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.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- 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
Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6(4):389–395
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70
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
Jain RK (2008) Taming vessels to treat cancer. Sci Am 298(1):56–63
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
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
Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Cancer 2(10):727–739
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
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
Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91–99
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
Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590
Humar RKFNBHRTJBEJ (2002 Jun) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) -dependent signaling. FASEB J 16(8):771–780
Patel PH, Chaganti RS, Motzer RJ (2006) Targeted therapy for metastatic renal cell carcinoma. Br J Cancer 94(5):614–619
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
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
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
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
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
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
Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22(24):4991–5004
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
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
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Cancer 3(6):401–410
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13(1):9–22
Matsumoto T, Claesson-Welsh L (2001) VEGF receptor signal transduction. Sci Stke 2001(112):RE21
Karkkainen MJ, Petrova TV (2000) Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19(49):5598–5605
Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250
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
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
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
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
Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603
Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Cancer 6(9):729–734
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
Kim DH, Sabatini DM (2003) Raptor and mTOR: subunits of a nutrient-sensitive complex. TOR 279:259–270
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
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
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
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
Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10(2):262–267
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
Hay N (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8(3):179–183
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
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
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
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
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
Sarbassov DD, Ali SM, Sengupta S et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22(2):159–168
Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22
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
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62
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
Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410(1):78–82
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
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
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
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
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
Vignot S, Faivre S, Aguirre D, Raymond E (2005) MTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537
Steinberg SF (2004) Distinctive activation mechanisms and functions for protein kinase C delta. Biochem J 384(Part 3):449–459
Fang JY, Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6(5):322–327
Roymans D, Slegers H (2001) Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 268(3):487–498
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
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
Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501
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
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
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
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
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
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
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
Aboujaoude W, Milgrom ML, Govani MV (2004) Lymphedema associated with sirolimus in renal transplant recipients. Transplantation 77(7):1094–1096
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
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
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
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
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
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
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
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
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
Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Drug Discov 5(8):671–688
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
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
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
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
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
Campistol JM, Gutierrez-Dalmau A, Torregrosa JV (2004) Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 77(5):760–762
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
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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)