Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells

Journal of Cellular and Molecular Medicine

Volumn 17, Issue 1, 2013, Pages 30-54

  Mimeault, Murielle ^a   Batra, Surinder K ^a  

^a UNIVERSITY OF NEBRASKA MEDICAL CENTER   (United States)

Author keywords

Cancer progression; Cancer stem progenitor cells; Cancer initiating cells; Hypoxia; Hypoxia inducible factors; Metabolic pathways; Metastases; Metastasis initiating cells; Targeted therapies

Indexed keywords

ANTINEOPLASTIC AGENT; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; ENDOTHELIAL PAS DOMAIN CONTAINING PROTEIN 1; ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1; HIF1A PROTEIN, HUMAN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; SIGNAL PEPTIDE; TRANSCRIPTION FACTOR;

ANOXIA; APOPTOSIS; ARTICLE; CANCER STEM CELL; CELL TRANSFORMATION; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETICS; HUMAN; METABOLISM; METASTASIS; MOLECULARLY TARGETED THERAPY; NEOPLASM; PATHOLOGY; SIGNAL TRANSDUCTION;

ANOXIA; ANTINEOPLASTIC AGENTS; APOPTOSIS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CELL TRANSFORMATION, NEOPLASTIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MOLECULAR TARGETED THERAPY; NEOPLASM METASTASIS; NEOPLASMS; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

ANIMALIA; GASTROPODA;

EID: 84873160542     PISSN: 15821838     EISSN: None     Source Type: Journal    
DOI: 10.1111/jcmm.12004     Document Type: Article

References (296)

1. Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible factor 1 alpha in common human cancers and their metastases. Cancer Res. 1999; 59: 5830-5.
2. Cangul H, Salnikow K, Yee HZ, et al. Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect. 2002; 110: 783-8.
3. 2-regulated gene expression. FASEB J. 2002; 16: 1151-62.
4. Mathieu J, Zhang Z, Zhou W, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 2011; 71: 4640-52.
5. Jubb AM, Buffa FM, Harris AL. Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis. J Cell Mol Med. 2010; 14: 18-29.
6. Giuntoli S, Tanturli M, Di Gesualdo F, et al. Glucose availability in hypoxia regulates the selection of chronic myeloid leukemia progenitor subsets with different resistance to imatinib-mesylate. Haematologica. 2011; 96: 204-12.
7. Blazek ER, Foutch JL, Maki G. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys. 2007; 67: 1-5.
8. Dai Y, Bae K, Siemann DW. Impact of hypoxia on the metastatic potential of human prostate cancer cells. Int J Radiat Oncol Biol Phys. 2011; 81: 521-8.
9. Milosevic M, Warde P, Menard C, et al. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 2012; 18: 2108-14.
10. Bos R, van der Groep P, Greijer AE, et al. Levels of hypoxia-inducible factor-1 alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003; 97: 1573-81.
11. Schwartz DL, Bankson JA, Lemos R Jr, et al. Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Mol Cancer Ther. 2010; 9: 2057-67.
12. Kasuya K, Tsuchida A, Nagakawa Y, et al. Hypoxia-inducible factor-1 alpha expression and gemcitabine chemotherapy for pancreatic cancer. Oncol Rep. 2011; 26: 1399-406.
13. Johansson A, Rudolfsson SH, Kilter S, et al. Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model. BJU Int. 2011; 107: 1818-24.
14. Ma Y, Liang D, Liu J, et al. Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. PLoS ONE. 2011; 6: e29170.
15. Xing F, Okuda H, Watabe M, et al. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene. 2011; 30: 4075-86.
16. Quail DF, Taylor MJ, Walsh LA, et al. Low oxygen levels induce the expression of the embryonic morphogen Nodal. Mol Biol Cell. 2011; 22: 4809-21.
17. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3: 721-32.
18. Wiesener MS, Jurgensen JS, Rosenberger C, et al. Widespread hypoxia-inducible expression of HIF-2 alpha in distinct cell populations of different organs. FASEB J. 2003; 17: 271-3.
19. Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol. 2004; 36: 189-204.
20. Partch CL, Gardner KH. Coactivator recruitment: a new role for PAS domains in transcriptional regulation by the bHLH-PAS family. J Cell Physiol. 2010; 223: 553-7.
21. Fong GH, Takeda K. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ. 2008; 15: 635-41.
22. Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004; 10: 6290S-5S.
23. D'Alterio C, Barbieri A, Portella L, et al. Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunol Immunother. 2012; 61: 1713-20.
24. Partch CL, Gardner KH. Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proc Natl Acad Sci USA. 2011; 108: 7739-44.
25. Stoeltzing O, Liu W, Reinmuth N, et al. Regulation of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol. 2003; 163: 1001-11.
26. Zhang M, Ma Q, Hu H, et al. Stem cell factor/c-kit signalling enhances invasion of pancreatic cancer cells via HIF-1 alpha under normoxic condition. Cancer Lett. 2011; 303: 108-17.
27. Nilsson CL, Dillon R, Devakumar A, et al. Quantitative phosphoproteomic analysis of the STAT3/IL-6/HIF1alpha signalling network: an initial study in GSC11 glioblastoma stem cells. J Proteome Res. 2010; 9: 430-43.
28. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000; 60: 1541-5.
29. Tonra JR, Corcoran E, Deevi DS, et al. Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models. Anticancer Res. 2009; 29: 1999-2007.
30. Azzariti A, Porcelli L, Gatti G, et al. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol. 2008; 75: 1035-44.
31. Peng XH, Karna P, Cao Z, et al. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 2006; 281: 25903-14.
32. Phillips RJ, Mestas J, Gharaee-Kermani M, et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signalling pathway and activation of hypoxia inducible factor-1 alpha. J Biol Chem. 2005; 280: 22473-81.
33. Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signalling pathways. Oncogene. 2005; 24: 5552-60.
34. Schoolmeesters A, Brown DD, Fedorov Y. Kinome-wide functional genomics screen reveals a novel mechanism of TNF alpha-induced nuclear accumulation of the HIF-1 alpha transcription factor in cancer cells. PLoS ONE. 2012; 7: e31270.
35. Chae KS, Kang MJ, Lee JH, et al. Opposite functions of HIF-alpha isoforms in VEGF induction by TGF-beta1 under non-hypoxic conditions. Oncogene. 2011; 30: 1213-28.
36. Harada H, Itasaka S, Kizaka-Kondoh S, et al. The Akt/mTOR pathway assures the synthesis of HIF-1 alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J Biol Chem. 2009; 284: 5332-42.
37. Fukuda R, Kelly B, Semenza GL. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 2003; 63: 2330-4.
38. Laughner E, Taghavi P, Chiles K, et al. HER2 (neu) signalling increases the rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001; 21: 3995-4004.
39. Qayum N, Muschel RJ, Im JH, et al. Tumor vascular changes mediated by inhibition of oncogenic signalling. Cancer Res. 2009; 69: 6347-54.
40. Fukuda R, Hirota K, Fan F, et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signalling in colon cancer cells. J Biol Chem. 2002; 277: 38205-11.
41. Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000; 14: 391-6.
42. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1 alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002; 22: 7004-14.
43. Hu HT, Ma QY, Zhang D, et al. HIF-1 alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition. Acta Pharmacol Sin. 2010; 31: 102-10.
44. Moeller BJ, Cao Y, Li CY, et al. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004; 5: 429-41.
45. Mimeault M, Hauke R, Mehta PP, et al. Recent advances on cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. J Cell Mol Med. 2007; 11: 981-1011.
46. Hashimoto O, Shimizu K, Semba S, et al. Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1 alpha-dependent manner in pancreatic cancer cells. Pathobiology. 2011; 78: 181-92.
47. Mimeault M, Batra SK. New advances on critical implications of tumor- and metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence. Histol Histopathol. 2010; 25: 1057-73.
48. Anderson KM, Guinan P, Rubenstein M. The effect of normoxia and hypoxia on a prostate (PC-3) CD44/CD41 cell side fraction. Anticancer Res. 2011; 31: 487-94.
49. Mimeault M, Batra SK. New promising drug targets in cancer- and metastasis-initiating cells. Drug Discov Today. 2010; 15: 354-64.
50. Oliveira-Costa JP, Zanetti JS, Silveira GG, et al. Differential expression of HIF-1 alpha in CD44+CD24-/low breast ductal carcinomas. Diagn Pathol. 2011; 6: 73.
51. Rausch V, Liu L, Apel A, et al. Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. J Pathol. 2012; 227: 325-35.
52. Mimeault M, Batra SK. Novel therapies against aggressive and recurrent epithelial cancers by molecular targeting tumor- and metastasis-initiating cells and their progenies. Anticancer Agents Med Chem. 2010; 10: 137-51.
53. Mimeault M, Johansson SL, Batra SK. Pathobiological implications of the expression of EGFR, pAkt, NF-kB and MIC-1 in prostate cancer stem cells and their progenies. PLoS ONE. 2012; 7: e31919.
54. Guan Y, Reddy KR, Zhu Q, et al. G-rich oligonucleotides inhibit HIF-1 alpha and HIF-2 alpha and block tumor growth. Mol Ther. 2010; 18: 188-97.
55. Zhang H, Li H, Xi HS, et al. HIF1 alpha is required for survival maintenance of chronic myeloid leukemia stem cells. Blood. 2012; 119: 2595-607.
56. Takeuchi M, Ashihara E, Yamazaki Y, et al. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Sci. 2011; 102: 591-6.
57. Huang Y, Yu J, Yan C, et al. Effect of small interfering RNA targeting hypoxia-inducible factor-1 alpha on radiosensitivity of PC3 cell line. Urology. 2012; 79: 744.e17-24.
58. Lee K, Qian DZ, Rey S, et al. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA. 2009; 106: 2353-8.
59. Manohar SM, Padgaonkar AA, Jalota-Badhwar A, et al. Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1alpha and induces G2/M arrest under hypoxia in prostate cancer cells. Prostate Cancer Prostatic Dis. 2012; 15: 15-27.
60. Baker LC, Boult JK, Walker-Samuel S, et al. The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. Br J Cancer. 2012; 106: 1638-47.
61. Manohar SM, Padgaonkar AA, Jalota-Badhwar A, et al. A novel inhibitor of hypoxia-inducible factor-1 alpha P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells. BMC Cancer. 2011; 11: 338.
62. Mizuno T, Nagao M, Yamada Y, et al. Small interfering RNA expression vector targeting hypoxia-inducible factor 1 alpha inhibits tumor growth in hepatobiliary and pancreatic cancers. Cancer Gene Ther. 2006; 13: 131-40.
63. Kawakami K, Hattori M, Inoue T, et al. A novel fusicoccin derivative preferentially targets hypoxic tumor cells and inhibits tumor growth in xenografts. Anticancer Agents Med Chem. 2012; 12: 791-800.
64. Liu Q, Sun JD, Wang J, et al., et al. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules. Cancer Chemother Pharmacol. 2012; 69: 1487-98.
65. Boreddy SR, Sahu RP, Srivastava SK. Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-alpha/VEGF/Rho-GTPases: pivotal role of STAT-3. PLoS ONE. 2011; 6: e25799.
66. Staab A, Fleischer M, Loeffler J, et al. Small interfering RNA targeting HIF-1 alpha reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro. Strahlenther Onkol. 2011; 187: 252-9.
67. Mimeault M, Batra SK. Recent advances on skin-resident stem/progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies. J Cell Mol Med. 2010; 14: 116-34.
68. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004; 351: 657-67.
69. Hu Y, Swerdlow S, Duffy TM, et al. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA. 2006; 103: 16870-5.
70. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007; 7: 441-53.
71. Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA. 2000; 97: 7521-6.
72. Colmone A, Amorim M, Pontier AL, et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 2008; 322: 1861-5.
73. Hwang-Verslues WW, Kuo WH, Chang PH, et al. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers. PLoS ONE. 2009; 4: e8377.
74. Conley SJ, Gheordunescu E, Kakarala P, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 2012; 109: 2784-9.
75. Milane L, Duan Z, Amiji M. Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS ONE. 2011; 6: e24075.
76. Al-Hajj M, Wicha MS, Ito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003; 100: 3983-8.
77. Wang Z, Shi Q, Wang Z, et al. Clinicopathologic correlation of cancer stem cell markers CD44, CD24, VEGF and HIF-1 alpha in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immunohistochemistry-based pilot study. Pathol Res Pract. 2011; 207: 505-13.
78. Jung JW, Park SB, Lee SJ, et al. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS ONE. 2011; 6: e28068.
79. Louie E, Nik S, Chen JS, et al. Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 2010; 12: R94.
80. Krohn A, Song YH, Muehlberg F, et al. CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro. Cancer Lett. 2009; 280: 65-71.
81. Mimeault M, Johansson SL, Henichart JP, et al. Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and non-side population cell fractions from human invasive prostate cancer cells. Mol Cancer Ther. 2010; 9: 617-30.
82. Mimeault M, Batra SK. Complex oncogenic signalling networks regulate brain tumor-initiating cells and their progenies: pivotal roles of wild-type EGFR, EGFRvIII mutant and hedgehog cascades and novel multitargeted therapies. Brain Pathol. 2011; 21: 479-500.
83. Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol. 2012; 3: 32-42.
84. Frankfurt O, Tallman MS. Growth factors in leukemia. J Natl Compr Canc Netw. 2007; 5: 203-15.
85. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009; 458: 776-9.
86. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003; 423: 255-60.
87. Mimeault M, Hauke R, Batra SK. Stem cells - A revolution in therapeutics-Recent advances on the stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther. 2007; 82: 252-64.
88. Han M, Wang Y, Liu M, et al. MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia-inducible factor-1 alpha expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci. 2012; 103: 1058-64.
89. Barbieri A, Palma G, Rosati A, et al. Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth. J Cell Mol Med. 2012; 16: 920-6.
90. Takeuchi M, Kimura S, Kuroda J, et al. Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment. Cell Death Differ. 2010; 17: 1211-20.
91. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344: 1038-42.
92. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002; 99: 319-25.
93. Hamilton A, Helgason GV, Schemionek M, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012; 119: 1501-10.
94. Tanturli M, Giuntoli S, Barbetti V, et al. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia. PLoS ONE. 2011; 6: e17008.
95. Ibanez E, Agliano A, Prior C, et al. The quinoline imidoselenocarbamate EI201 blocks AKT/mTOR pathway and targets cancer stem cells leading to a strong antitumor activity. Curr Med Chem. 2012; 19: 3031-43.
96. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, et al. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011; 126: 355-64.
97. Mimeault M, Batra SK. Frequent deregulations in the hedgehog signalling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies. Pharmacol Rev. 2010; 62: 497-524.
98. Annabi B, Rojas-Sutterlin S, Laflamme C, et al. Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res. 2008; 6: 907-16.
99. Yang MH, Wu MZ, Chiou SH, et al. Direct regulation of TWIST by HIF-1 alpha promotes metastasis. Nat Cell Biol. 2008; 10: 295-305.
100. Jing SW, Wang YD, Chen LQ, et al. Hypoxia suppresses E-cadherin and enhances matrix metalloproteinase-2 expression favoring esophageal carcinoma migration and invasion via hypoxia inducible factor-1 alpha activation. Dis Esophagus. 2012; in press: doi: 10.1111/j.1442-2050.2011.01321.x.
101. Gravdal K, Halvorsen OJ, Haukaas SA, et al. Proliferation of immature tumor vessels is a novel marker of clinical progression in prostate cancer. Cancer Res. 2009; 69: 4708-15.
102. Zhang L, Hill RP. Hypoxia enhances metastatic efficiency in HT1080 fibrosarcoma cells by increasing cell survival in lungs, not cell adhesion and invasion. Cancer Res. 2007; 67: 7789-97.
103. Karlsson H, Fryknas M, Larsson R, et al. Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exp Cell Res. 2012; 318: 1577-85.
104. Saigusa S, Tanaka K, Toiyama Y, et al. Clinical significance of CD133 and hypoxia inducible factor-1 alpha gene expression in rectal cancer after preoperative chemoradiotherapy. Clin Oncol. 2011; 23: 323-32.
105. Das B, Tsuchida R, Malkin D, et al. Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells. 2008; 26: 1818-30.
106. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, et al. Recruitment of HIF-1 alpha and HIF-2 alpha to common target genes is differentially regulated in neuroblastoma: HIF-2 alpha promotes an aggressive phenotype. Cancer Cell. 2006; 10: 413-23.
107. Chen B, Yuping S, Ni J. Rapamycin decreases survivin expression to induce NSCLC cell apoptosis under hypoxia through inhibiting HIF-1 alpha induction. Mol Biol Rep. 2012; 39: 185-91.
108. Heddleston JM, Wu Q, Rivera M, et al. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ. 2012; 19: 428-39.
109. Krieg AJ, Rankin EB, Chan D, et al. Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol. 2010; 30: 344-53.
110. Elvidge GP, Glenny L, Appelhoff RJ, et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1 alpha, HIF-2 alpha, and other pathways. J Biol Chem. 2006; 281: 15215-26.
111. Chen N, Chen X, Huang R, et al. BCL-xL is a target gene regulated by hypoxia-inducible factor-1 alpha. J Biol Chem. 2009; 284: 10004-12.
112. Kumar SM, Liu S, Lu H, et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene. 2012; 31: 4898-911.
113. Chiche J, Brahimi-Horn MC, Pouyssegur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med. 2010; 14: 771-94.
114. Svastova E, Witarski W, Csaderova L, et al. Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem. 2012; 287: 3392-402.
115. Lou Y, McDonald PC, Oloumi A, et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011; 71: 3364-76.
116. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1 alpha-dependent mechanism. J Biol Chem. 2006; 281: 9030-7.
117. Shinojima T, Oya M, Takayanagi A, et al. Renal cancer cells lacking hypoxia inducible factor (HIF)-1 alpha expression maintain vascular endothelial growth factor expression through HIF-2 alpha. Carcinogenesis. 2007; 28: 529-36.
118. Shibaji T, Nagao M, Ikeda N, et al. Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res. 2003; 23: 4721-7.
119. Fang J, Ding M, Yang L, et al. PI3K/PTEN/AKT signalling regulates prostate tumor angiogenesis. Cell Signal. 2007; 19: 2487-97.
120. Gordan JD, Bertout JA, Hu CJ, et al. HIF-2 alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007; 11: 335-47.
121. Covello KL, Kehler J, Yu H, et al. HIF-2 alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006; 20: 557-70.
122. Carrero P, Okamoto K, Coumailleau P, et al. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1 alpha. Mol Cell Biol. 2000; 20: 402-15.
123. Ruas JL, Berchner-Pfannschmidt U, Malik S, et al. Complex regulation of the transactivation function of hypoxia-inducible factor-1 alpha by direct interaction with two distinct domains of the CREB-binding protein/p300. J Biol Chem. 2010; 285: 2601-9.
124. Hasmim M, Noman MZ, Lauriol J, et al. Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells. J Immunol. 2011; 187: 4031-9.
125. Wong CC, Gilkes DM, Zhang H, et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA. 2011; 108: 16369-74.
126. Heddleston JM, Li Z, McLendon RE, et al. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009; 8: 3274-84.
127. Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009; 15: 501-13.
128. Gibbs BF, Yasinska IM, Oniku AE, et al. Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells. PLoS ONE. 2011; 6: e22502.
129. Rizo A, Vellenga E, de Haan G, et al. Signalling pathways in self-renewing hematopoietic and leukemic stem cells: do all stem cells need a niche? Hum Mol Genet. 2006; 15: R210-9.
130. Nagao R, Ashihara E, Kimura S, et al. Growth inhibition of imatinib-resistant CML cells with the T315I mutation and hypoxia-adaptation by AV65-a novel Wnt/beta-catenin signalling inhibitor. Cancer Lett. 2011; 312: 91-100.
131. Sengupta A, Banerjee D, Chandra S, et al. B Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signalling in chronic myeloid leukemia progression. Leukemia. 2007; 21: 949-55.
132. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006; 354: 2531-41.
133. Giuffrida D, Rogers IM. Targeting cancer stem cell lines as a new treatment of human cancer. Recent Pat Anticancer Drug Discov. 2010; 5: 205-18.
134. Wang Y, Liu Y, Malek SN, et al. Targeting HIF1 alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011; 8: 399-411.
135. Calabretta B, Salomoni P. Suppression of autophagy by BCR/ABL. Front Biosci. 2012; 4: 453-60.
136. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352: 987-96.
137. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007; 21: 2683-710.
138. Karpel-Massler G, Schmidt U, Unterberg A, et al. Therapeutic inhibition of the epidermal growth factor receptor in high-grade gliomas: where do we stand? Mol Cancer Res. 2009; 7: 1000-12.
139. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444: 756-60.
140. Eramo A, Ricci-Vitiani L, Zeuner A, et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006; 13: 1238-41.
141. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007; 11: 69-82.
142. Li A, Walling J, Ahn S, et al. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes. Cancer Res. 2009; 69: 2091-9.
143. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010; 17: 98-110.
144. Brennan C, Momota H, Hambardzumyan D, et al. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS ONE. 2009; 4: e7752.
145. Platet N, Liu SY, Atifi ME, et al. Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Lett. 2007; 258: 286-90.
146. Hjelmeland AB, Wu Q, Heddleston JM, et al. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 2011; 18: 829-40.
147. Seidel S, Garvalov BK, Wirta V, et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain. 2010; 133: 983-95.
148. Soeda A, Park M, Lee D, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1 alpha. Oncogene. 2009; 28: 3949-59.
149. Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006; 66: 7843-8.
150. Wang J, Wang H, Li Z, et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE. 2008; 3: e3769.
151. Bao S, Wu Q, Li Z, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res. 2008; 68: 6043-8.
152. Andersson U, Schwartzbaum J, Wiklund F, et al. A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk. Acta Oncol. 2010; 49: 767-75.
153. Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008; 5: e8.
154. Galavotti S, Bartesaghi S, Faccenda D, et al. The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene. 2012; in press: doi: 10.1038/onc.2012.111.
155. Yin S, Kaluz S, Devi NS, et al. Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signalling by disrupting HIF-1 alpha interaction with co-factors p300/CBP. Clin Cancer Res. 2012; in press: doi: 10.1158/1078-0432.CCR-12-0861.
156. Sotelo J, Briceno E, Lopez-Gonzalez MA, et al. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006; 144: 337-43.
157. Tsao H, Atkins MB, Sober AJ, et al. Management of cutaneous melanoma. N Engl J Med. 2004; 351: 998-1012.
158. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007; 445: 851-7.
159. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol. 2009; 27: 3-9.
160. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69-90.
161. Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005; 65: 9328-37.
162. Monzani E, Facchetti F, Galmozzi E, et al. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer. 2007; 43: 935-46.
163. Schatton T, Murphy GF, Frank NY, et al. Identification of cells initiating human melanomas. Nature. 2008; 451: 345-9.
164. Boiko AD, Razorenova OV, van de Rijn M, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010; 466: 133-7.
165. Strizzi L, Abbott DE, Salomon DS, et al. Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma. Cell Cycle. 2008; 7: 1931-5.
166. Giatromanolaki A, Sivridis E, Kouskoukis C, et al. Hypoxia-inducible factors 1 alpha and 2 alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res. 2003; 13: 493-501.
167. Valencak J, Kittler H, Schmid K, et al. Prognostic relevance of hypoxia inducible factor-1 alpha expression in patients with melanoma. Clin Exp Dermatol. 2009; 34: e962-4.
168. Konstantina A, Lazaris AC, Ioannidis E, et al. Immunohistochemical expression of VEGF, HIF1-a, and PlGF in malignant melanomas and dysplastic nevi. Melanoma Res. 2011; 21: 389-94.
169. Sivridis E, Koukourakis MI, Mendrinos SE, et al. Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1. Melanoma Res. 2011; 21: 188-95.
170. Strizzi L, Bianco C, Normanno N, et al. Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis. Oncogene. 2005; 24: 5731-41.
171. Rofstad EK, Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999; 80: 1697-707.
172. Braig S, Wallner S, Junglas B, et al. CTGF is overexpressed in malignant melanoma and promotes cell invasion and migration. Br J Cancer. 2011; 105: 231-8.
173. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003; 9: 6483-8.
174. Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011; 480: 94-8.
175. Busca R, Berra E, Gaggioli C, et al. Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells. J Cell Biol. 2005; 170: 49-59.
176. Spinella F, Rosano L, Del Duca M, et al. Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1 alpha in melanoma cells. PLoS ONE. 2010; 5: e11241.
177. Kumar SM, Yu H, Edwards R, et al. Mutant V600E BRAF increases hypoxia inducible factor-1 alpha expression in melanoma. Cancer Res. 2007; 67: 3177-84.
178. Mills CN, Joshi SS, Niles RM. Expression and function of hypoxia inducible factor-1 alpha in human melanoma under non-hypoxic conditions. Mol Cancer. 2009; 8: 104.
179. Comito G, Calvani M, Giannoni E, et al. HIF-1alpha stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. Free Radic Biol Med. 2011; 51: 893-904.
180. Kuphal S, Winklmeier A, Warnecke C, et al. Constitutive HIF-1 activity in malignant melanoma. Eur J Cancer. 2010; 46: 1159-69.
181. Chun YS, Lee KH, Choi E, et al. Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1 alpha isoform: implications for tumor promotion. Cancer Res. 2003; 63: 8700-7.
182. Trevino-Villarreal JH, Cotanche DA, Sepulveda R, et al. Host-derived pericytes and Sca-1+ cells predominate in the MART-1- stroma fraction of experimentally induced melanoma. J Histochem Cytochem. 2011; 59: 1060-75.
183. Frank NY, Schatton T, Kim S, et al. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res. 2011; 71: 1474-85.
184. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006; 12: 406-14.
185. Hamsa TP, Kuttan G. Antiangiogenic activity of berberine is mediated through the downregulation of hypoxia-inducible factor-1, VEGF, and proinflammatory mediators. Drug Chem Toxicol. 2012; 35: 57-70.
186. Trapp V, Parmakhtiar B, Papazian V, et al. Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture. Angiogenesis. 2010; 13: 305-15.
187. Yang XC, Tu CX, Luo PH, et al. Antimetastatic activity of MONCPT in preclinical melanoma mice model. Invest New Drugs. 2010; 28: 800-11.
188. Franco R, Cantile M, Scala S, et al. Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome. Cancer Biol Ther. 2010; 9: 423-9.
189. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004; 351: 1513-20.
190. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351: 1502-12.
191. Mimeault M, Batra SK. Animal models of prostate carcinogenesis underlining the critical implication of prostatic stem progenitor cells. Biochim Biophys Acta. 2011; 1816: 25-37.
192. Tu SM, Lin SH. Prostate cancer stem cells. Clin Genitourin Cancer. 2012; 10: 69-76.
193. Jeter CR, Liu B, Liu X, et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 2011; 30: 3833-45.
194. Dubrovska A, Elliott J, Salamone RJ, et al. CXCR4 expression in prostate cancer progenitor cells. PLoS ONE. 2012; 7: e31226.
195. Nanni S, Benvenuti V, Grasselli A, et al. Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest. 2009; 119: 1093-108.
196. Shaida N, Chan P, Turley H, et al. Nuclear localization of factor inhibitor hypoxia-inducible factor in prostate cancer is associated with poor prognosis. J Urol. 2011; 185: 1513-8.
197. Al-Ubaidi FL, Schultz N, Egevad L, et al. Castration therapy of prostate cancer results in downregulation of HIF-1 alpha levels. Int J Radiat Oncol Biol Phys. 2012; 82: 1243-8.
198. Hennessey D, Martin LM, Atzberger A, et al. Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol Oncol. 2011; in press: doi: 10.1016/j.urolonc.2011.10.008.
199. Mitani T, Yamaji R, Higashimura Y, et al. Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1 alpha in a low androgen environment. J Steroid Biochem Mol Biol. 2011; 123: 58-64.
200. Mishra A, Wang J, Shiozawa Y, et al. Hypoxia stabilizes GAS6/AXl signalling in metastatic prostate cancer. Mol Cancer Res. 2012; 10: 703-12.
201. Hagtvet E, Roe K, Olsen DR. Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts. Radiat Oncol. 2011; 6: 135.
202. Cho SY, Lee HJ, Jeong SJ, et al. Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1 alpha inactivation in hypoxic PC-3 prostate cancer cells. J Pineal Res. 2011; 51: 87-93.
203. Branco-Price C, Zhang N, Schnelle M, et al. Endothelial cell HIF-1 alpha and HIF-2 alpha differentially regulate metastatic success. Cancer Cell. 2012; 21: 52-65.
204. Yamasaki M, Nomura T, Sato F, et al. Chronic hypoxia induces androgen-independent and invasive behavior in LNCaP human prostate cancer cells. Urol Oncol. 2012; in press:. doi:10.1016/j.urolonc.2011.12.007.
205. Giannoni E, Bianchini F, Masieri L, et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010; 70: 6945-56.
206. Giannoni E, Bianchini F, Calorini L, et al. Cancer associated fibroblasts exploit reactive oxygen species through a pro-inflammatory signature leading to EMT and stemness. Antioxid Redox Signal. 2011; 14: 2361-71.
207. Melchior SW, Corey E, Ellis WJ, et al. Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate. Clin Cancer Res. 1997; 3: 249-56.
208. Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011; 121: 1298-312.
209. Selander KS, Brown DA, Sequeiros GB, et al. Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases. Cancer Epidemiol. Biomarkers Prev. 2007; 16: 532-7.
210. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006; 107: 1761-7.
211. Shiozawa Y, Pienta KJ, Taichman RS. Hematopoietic stem cell niche is a potential therapeutic target for bone metastatic tumors. Clin Cancer Res. 2011; 17: 5553-8.
212. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010; 7: 150-61.
213. Chinni SR, Sivalogan S, Dong Z, et al. FCXCL12/CXCR4 signalling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate. 2006; 66: 32-48.
214. Chinni SR, Yamamoto H, Dong Z, et al. CXCL12/CXCR4 transactivates HER2 in lipid rafts of prostate cancer cells and promotes growth of metastatic deposits in bone. Mol Cancer Res. 2008; 6: 446-57.
215. Joseph J, Shiozawa Y, Jung Y, et al. Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype. Mol Cancer Res. 2012; 10: 282-92.
216. Kobayashi A, Okuda H, Xing F, et al. PBone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011; 208: 2641-55.
217. Mimeault M, Batra SK. Frequent gene products and molecular pathways altered in prostate cancer- and metastasis-initiating cells and novel promising multitargeted therapies. Mol Med. 2011; 17: 649-64.
218. Reddy KR, Guan Y, Qin G, et al. Combined treatment targeting HIF-1 alpha and Stat3 is a potent strategy for prostate cancer therapy. Prostate. 2011; 71: 1796-809.
219. Jeong CW, Yoon CY, Jeong SJ, et al. The role of hypoxia-inducible factor-1 alpha and -2 alpha in androgen insensitive prostate cancer cells. Urol Oncol. 2012; in press: doi: 10.1016/j.urolonc.2012.03.022.
220. Ellis L, Lehet K, Ramakrishnan S, et al. Concurrent HDAC and mTORC1 inhibition attenuate androgen receptor and hypoxia signalling associated with alterations in microRNA expression. PLoS ONE. 2011; 6: e27178.
221. Befani CD, Vlachostergios PJ, Hatzidaki E, et al. Bortezomib represses HIF-1alpha protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells. J Mol Med. 2012; 90: 45-54.
222. Sinha I, Null K, Wolter W, et al. Methylseleninic acid downregulates hypoxia-inducible factor-1 alpha in invasive prostate cancer. Int J Cancer. 2012; 130: 1430-9.
223. Jung SJ, Kim CI, Park CH, et al. Correlation between chemokine receptor CXCR4 expression and prognostic factors in patients with prostate cancer. Korean J Urol. 2011; 52: 607-11.
224. Sun YX, Schneider A, Jung Y, et al. Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res. 2005; 20: 318-29.
225. Baron A, Migita T, Tang D, et al. Fatty acid synthase: a metabolic oncogene in prostate cancer? J Cell Biochem. 2004; 91: 47-53.
226. Yamaguchi R, Janssen E, Perkins G, et al. Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy. PLoS ONE. 2011; 6: e24102.
227. Moon JS, Jin WJ, Kwak JH, et al. Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 in prostate cancer cells. Biochem J. 2011; 433: 225-33.
228. Stein M, Lin H, Jeyamohan C, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate. 2010; 70: 1388-94.
229. Gottfried E, Rogenhofer S, Waibel H, et al. Pioglitazone modulates tumor cell metabolism and proliferation in multicellular tumor spheroids. Cancer Chemother Pharmacol. 2011; 67: 117-26.
230. Sotgia F, Martinez-Outschoorn UE, Howell A, et al. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol. 2012; 7: 423-67.
231. Hu H, Chai Y, Wang L, et al. Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells. Mol Cancer Ther. 2009; 8: 2833-43.
232. Ben Sahra I, Laurent K, Giuliano S, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010; 70: 2465-75.
233. Chhipa RR, Wu Y, Ip C. AMPK-mediated autophagy is a survival mechanism in androgen-dependent prostate cancer cells subjected to androgen deprivation and hypoxia. Cell Signal. 2011; 23: 1466-72.
234. Nomura DK, Lombardi DP, Chang JW, et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol. 2011; 18: 846-56.
235. Sorlie T, Wang Y, Xiao C, et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics. 2006; 7: 127.
236. Guedj M, Marisa L, de Reynies A, et al. A refined molecular taxonomy of breast cancer. Oncogene. 2011; 31: 1196-206.
237. Punglia RS, Morrow M, Winer EP, et al. Local therapy and survival in breast cancer. N Engl J Med. 2007; 356: 2399-405.
238. Arteaga CL, Sliwkowski MX, Osborne CK, et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012; 9: 16-32.
239. Dunn LK, Mohammad KS, Fournier PG, et al. Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signalling pathways in tumor cells and the bone microenvironment. PLoS ONE. 2009; 4: e6896.
240. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007; 11: 259-73.
241. Bandyopadhyay A, Wang L, Agyin J, et al. Doxorubicin in combination with a small TGFbeta inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. PLoS ONE. 2010; 5: e10365.
242. Yin X, Wolford CC, Chang YS, et al. ATF3, an adaptive-response gene, enhances TGF{beta} signalling and cancer-initiating cell features in breast cancer cells. J Cell Sci. 2010; 123: 3558-65.
243. Wang Y, Yu Y, Tsuyada A, et al. Transforming growth factor-beta regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene. 2011; 30: 1470-80.
244. Oliveras-Ferraros C, Cufi S, Vazquez-Martin A, et al. Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFbeta-induced oncomiR miRNA-181a. Cell Cycle. 2011; 10: 1144-51.
245. Asiedu MK, Ingle JN, Behrens MD, et al. TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res. 2011; 71: 4707-19.
246. Natarajan K, Xie Y, Baer MR, et al. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012; 83: 1084-103.
247. Hirsch HA, Iliopoulos D, Tsichlis PN, et al. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009; 69: 7507-11.
248. Dubrovska A, Hartung A, Bouchez LC, et al. CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling. Br J Cancer. 2012; 107: 43-52.
249. Van Phuc P, Nhan PL, Nhung TH, et al. TDownregulation of CD44 reduces doxorubicin resistance of CD44CD24 breast cancer cells. Onco Targets Ther. 2011; 4: 71-8.
250. Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012; 2: 362.
251. Bendinelli P, Matteucci E, Maroni P, et al. NF-kappaB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells. Mol Cancer Res. 2009; 7: 1328-41.
252. Huang M, Li Y, Zhang H, et al. Breast cancer stromal fibroblasts promote the generation of CD44+CD24- cells through SDF-1/CXCR4 interaction. J Exp Clin Cancer Res. 2010; 29: 80.
253. Ling LJ, Wang S, Liu XA, et al. A novel mouse model of human breast cancer stem-like cells with high CD44+CD24-/lower phenotype metastasis to human bone. Chin Med J. 2008; 121: 1980-6.
254. Liang Z, Wu T, Lou H, et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004; 64: 4302-8.
255. Okuda H, Kobayashi A, Xia B, et al. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res. 2012; 72: 537-47.
256. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410: 50-6.
257. Erler JT, Bennewith KL, Cox TR, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009; 15: 35-44.
258. Ibrahim T, Sacanna E, Gaudio M, et al. Role of RANK, RANKL, OPG, and CXCR4 tissue markers in predicting bone metastases in breast cancer patients. Clin Breast Cancer. 2011; 11: 369-75.
259. Lu X, Mu E, Wei Y, et al., et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell. 2011; 20: 701-14.
260. Suva LJ, Griffin RJ, Makhoul I. Mechanisms of bone metastases of breast cancer. Endocr Relat Cancer. 2009; 16: 703-13.
261. Buijs JT, Henriquez NV, van Overveld PG, et al. vTGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis. 2007; 24: 609-17.
262. Buijs JT, van der Horst G, van den Hoogen C, et al. The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene. 2012; 31: 2164-74.
263. Lee KH, Hsu EC, Guh JH, et al. Targeting energy metabolic and oncogenic signalling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J Biol Chem. 2011; 286: 39247-58.
264. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011; 71: 3196-201.
265. Furuta E, Pai SK, Zhan R, et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008; 68: 1003-11.
266. Pandey PR, Okuda H, Watabe M, et al. Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res Treat. 2011; 130: 387-98.
267. Pham PV, Phan NL, Nguyen NT, et al. Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy. J Transl Med. 2011; 9: 209.
268. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006; 66: 10269-73.
269. Del Barco S, Vazquez-Martin A, Cufi S, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011; 2: 896-917.
270. Brand RE, Lerch MM, Rubinstein WS, et al. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007; 56: 1460-9.
271. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010; 362: 1605-17.
272. Di Marco M, Di Cicilia R, Macchini M, et al. Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? Oncol Rep. 2010; 23: 1183-92.
273. Mimeault M, Brand RE, Sasson AA, et al. Recent advances on the molecular mechanisms involved in pancreatic cancer progression and therapies. Pancreas. 2005; 31: 301-16.
274. Onozuka H, Tsuchihara K, Esumi H. Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. Cancer Sci. 2011; 102: 975-82.
275. Mimeault M, Batra SK. Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer. Gut. 2008; 57: 1456-68.
276. Bao B, Wang Z, Ali S, et al. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res. 2012; 5: 355-64.
277. Chaika NV, Yu F, Purohit V, et al. Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma. PLoS ONE. 2012; 7: e32996.
278. Kim EJ, Simeone DM. Advances in pancreatic cancer. Curr Opin Gastroenterol. 2011; 27: 460-6.
279. Akakura N, Kobayashi M, Horiuchi I, et al. Constitutive expression of hypoxia-inducible factor-1 alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001; 61: 6548-54.
280. Wei H, Wang C, Chen L. Proliferating cell nuclear antigen, survivin, and CD34 expressions in pancreatic cancer and their correlation with hypoxia-inducible factor 1 alpha. Pancreas. 2006; 32: 159-63.
281. Cheng BQ, Segersvard R, Permert J, et al. Pancreatic cancer cells expressing hypoxia-inducible factor-1 alpha tend to be adjacent to intratumoral blood vessels. Eur Surg Res. 2010; 45: 134-7.
282. Zhang JJ, Wu HS, Wang L, et al. Expression and significance of TLR4 and HIF-1 alpha in pancreatic ductal adenocarcinoma. World J Gastroenterol. 2010; 16: 2881-8.
283. Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012; 149: 656-70.
284. Goldberg L, Israeli R, Kloog Y. FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice. Cell Death Dis. 2012; 3: e284.
285. Taly S-K, Galen H, Daniel VH, et al. Hedgehog signaling and desmoplasia are regulated by hypoxia in pancreatic cancer. Fourth AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Sep 27-30, 2010; Denver, CO.
286. Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer. 2009; 100: 1444-51.
287. Onishi H, Kai M, Odate S, et al. Hypoxia activates the hedgehog signalling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci. 2011; 102: 1144-50.
288. Onishi H, Morifuji Y, Kai M, et al. Hedgehog inhibitor decreases chemosensitivity to 5-FU and gemcitabine under hypoxic conditions in pancreatic cancer. Cancer Sci. 2012; in press.
289. Chang Q, Jurisica I, Do T, et al. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res. 2011; 71: 3110-20.
290. Melstrom LG, Salabat MR, Ding XZ, et al. Apigenin down-regulates the hypoxia response genes: HIF-1 alpha, GLUT-1, and VEGF in human pancreatic cancer cells. J Surg Res. 2011; 167: 173-81.
291. Sun JD, Liu Q, Wang J, et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin Cancer Res. 2012; 18: 758-70.
292. Yang S, Kimmelman AC. A critical role for autophagy in pancreatic cancer. Autophagy. 2011; 7: 912-3.
293. Xi H, Kurtoglu M, Liu H, et al. 2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol. 2011; 67: 899-910.
294. Bhardwaj V, Rizvi N, Lai MB, et al. Glycolytic enzyme inhibitors affect pancreatic cancer survival by modulating its signalling and energetics. Anticancer Res. 2010; 30: 743-9.
295. Cao X, Bloomston M, Zhang T, et al. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin Cancer Res. 2008; 14: 1831-9.
296. Cheng ZX, Sun B, Wang SJ, et al. Nuclear factor-kappaB-dependent epithelial to mesenchymal transition induced by HIF-1 alpha activation in pancreatic cancer cells under hypoxic conditions. PLoS ONE. 2011; 6: e23752.