurofibromin 1

PTEN:

phosphatase and tensin homolog on chromosome 10

PI3K:

phosphatidylinositol 3 kinase

PI3P:

phosphatidylinositol 3,4,5-triphosphates

PDK1:

phosphoinositol-dependent protein kinase 1

PGF:

placental growth factor

PDGF:

platelet-derived growth factor

PKC:

protein kinase C

PKD1:

pyruvate dehydrogenase kinase 1

RHEB:

RAS homolog enriched in brain

RTK:

receptor tyrosine kinase

RCC:

renal cell carcinoma

p70S6K1:

ribosomal p70S6 kinase

STK:

serine/theronine kinase

TF:

tissue factor

TGF:

transforming growth factor

4E-BP:

translation initiation factor 4E-binding protein

TSC:

tuberous sclerosis complex

TAMs:

tumor-associated macrophages

TGBβ:

tumor growth factor-β

VCAM1:

vascular cell adhesion molecule 1

VEGF:

vascular endothelial growth factor

VSMCs:

vascular smooth muscle cells

VEGF-R:

VEGF receptor

VHL:

von Hippel–Lindau

References

  1. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6(4):389–395

    Article  PubMed  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  3. Dor Y, Porat R, Keshet E (2001) Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol 280(6):C1367–C1374

    PubMed  CAS  Google Scholar 

  4. Jain RK (2008) Taming vessels to treat cancer. Sci Am 298(1):56–63

    Article  PubMed  Google Scholar 

  5. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000

    Article  PubMed  Google Scholar 

  6. Rafii S, Heissig B, Hattori K (2002) Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther 9(10 Special Issue SI):631–641

    Article  PubMed  CAS  Google Scholar 

  7. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Cancer 2(10):727–739

    PubMed  CAS  Google Scholar 

  8. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ (1995) Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 121(6):1845–1854

    PubMed  CAS  Google Scholar 

  9. Hamada K, Sasaki T, Koni PA et al (2005) The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev 19(17):2054–2065

    Article  PubMed  CAS  Google Scholar 

  10. Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91–99

    Article  PubMed  CAS  Google Scholar 

  11. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273(22):13375–13378

    Article  PubMed  CAS  Google Scholar 

  12. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590

    Article  PubMed  CAS  Google Scholar 

  13. Humar RKFNBHRTJBEJ (2002 Jun) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) -dependent signaling. FASEB J 16(8):771–780

    Article  PubMed  CAS  Google Scholar 

  14. Patel PH, Chaganti RS, Motzer RJ (2006) Targeted therapy for metastatic renal cell carcinoma. Br J Cancer 94(5):614–619

    PubMed  CAS  Google Scholar 

  15. Trisciuoglio D, Iervolino A, Zupi G, Del Bufalo D (2005) Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol Biol Cell 16(9):4153–4162

    Article  PubMed  CAS  Google Scholar 

  16. Thomas GV, Tran C, Mellinghoff IK et al (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12(1):122–127

    Article  PubMed  CAS  Google Scholar 

  17. Costa LF, Balcells M, Edelman ER, Nadler LM, Cardoso AA (2006) Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-kappaB. Blood 107(1):285–292

    Article  PubMed  CAS  Google Scholar 

  18. Guba M, von Breitenbuch P, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor [see comment]. Nat Med 8(2):128–135

    Article  PubMed  CAS  Google Scholar 

  19. Bernardi R, Guernah I, Jin D et al (2006) PML inhibits HIF-1 alpha translation and neoangiogenesis through repression of mTOR. Nature 442(7104):779–785

    Article  PubMed  CAS  Google Scholar 

  20. Stallone G, Schena A, Infante B, Di Paolo S, Grandaliano G et al (2005) Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352(13):1317–1323

    Article  PubMed  CAS  Google Scholar 

  21. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22(24):4991–5004

    Article  PubMed  CAS  Google Scholar 

  22. Thomas GV, Tran C, Mellinghoff IK et al (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12(1):122–127

    Article  PubMed  CAS  Google Scholar 

  23. Gerber HP, McMurtrey A, Kowalski J et al (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273(46):30336–30343

    Article  PubMed  CAS  Google Scholar 

  24. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Cancer 3(6):401–410

    PubMed  CAS  Google Scholar 

  25. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611

    Article  PubMed  CAS  Google Scholar 

  26. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13(1):9–22

    PubMed  CAS  Google Scholar 

  27. Matsumoto T, Claesson-Welsh L (2001) VEGF receptor signal transduction. Sci Stke 2001(112):RE21

    Article  PubMed  CAS  Google Scholar 

  28. Karkkainen MJ, Petrova TV (2000) Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19(49):5598–5605

    Article  PubMed  CAS  Google Scholar 

  29. Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250

    Article  PubMed  CAS  Google Scholar 

  30. Somanath PR, Kandel ES, Hay N, Byzova TV (2007) Akt1 signaling regulates integrin activation, matrix recognition, and fibronectin assembly. J Biol Chem 282(31):22964–22976

    Article  PubMed  CAS  Google Scholar 

  31. Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128

    Article  PubMed  CAS  Google Scholar 

  32. Hresko RC, Mueckler M (2005) mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280(49):40406–40416

    Article  PubMed  CAS  Google Scholar 

  33. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  PubMed  CAS  Google Scholar 

  34. Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603

    Article  PubMed  CAS  Google Scholar 

  35. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Cancer 6(9):729–734

    PubMed  CAS  Google Scholar 

  36. Zeng Z, Sarbassov dos D, Samudio IJ et al (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109(8):3509–3512

    Article  PubMed  CAS  Google Scholar 

  37. Kim DH, Sabatini DM (2003) Raptor and mTOR: subunits of a nutrient-sensitive complex. TOR 279:259–270

    Article  Google Scholar 

  38. Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868

    Article  PubMed  CAS  Google Scholar 

  39. Morales-Ruiz M, Fulton D, Sowa G et al (2000) Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ Res 86(8):892–896

    Article  PubMed  CAS  Google Scholar 

  40. Fosbrink M, Niculescu F, Rus V, Shin ML, Rus H (2006) C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem 281(28):19009–19018

    Article  PubMed  CAS  Google Scholar 

  41. Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC (2001) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells [see comment]. Nat Cell Biol 3(3):245–252

    Article  PubMed  CAS  Google Scholar 

  42. Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10(2):262–267

    Article  PubMed  CAS  Google Scholar 

  43. Phung TL, Ziv K, Dabydeen D et al (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin [see comment]. Cancer Cell 10(2):159–170

    Article  PubMed  CAS  Google Scholar 

  44. Hay N (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8(3):179–183

    Article  PubMed  CAS  Google Scholar 

  45. Dormond O, Madsen JC, Briscoe DM (2007) The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 282(32):23679–23686

    Article  PubMed  CAS  Google Scholar 

  46. Harrington LS, Findlay GM, Gray A et al (2004) The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166(2):213–223

    Article  PubMed  CAS  Google Scholar 

  47. Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S (2006) Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 25(53):7029–7040

    Article  PubMed  CAS  Google Scholar 

  48. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24(1):200–216

    Article  PubMed  CAS  Google Scholar 

  49. Potente M, Urbich C, Sasaki K et al (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115(9):2382–2392

    Article  PubMed  CAS  Google Scholar 

  50. Sarbassov DD, Ali SM, Sengupta S et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168

    Article  PubMed  CAS  Google Scholar 

  51. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22

    Article  PubMed  CAS  Google Scholar 

  52. Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ (2007) Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 26(3–4):611–621

    Article  PubMed  Google Scholar 

  53. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62

    Article  PubMed  CAS  Google Scholar 

  54. Shen BQ, Lee DY, Cortopassi KM, Damico LA, Zioncheck TF (2001) Vascular endothelial growth factor KDR receptor signaling potentiates tumor necrosis factor-induced tissue factor expression in endothelial cells. J Biol Chem 276(7):5281–5286

    Article  PubMed  CAS  Google Scholar 

  55. Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410(1):78–82

    Article  PubMed  CAS  Google Scholar 

  56. Guba M, Yezhelyev M, Eichhorn ME et al (2005) Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood 105(11):4463–4469

    Article  PubMed  CAS  Google Scholar 

  57. Blum S, Issbruker K, Willuweit A et al (2001) An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression. J Biol Chem 276(36):33428–33434

    Article  PubMed  CAS  Google Scholar 

  58. Steffel J, Latini RA, Akhmedov A et al (2005 Sep 27) Rapamycin, but not FK-506, increases endothelial tissue factor expression – Implications for drug-eluting stent design. Circulation 112(13):2002–2011, 27 Sep 2005

    Article  PubMed  CAS  Google Scholar 

  59. Stoeltzing O, Meric-Bernstam F, Ellis LM (2006) Intracellular signaling in tumor and endothelial cells: the expected and, yet again, the unexpected [comment]. Cancer Cell 10(2):89–91

    Article  PubMed  CAS  Google Scholar 

  60. O’Reilly KE, Rojo F, She Q-B et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66(3):1500–1508

    Article  PubMed  Google Scholar 

  61. Vignot S, Faivre S, Aguirre D, Raymond E (2005) MTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537

    Article  PubMed  CAS  Google Scholar 

  62. Steinberg SF (2004) Distinctive activation mechanisms and functions for protein kinase C delta. Biochem J 384(Part 3):449–459

    PubMed  CAS  Google Scholar 

  63. Fang JY, Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6(5):322–327

    Article  PubMed  CAS  Google Scholar 

  64. Roymans D, Slegers H (2001) Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 268(3):487–498

    Article  PubMed  CAS  Google Scholar 

  65. Hernando E, Charytonowicz E, Dudas ME et al (2007) The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13(6):748–753

    Article  PubMed  CAS  Google Scholar 

  66. Shi Y, Gera J, Hu L et al (2002 Sep 1) Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62(17):5027–5034

    PubMed  CAS  Google Scholar 

  67. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257

    Article  PubMed  CAS  Google Scholar 

  68. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501

    Article  PubMed  CAS  Google Scholar 

  69. Zundel W, Schindler C, Haas-Kogan D et al (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14(4):391–396

    PubMed  CAS  Google Scholar 

  70. Li L, Liu F, Salmonsen RA et al (2002) PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol Cell Neurosci 20(1):21–29

    Article  PubMed  CAS  Google Scholar 

  71. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM (1998) Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280(5369):1614–1617

    Article  PubMed  CAS  Google Scholar 

  72. Lee D-F, Kuo H-P, Chen C-T et al (2007) IKK[beta] Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway. Cell 130(3):440–455

    Article  PubMed  CAS  Google Scholar 

  73. Sola-Villa D, Camacho M, Sola R, Soler M, Diaz JM, Vila LIL- (2006) 1[beta] induces VEGF, independently of PGE2 induction, mainly through the PI3-K//mTOR pathway in renal mesangial cells. Kidney Int 70(11):1935–1941

    PubMed  CAS  Google Scholar 

  74. Cueni LN, Detmar M (2006) New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 126(10):2167–2177

    Article  PubMed  CAS  Google Scholar 

  75. Langer RM, Kahan BD (2002) Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 74(6):804–808

    Article  PubMed  CAS  Google Scholar 

  76. Aboujaoude W, Milgrom ML, Govani MV (2004) Lymphedema associated with sirolimus in renal transplant recipients. Transplantation 77(7):1094–1096

    Article  PubMed  Google Scholar 

  77. Huber S, Bruns CJ, Schmid G et al (2007) Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis [see comment]. Kidney Int 71(8):771–777

    Article  PubMed  CAS  Google Scholar 

  78. Matsuo M, Yamada S, KoizUyni K, Sakurai F, Saiki I (2007) Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells. Eur J Cancer 43(11):1748–1754

    Article  PubMed  CAS  Google Scholar 

  79. Kobayashi S, Kishimoto T, Kamata S, Otsuka M, Miyazaki M, Ishikura H (2007) Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis [see comment]. Cancer Sci 98(5):726–733

    Article  PubMed  CAS  Google Scholar 

  80. Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD (2005) Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 80(7):883–889

    Article  PubMed  CAS  Google Scholar 

  81. Wimmer CD, Rentsch M, Crispin A et al (2007) The janus face of immunosuppression – de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich. Kidney Int 71(12):1271–1278

    Article  PubMed  CAS  Google Scholar 

  82. Sivakurnar R, Sharma-Walia N, Raghu H et al (2008) Kaposi’s sarcoma-associated herpesvirus induces sustained levels of vascular endothelial growth factors A and C early during in vitro infection of human microvascular dermal endothelial cells: biological implications. J Virol 83(4):1759–1776

    Article  Google Scholar 

  83. Gutierrez-Dalmau A, Sanchez-Fructuoso A, Sanz-Guajardo A et al (2005) Efficacy of conversion to sirolimus in posttransplantation Kaposi’s sarcoma. Transplant Proc 37(9):3836–3838

    Article  PubMed  CAS  Google Scholar 

  84. Atkins MB, Hidalgo M, Stadler WM et al (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22(5):909–918

    Article  PubMed  CAS  Google Scholar 

  85. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma [see comment]. N Engl J Med 356(22):2271–2281

    Article  PubMed  CAS  Google Scholar 

  86. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Drug Discov 5(8):671–688

    Article  CAS  Google Scholar 

  87. Kim DH, Sarbassov DD, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175

    Article  PubMed  CAS  Google Scholar 

  88. Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128

    Article  PubMed  CAS  Google Scholar 

  89. Rao RD, Buckner JC, Sarkaria JN (2004) Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 4(8):621–635

    Article  PubMed  CAS  Google Scholar 

  90. Del Bufalo D, Ciuffreda L, Trisciuoglio D et al (2006) Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554

    Article  PubMed  Google Scholar 

  91. Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1 alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22(20):7004–7014

    Article  PubMed  CAS  Google Scholar 

  92. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV (2004) Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 77(5):760–762

    Article  PubMed  Google Scholar 

  93. Stallone G, Schena A, Infante B et al (2005) Sirolimus for Kaposi’s sarcoma in renal-transplant recipients [see comment]. N Engl J Med 352(13):1317–1323

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Wyeth Research, Collegeville, PA, 19426, USA

    Henry Mead

  2. Wyeth Pharmaceuticals – Scientific Affairs, Toronto, ON, L3T 7Y2, Canada

    Mirjana Zeremski

  3. Multi-Organ Transplantation Program, Toronto General Hospital, University of Toronto, Toronto, ON, M5G2N2, Canada

    Markus Guba

Authors
  1. Henry Mead
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirjana Zeremski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Guba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Henry Mead .

Editor information

Editors and Affiliations

  1. Dept. Family Medicine, University of Minnesota, Minneapolis, 55455, USA

    Vitaly A. Polunovsky

  2. Director, Center for Childhood Cancer, Nationwide Children’s Hospital, The Research Institute, 700 Children’s Drive 332, Columbus, 43205, USA

    Peter J. Houghton

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Mead, H., Zeremski, M., Guba, M. (2009). mTOR Signaling in Angiogenesis. In: Polunovsky, V., Houghton, P. (eds) mTOR Pathway and mTOR Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-271-1_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-271-1_3

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-270-4

  • Online ISBN: 978-1-60327-271-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation