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Insights into the Regulation of Tumor Dormancy by Angiogenesis in Experimental Tumors

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Systems Biology of Tumor Dormancy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 734))

Abstract

While it is well established that an angiogenic switch marks escape from tumor dormancy in xenograft models, the molecular pathways involved in the control of tumor cell proliferation or survival by angiogenesis remain substantially uncharted. We recently demonstrated that signals stemming from angiogenic endothelial cells (EC) regulate the behavior of dormant cancer cells. Specifically, we observed that the Notch ligand Dll4, induced by angiogenic factors in EC, triggers Notch3 activation in neighboring tumor cells and promotes a tumorigenic phenotype. Evidence that Notch signaling is involved in tumor dormancy was further strengthened by the observation that MKP-1 levels—a broadly expressed phosphatase—are controlled by Notch3 by regulation of protein ubiquitination and stability. Notch3 and MKP-1 levels are consistently low in dormant tumors, and this is accompanied by relatively high levels of phosphorylated p38, a canonical MKP-1 target previously associated with maintenance of tumor dormancy. These results elucidate a novel angiogenesis-driven mechanism involving the Notch and MAPK pathways that controls tumor dormancy. More in general, angiogenic EC could form part of the vascular niche, a specialized microenvironment which appears to regulate metastatic outgrowth and future studies are needed to clarify the contribution of EC in the regulation of cancer stem cell behavior in the niche.

The notion that EC could communicate signals to tumor cells raises questions about the possibility of achieving tumor dormancy by counteracting angiogenesis. In experimental tumors, anti-VEGF drugs typically prune the newly formed vasculature, thus reducing microvessel density, blood flow, and perfusion. These drugs eventually increase hypoxia and cause tumor necrosis but dormancy is rarely observed. Our group recently reported that anti-VEGF therapy causes a dramatic depletion of glucose and an exhaustion of ATP levels in tumors. Moreover, we found that the central metabolic checkpoint LKB1/AMPK—a cellular sensor of ATP levels that supports cell viability in response to energy stress—is activated by anti-VEGF therapy in experimental tumors and it has a key role in induction of sustained tumor regression. These functional links between activation of the LKB1/AMPK by anti-angiogenic therapy and tumor dormancy suggest a role for metabolism in the regulation of this phenomenon.

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References

  1. Folkman J, Kalluri R (2004) Cancer without disease. Nature 427(6977):787

    Article  PubMed  CAS  Google Scholar 

  2. Uhr JW, Pantel K (2011) Controversies in clinical cancer dormancy. Proc Natl Acad Sci USA 108(30):12396–12400

    Article  PubMed  CAS  Google Scholar 

  3. Strauss DC, Thomas JM (2010) Transmission of donor melanoma by organ transplantation. Lancet Oncol 11(8):790–796

    Article  PubMed  Google Scholar 

  4. Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8(5):329–340

    Article  PubMed  CAS  Google Scholar 

  5. Goldberg SF, Harms JF, Quon K, Welch DR (1999) Metastasis-suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin Exp Metastasis 17(7):601–607

    Article  PubMed  CAS  Google Scholar 

  6. Goodison S, Kawai K, Hihara J, Jiang P, Yang M, Urquidi V et al (2003) Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. Clin Cancer Res 9(10 Pt 1):3808–3814

    PubMed  CAS  Google Scholar 

  7. Naumov GN, Townson JL, MacDonald IC, Wilson SM, Bramwell VH, Groom AC et al (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82(3):199–206

    Article  PubMed  CAS  Google Scholar 

  8. Pantel K, Cote RJ, Fodstad O (1999) Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 91(13):1113–1124

    Article  PubMed  CAS  Google Scholar 

  9. Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85(17):1419–1424

    Article  PubMed  CAS  Google Scholar 

  10. Achilles EG, Fernandez A, Allred EN, Kisker O, Udagawa T, Beecken WD et al (2001) Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for “no take” of human tumors in mice. J Natl Cancer Inst 93(14):1075–1081

    Article  PubMed  CAS  Google Scholar 

  11. Almog N, Henke V, Flores L, Hlatky L, Kung AL, Wright RD et al (2006) Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J 20(7):947–949

    Article  PubMed  CAS  Google Scholar 

  12. Indraccolo S, Favaro E, Amadori A (2006) Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis. Cell Cycle 5(16):1751–1755, Georgetown, Tex

    Article  PubMed  CAS  Google Scholar 

  13. Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E et al (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98(5):316–325

    Article  PubMed  Google Scholar 

  14. Udagawa T, Fernandez A, Achilles EG, Folkman J, D’Amato RJ (2002) Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy. FASEB J 16(11):1361–1370

    Article  PubMed  CAS  Google Scholar 

  15. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R et al (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57(5):963–969

    PubMed  CAS  Google Scholar 

  18. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS et al (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285

    Article  PubMed  Google Scholar 

  19. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Cao Y et al (1994) Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 59:471–482

    Article  PubMed  Google Scholar 

  20. Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M et al (2010) Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 120(6):2030–2039

    Article  PubMed  CAS  Google Scholar 

  21. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ et al (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907

    Article  PubMed  CAS  Google Scholar 

  22. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6(1):24–37

    Article  PubMed  Google Scholar 

  23. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401

    Article  PubMed  CAS  Google Scholar 

  24. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25(3):315–322

    Article  PubMed  Google Scholar 

  25. Orimo A, Weinberg RA (2006) Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5(15):1597–1601, Georgetown, Tex

    Article  PubMed  CAS  Google Scholar 

  26. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78

    Article  PubMed  CAS  Google Scholar 

  27. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  PubMed  CAS  Google Scholar 

  28. Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104(8):2224–2234

    Article  PubMed  CAS  Google Scholar 

  29. Nardo G, Favaro E, Curtarello M, Moserle L, Zulato E, Persano L et al (2011) Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization. Cancer Res 71(12):4214–4225

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z et al (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13(11):1382–1397

    Article  PubMed  CAS  Google Scholar 

  32. Folkman J, Watson K, Ingber D, Hanahan D (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339(6219):58–61

    Article  PubMed  CAS  Google Scholar 

  33. Huss WJ, Hanrahan CF, Barrios RJ, Simons JW, Greenberg NM (2001) Angiogenesis and prostate cancer: identification of a molecular progression switch. Cancer Res 61(6):2736–2743

    PubMed  CAS  Google Scholar 

  34. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA et al (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238–11246

    Article  PubMed  CAS  Google Scholar 

  35. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744

    Article  PubMed  CAS  Google Scholar 

  36. Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103(3):481–490

    Article  PubMed  CAS  Google Scholar 

  37. Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114(5):623–633

    PubMed  CAS  Google Scholar 

  38. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103(33):12493–12498

    Article  PubMed  CAS  Google Scholar 

  39. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217

    Article  PubMed  CAS  Google Scholar 

  40. Lewis C, Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167(3):627–635

    Article  PubMed  CAS  Google Scholar 

  41. Crescenzi M, Persano L, Esposito G, Zulato E, Borsi L, Balza E et al (2011) Vandetanib improves anti-tumor effects of L19mTNFalpha in xenograft models of esophageal cancer. Clin Cancer Res 17(3):447–458

    Article  PubMed  CAS  Google Scholar 

  42. Shojaei F, Ferrara N (2008) Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res 68(14):5501–5504

    Article  PubMed  CAS  Google Scholar 

  43. Indraccolo S, Stievano L, Minuzzo S, Tosello V, Esposito G, Piovan E et al (2006) Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci USA 103(11):4216–4221

    Article  PubMed  CAS  Google Scholar 

  44. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68

    Article  PubMed  Google Scholar 

  45. Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21:605–631

    Article  PubMed  CAS  Google Scholar 

  46. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293

    Article  PubMed  CAS  Google Scholar 

  47. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848

    Article  PubMed  CAS  Google Scholar 

  48. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82

    Article  PubMed  CAS  Google Scholar 

  49. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67(8):3560–3564

    Article  PubMed  CAS  Google Scholar 

  50. Sonoshita M, Aoki M, Fuwa H, Aoki K, Hosogi H, Sakai Y et al (2011) Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19(1):125–137

    Article  PubMed  CAS  Google Scholar 

  51. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827

    Article  PubMed  CAS  Google Scholar 

  52. Kaplan RN, Rafii S, Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Res 66(23):11089–11093

    Article  PubMed  CAS  Google Scholar 

  53. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG et al (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17(7):867–874

    Article  PubMed  CAS  Google Scholar 

  54. Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL (2005) Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65(19):8690–8697

    Article  PubMed  CAS  Google Scholar 

  55. Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle L et al (2009) Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy. Cancer Res 69(4):1314–1323

    Article  PubMed  CAS  Google Scholar 

  56. Masiero M, Minuzzo S, Pusceddu I, Moserle L, Persano L, Agnusdei V et al (2011) Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia 25(4):588–598

    Article  PubMed  CAS  Google Scholar 

  57. Aguirre Ghiso JA, Kovalski K, Ossowski L (1999) Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 147(1):89–104

    Article  PubMed  CAS  Google Scholar 

  58. Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63(7):1684–1695

    PubMed  CAS  Google Scholar 

  59. Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12(4):863–879

    PubMed  CAS  Google Scholar 

  60. Leong KG, Karsan A (2006) Recent insights into the role of Notch signaling in tumorigenesis. Blood 107(6):2223–2233

    Article  PubMed  CAS  Google Scholar 

  61. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M et al (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117(12):3988–4002

    Article  PubMed  CAS  Google Scholar 

  62. Serafin V, Persano L, Moserle L, Esposito G, Ghisi M, Curtarello M et al (2011) Notch3 signalling promotes tumour growth in colorectal cancer. J Pathol 224(4):448–460

    Article  PubMed  CAS  Google Scholar 

  63. Sivasankaran B, Degen M, Ghaffari A, Hegi ME, Hamou MF, Ionescu MC et al (2009) Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas. Cancer Res 69(2):458–465

    Article  PubMed  CAS  Google Scholar 

  64. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294(5542):564–567, New York, NY

    Article  PubMed  CAS  Google Scholar 

  65. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS (2001) Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294(5542):559–563, New York, NY

    Article  PubMed  CAS  Google Scholar 

  66. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N et al (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304(5675):1338–1340, New York, NY

    Article  PubMed  CAS  Google Scholar 

  67. Folkman J (1998) Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence. Endocrinology 139(2):441–442

    Article  PubMed  CAS  Google Scholar 

  68. LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP et al (2003) Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299(5608):890–893, New York, NY

    Article  PubMed  CAS  Google Scholar 

  69. Zhu AX, Duda DG, Sahani DV, Jain RK (2011) HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol 8(5):292–301

    Article  PubMed  CAS  Google Scholar 

  70. Bandyopadhyay S, Zhan R, Chaudhuri A, Watabe M, Pai SK, Hirota S et al (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12(8):933–938

    Article  PubMed  CAS  Google Scholar 

  71. Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6(9):734–745

    Article  PubMed  CAS  Google Scholar 

  72. Vaupel P (2004) Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14(3):198–206

    Article  PubMed  Google Scholar 

  73. Walenta S, Schroeder T, Mueller-Klieser W (2004) Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem 11(16):2195–2204

    Article  PubMed  CAS  Google Scholar 

  74. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10(2):145–147

    Article  PubMed  CAS  Google Scholar 

  75. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F et al (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108(9):3749–3754

    Article  PubMed  CAS  Google Scholar 

  76. Howe FA, Barton SJ, Cudlip SA, Stubbs M, Saunders DE, Murphy M et al (2003) Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 49(2):223–232

    Article  PubMed  CAS  Google Scholar 

  77. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62, New York, NY

    Article  PubMed  CAS  Google Scholar 

  78. Alexander A, Walker CL (2011) The role of LKB1 and AMPK in cellular responses to stress and damage. FEBS Lett 585(7):952–957

    Article  PubMed  CAS  Google Scholar 

  79. Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9(8):563–575

    Article  PubMed  CAS  Google Scholar 

  80. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM et al (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2(1):9–19

    Article  PubMed  CAS  Google Scholar 

  81. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D et al (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13(22):2004–2008

    Article  PubMed  CAS  Google Scholar 

  82. Zhang BB, Zhou G, Li C (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9(5):407–416

    Article  PubMed  Google Scholar 

  83. Luo Z, Zang M, Guo W (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol 6(3):457–470

    Article  PubMed  CAS  Google Scholar 

  84. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210

    Article  PubMed  CAS  Google Scholar 

  85. Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V (2011) Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia 13(5):483–491

    PubMed  CAS  Google Scholar 

  86. Rocha GZ, Dias MM, Ropelle ER, Osorio-Costa F, Rossato FA, Vercesi AE et al (2011) Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res 17(12):3993–4005

    Article  PubMed  CAS  Google Scholar 

  87. Laderoute KR, Amin K, Calaoagan JM, Knapp M, Le T, Orduna J et al (2006) 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol 26(14):5336–5347

    Article  PubMed  CAS  Google Scholar 

  88. Tsavachidou-Fenner D, Tannir N, Tamboli P, Liu W, Petillo D, Teh B et al (2010) Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma. Ann Oncol 21(8):1599–1606

    Article  PubMed  CAS  Google Scholar 

  89. Carretero J, Medina PP, Blanco R, Smit L, Tang M, Roncador G et al (2007) Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene 26(11):1616–1625

    Article  PubMed  CAS  Google Scholar 

  90. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101(10):3329–3335

    Article  PubMed  CAS  Google Scholar 

  91. Fabian C, Koetz L, Favaro E, Indraccolo S, Mueller-Klieser W, Sattler UG (2012) Protein profiles in human ovarian cancer cell lines correspond to their metabolic activity and to metabolic profiles of respective tumor xenografts. FEBS J 279:882–891

    Article  PubMed  CAS  Google Scholar 

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  1. Istituto Oncologico Veneto—IRCCS, via Gattamelata, 64, 35128, Padua, Italy

    Stefano Indraccolo MD

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  1. Stefano Indraccolo MD
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Correspondence to Stefano Indraccolo MD .

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  1. St. Elizabeth's Medical Center, Tufts University School of Medicine, 145 Harrison Avenue, Boston, 02135, Massachusetts, USA

    Heiko Enderling

  2. , Center of Cancer Systems Biology, Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, Massachusetts, USA

    Nava Almog

  3. , Center of Cancer Systems Biology, Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, Massachusetts, USA

    Lynn Hlatky

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Indraccolo, S. (2013). Insights into the Regulation of Tumor Dormancy by Angiogenesis in Experimental Tumors. In: Enderling, H., Almog, N., Hlatky, L. (eds) Systems Biology of Tumor Dormancy. Advances in Experimental Medicine and Biology, vol 734. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1445-2_3

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