Impact of the hypoxic tumor microenvironment on the regulation of cancer stem cell characteristics

Cancer Biology and Therapy

Volumn 9, Issue 12, 2010, Pages 949-956

  Lin, Qun ^a   Yun, Zhong ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer stem cells; Differentiation; Hypoxia; Niche; Oxygen; Tumor microenvironment

Indexed keywords

CANCER STEM CELL; CELL DIFFERENTIATION; CELL HYPOXIA; DISEASE FREE SURVIVAL; HUMAN; MESENCHYME CELL; NONHUMAN; REVIEW; SOLID TUMOR; TUMOR GROWTH;

ANIMALS; CELL DIFFERENTIATION; CELL HYPOXIA; DISEASE PROGRESSION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; NEOPLASMS; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 77954414428     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.9.12.12347     Document Type: Review

References (130)

1. Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, et al. Genetic progression and the waiting time to cancer. PLoS Comput Biol 2007; 3:225.
2. Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 2008; 105:4283-8.
3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70.
4. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10:789-99. (Pubitemid 39070849)
5. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730-7. (Pubitemid 27298715)
6. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983-8.
7. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007; 104:10158-63.
8. O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445:106-10. (Pubitemid 46067310)
9. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445:111-5.
10. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64:7011-21.
11. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63:5821-8. (Pubitemid 37187480)
12. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004; 432:396-401.
13. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007; 104:973-8.
14. Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 2007; 67:4827-33.
15. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008; 15:504-14.
16. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67:1030-7.
17. Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle 2007; 6:2332-8.
18. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature reviews 2008; 8:755-68.
19. Andrews PW. From teratocarcinomas to embryonic stem cells. Philos Trans R Soc Lond B Biol Sci 2002; 357:405-17.
20. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer cell 2006; 9:157-73.
21. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005; 434:843-50.
22. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nature reviews 2003; 3:895-902. (Pubitemid 37500174)
23. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004; 118:409-18.
24. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell 2004; 116:769-78.
25. Moore KA, Lemischka IR. Stem cells and their niches. Science 2006; 311:1880-5.
26. Scadden DT. The stem-cell niche as an entity of action. Nature 2006; 441:1075-9.
27. Wilson A, Trumpp A. Bone-marrow haematopoieticstem-cell niches. Nat Rev Immunol 2006; 6:93-106.
28. Nordsmark M, Overgaard J. Tumor hypoxia is independent of hemoglobin and prognostic for locoregional tumor control after primary radiotherapy in advanced head and neck cancer. Acta Oncol 2004; 43:396-403.
29. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996; 56:941-3.
30. Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999; 53:113-7.
31. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996; 56:4509-15. (Pubitemid 26330463)
32. Young SD, Marshall RS, Hill RP. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci USA 1988; 85:9533-7.
33. Evans SM, Hahn SM, Magarelli DP, Koch CJ. Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis and proliferation. Am J Clin Oncol 2001; 24:467-72.
34. Wartenberg M, Ling FC, Muschen M, Klein F, Acker H, Gassmann M, et al. Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J 2003; 17:503-5.
35. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002; 62:3387-94. (Pubitemid 34651384)
36. Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996; 379:88-91.
37. Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol 2000; 76:589-605.
38. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 2003; 20:237-50.
39. Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P, et al. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell 2005; 17:793-803.
40. Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, et al. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 2003; 23:3265-73.
41. Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, et al. Hypoxia-induced downregulation of BRCA1 expression by E2Fs. Cancer Res 2005; 65:11597-604.
42. Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, et al. Downregulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004; 24:8504-18.
43. Yuan J, Narayanan L, Rockwell S, Glazer PM. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res 2000; 60:4372-6. (Pubitemid 32103614)
44. Coquelle A, Toledo F, Stern S, Bieth A, Debatisse M. A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol Cell 1998; 2:259-65. (Pubitemid 128373652)
45. Semenza GL. Targeting HIF-1 for cancer therapy. Nature reviews 2003; 3:721-32.
46. Giaccia AJ, Simon MC, Johnson R. The biology of hypoxia: the role of oxygen sensing in development, normal function and disease. Genes Dev 2004; 18:2183-94.
47. Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA, Simon MC. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol 2006; 26:3514-26.
48. Harris AL. Hypoxia - a key regulatory factor in tumour growth. Nature reviews 2002; 2:38-47.
49. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007; 26:225-39.
50. Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 2001; 61:2911-6.
51. Burri P, Djonov V, Aebersold DM, Lindel K, Studer U, Altermatt HJ, et al. Significant correlation of hypoxiainducible factor-1alpha with treatment outcome in cervical cancer treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 2003; 56:494-501.
52. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer cell 2006; 10:413-23.
53. Couvelard A, O'Toole D, Turley H, Leek R, Sauvanet A, Degott C, et al. Microvascular density and hypoxia- inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer 2005; 92:94-101.
54. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998; 394:485-90.
55. Acker T, Diez-Juan A, Aragones J, Tjwa M, Brusselmans K, Moons L, et al. Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer cell 2005; 8:131-41.
56. Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, et al. High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol 2008; 214:482-8. (Pubitemid 351340568)
57. Pietras A, Hansford LM, Johnsson AS, Bridges E, Sjolund J, Gisselsson D, et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc Natl Acad Sci USA 2009; 106:16805-10.
58. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer cell 2009; 15:501-13.
59. Kim Y, Lin Q, Zelterman D, Yun Z. Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity. Cancer Res 2009.
60. Floridon C, Jensen CH, Thorsen P, Nielsen O, Sunde L, Westergaard JG, et al. Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal and placental tissue and in maternal circulation. Differentiation 2000; 66:49-59.
61. Jensen CH, Krogh TN, Hojrup P, Clausen PP, Skjodt K, Larsson LI, et al. Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growthfactor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2. Eur J Biochem 1994; 225:83-92.
62. Tornehave D, Jensen CH, Teisner B, Larsson LI. FA1 immunoreactivity in endocrine tumours and during development of the human fetal pancreas; negative correlation with glucagon expression. Histochem Cell Biol 1996; 106:535-42.
63. Yin D, Xie D, Sakajiri S, Miller CW, Zhu H, Popoviciu ML, et al. DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene 2006; 25:1852-61.
64. Sakajiri S, O'Kelly J, Yin D, Miller CW, Hofmann WK, Oshimi K, et al. Dlk1 in normal and abnormal hematopoiesis. Leukemia 2005; 19:1404-10.
65. Van Limpt VA, Chan AJ, Van Sluis PG, Caron HN, Van Noesel CJ, Versteeg R. High delta-like 1 expression in a subset of neuroblastoma cell lines corresponds to a differentiated chromaffin cell type. Int J Cancer 2003; 105:61-9.
66. Li L, Forman SJ, Bhatia R. Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation. Oncogene 2005; 24:4472-6.
67. Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005; 2005:12.
68. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382:635-8.
69. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998; 393:591-4.
70. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393:595-9. (Pubitemid 28319251)
71. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10:858-64.
72. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003; 425:307-11.
73. Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, et al. Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 2005; 65:6178-88.
74. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 2003; 198:1391-402.
75. Hung SC, Pochampally RR, Hsu SC, Sanchez C, Chen SC, Spees J, et al. Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo. PLoS ONE 2007; 2:416.
76. Richard CL, Blay J. CXCR4 in Cancer and Its Regulation by PPARgamma. PPAR Res 2008; 2008:769413.
77. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-6.
78. Salvucci O, Bouchard A, Baccarelli A, Deschenes J, Sauter G, Simon R, et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study. Breast Cancer Res Treat 2006; 97:275-83.
79. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 2004; 64:8604-12.
80. Zeelenberg IS, Ruuls-Van Stalle L, Roos E. The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res 2003; 63:3833-9. (Pubitemid 36793074)
81. Hermann PC, Huber SL, Herrler T, Alexandra Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell stem cell 2007; 1:313-23.
82. Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol 2007; 25:1177-81.
83. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131:861-72.
84. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318:1917-20.
85. Cheng L. Establishing a germ cell origin for metastatic tumors using OCT4 immunohistochemistry. Cancer 2004; 101:2006-10.
86. Gidekel S, Pizov G, Bergman Y, Pikarsky E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer cell 2003; 4:361-70.
87. Jones TD, Ulbright TM, Eble JN, Cheng L. OCT4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin Cancer Res 2004; 10:8544-7.
88. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 2005; 26:495-502.
89. Hochedlinger K, Yamada Y, Beard C, Jaenisch R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 2005; 121:465-77. (Pubitemid 40692305)
90. Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development and tumor growth. Genes Dev 2006; 20:557-70.
91. Forristal CE, Wright KL, Hanley NA, Oreffo RO, Houghton FD. Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 2010; 139:85-97.
92. Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR Jr, et al. CD133 is a marker of bioenergetic stress in human glioma. PLoS One 2008; 3:3655.
93. Seidel S, Garvalov BK, Wirta V, von Stechow L, Schanzer A, Meletis K, et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2{alpha}. Brain 2010; 133:983-95.
94. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 2009.
95. Matsumoto K, Arao T, Tanaka K, Kaneda H, Kudo K, Fujita Y, et al. mTOR signal and hypoxia-inducible factor-1alpha regulate CD133 expression in cancer cells. Cancer Res 2009; 69:7160-4.
96. Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 2004; 103:3258-64.
97. Corral DA, Amling M, Priemel M, Loyer E, Fuchs S, Ducy P, et al. Dissociation between bone resorption and bone formation in osteopenic transgenic mice. Proc Natl Acad Sci USA 1998; 95:13835-40.
98. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 2007; 131:324-36.
99. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004; 118:149-61.
100. Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, et al. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nat Med 2006; 12:240-5.
101. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432:332-7.
102. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 1996; 76:69-125. (Pubitemid 26048279)
103. Tlsty TD, Hein PW. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 2001; 11:54-9.
104. Bissell MJ, Labarge MA. Context, tissue plasticity and cancer: are tumor stem cells also regulated by the microenvironment? Cancer cell 2005; 7:17-23.
105. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449:557-63.
106. Pine SR, Ryan BM, Varticovski L, Robles AI, Harris CC. Microenvironmental modulation of asymmetric cell division in human lung cancer cells. Proc Natl Acad Sci USA 2010; 107:2195-200.
107. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284:143-7.
108. Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, Marini F. Mesenchymal stem cells in cancer: tumorassociated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007; 86:8-16.
109. LaRue AC, Masuya M, Ebihara Y, Fleming PA, Visconti RP, Minamiguchi H, et al. Hematopoietic origins of fibroblasts: I. In vivo studies of fibroblasts associated with solid tumors. Exp Hematol 2006; 34:208-18.
110. Kim KH, Song MJ, Chung J, Park H, Kim JB. Hypoxia inhibits adipocyte differentiation in a HDACindependent manner. Biochem Biophys Res Commun 2005; 333:1178-84.
111. Sahai A, Patel MS, Zavosh AS, Tannen RL. Chronic hypoxia impairs the differentiation of 3T3-L1 fibroblast in culture: role of sustained protein kinase C activation. J Cell Physiol 1994; 160:107-12.
112. Lin Q, Lee YJ, Yun Z. Differentiation arrest by hypoxia. J Biol Chem 2006; 281:30678-83.
113. Yun Z, Maecker HL, Johnson RS, Giaccia AJ. Inhibition of PPARγ2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell 2002; 2:331-41.
114. Zhou S, Lechpammer S, Greenberger JS, Glowacki J. Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires transforming growth factor-beta/Smad3 signaling. J Biol Chem 2005; 280:22688-96.
115. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005; 9:617-28. (Pubitemid 41555144)
116. Yun Z, Lin Q, Giaccia AJ. Adaptive myogenesis under hypoxia. Mol Cell Biol 2005; 25:3040-55.
117. Sun H, Li L, Vercherat C, Gulbagci NT, Acharjee S, Li J, et al. Stra13 regulates satellite cell activation by antagonizing Notch signaling. J Cell Biol 2007; 177:647-57.
118. Miyazaki K, Kawamoto T, Tanimoto K, Nishiyama M, Honda H, Kato Y. Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. J Biol Chem 2002; 277:47014-21.
119. Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ. Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 2000; 19:6297-305.
120. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer cell 2007; 11:69-82.
121. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 2008; 22:436-48.
122. Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58:1408-16.
123. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004; 14:198-206. (Pubitemid 38903223)
124. Wagemaker G. Heterogeneity of radiation sensitivity of hemopoietic stem cell subsets. Stem Cells 1995; 13:257-60.
125. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444:756-60.
126. Onnis B, Rapisarda A, Melillo G. Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 2009; 13:2780-6.
127. Semenza GL. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des 2009; 15:3839-43.
128. Dimova EY, Michiels C, Kietzmann T. Kinases as upstream regulators of the HIF system: their emerging potential as anti-cancer drug targets. Curr Pharm Des 2009; 15:3867-77.
129. Heath VL, Bicknell R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 2009; 6:395-404.
130. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307:58-62.