The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis

Stem Cell Reviews and Reports

Volumn 11, Issue 6, 2015, Pages 919-943

  Myszczyszyn, Adam ^a   Czarnecka, Anna M ^a   Matak, Damian ^a,b   Szymanski, Lukasz ^a,c   Lian, Fei ^d   Kornakiewicz, Anna ^a,b   Bartnik, Ewa ^c,e   Kukwa, Wojciech ^b   Kieda, Claudine ^f   Szczylik, Cezary ^a  

^a MILITARY INSTITUTE OF MEDICINE   (Poland)

^b MEDICAL UNIVERSITY OF WARSAW   (Poland)

^c UNIVERSITY OF WARSAW   (Poland)

^d EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e INSTITUTE OF BIOCHEMISTRY AND BIOPHYSICS   (Poland)

^f CENTRE DE BIOPHYSIQUE MOLÉCULAIRE   (France)

Author keywords

Cancer stem cells; Epithelial to mesenchymal transition; Hypoxia inducible factors (HIF 1 , HIF 2 ); Renal cancer; von Hippel Lindau protein (pVHL)

Indexed keywords

ALDEHYDE DEHYDROGENASE; ALPHA INTERFERON; CD133 ANTIGEN; CHEMOKINE RECEPTOR CXCR; ENDOGLIN; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1BETA; MAMMALIAN TARGET OF RAPAMYCIN; PROTEIN TYROSINE KINASE; TRANSCRIPTION FACTOR PAX2; VON HIPPEL LINDAU PROTEIN; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1; HIF1A PROTEIN, HUMAN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; VHL PROTEIN, HUMAN;

CANCER STEM CELL; CARCINOGENICITY; CELL DEDIFFERENTIATION; CELL PROLIFERATION; CELL TRANSFORMATION; ENZYME ACTIVITY; EPITHELIAL MESENCHYMAL TRANSITION; HEMATOPOIETIC STEM CELL; HUMAN; HYPOXIA; KIDNEY CARCINOMA; MESENCHYMAL STEM CELL; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; TUMOR MICROENVIRONMENT; CELL HYPOXIA; CYTOLOGY; GENE EXPRESSION REGULATION; KIDNEY TUMOR; METABOLISM; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION;

BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CARCINOMA, RENAL CELL; CELL DEDIFFERENTIATION; CELL HYPOXIA; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; KIDNEY NEOPLASMS; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; VON HIPPEL-LINDAU TUMOR SUPPRESSOR PROTEIN;

EID: 84947617404     PISSN: 15508943     EISSN: 15586804     Source Type: Journal    
DOI: 10.1007/s12015-015-9611-y     Document Type: Review

References (268)

1. Siegel, R. L., Miller, K. D., & Jemal, A. (2015). Cancer Statistics, 2015. CA: A Cancer Journal for Clinicians, 65(1), 5–29.
2. Koul, H., Huh, J. S., Rove, K. O., et al. (2011). Molecular aspects of renal cell carcinoma: a review. American Journal of Cancer Research, 1(2), 240–254.
3. Bussolati, B., Dekel, B., Azzarone, B., & Camussi, G. (2013). Human renal cancer stem cells. Cancer Letters, 338(1), 141–146.
4. Axelson, H., & Johansson, M. E. (2013). Renal stem cells and their implications for kidney cancer. Seminars in Cancer Biology, 23(1), 56–61.
5. Novick, A. C. (2007). Kidney cancer: past, present, and future. Urologic Oncology, 25(3), 188–195.
6. Gerlinger, M., Rowan, A. J., Horswell, S., et al. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England Journal of Medicine, 366(10), 883–892.
7. Marusyk, A., & Polyak, K. (2010). Tumor heterogeneity: causes and consequences. Biochimica et Biophysica Acta, 1805(1), 105–117.
8. Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Reviews Cancer, 8(10), 755–768.
9. Visvader, J. E., & Lindeman, G. J. (2012). Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 10(6), 717–728.
10. Clevers, H. (2011). The cancer stem cell: premises, promises and challenges. Nature Medicine, 17(3), 313–319.
11. Pardal, R., Clarke, M. F., & Morrison, S. J. (2003). Applying the principles of stem-cell biology to cancer. Nature Reviews Cancer, 3(12), 895–902.
12. Greaves, M. (2007). Darwinian medicine: a case for cancer. Nature Reviews Cancer, 7(3), 213–221.
13. Michor, F., & Polyak, K. (2010). The origins and implications of intratumor heterogeneity. Cancer Prevention Research (Philadelphia), 3(11), 1361–1364.
14. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3983–3988.
15. Singh, S. K., Hawkins, C., Clarke, I. D., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432(7015), 396–401.
16. Vaiopoulos, A. G., Kostakis, I. D., Koutsilieris, M., & Papavassiliou, A. G. (2012). Colorectal cancer stem cells. Stem Cells, 30(3), 363–371.
17. Fitzgerald, T. L., & McCubrey, J. A. (2014). Pancreatic cancer stem cells: association with cell surface markers, prognosis, resistance, metastasis and treatment. Advances in Biological Regulation, 56, 45–50.
18. Yang, Z. F., Ho, D. W., Ng, M. N., et al. (2008). Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 13(2), 153–166.
19. Bertolini, G., Roz, L., Perego, P., et al. (2009). Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proceedings of the National Academy of Sciences of the United States of America, 106(38), 16281–16286.
20. Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J., & Maitland, N. J. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65(23), 10946–10951.
21. Foster, R., Buckanovich, R. J., & Rueda, B. R. (2013). Ovarian cancer stem cells: working towards the root of stemness. Cancer Letters, 338(1), 147–157.
22. Rutella, S., Bonanno, G., Procoli, A., et al. (2009). Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clinical Cancer Research, 15(13), 4299–4311.
23. Shakhova, O., & Sommer, L. (2013). Testing the cancer stem cell hypothesis in melanoma: the clinics will tell. Cancer Letters, 338(1), 74–81.
24. Gedye, C., Sirskyj, D., Lobo, N. C., et al. (2014). Essential experimental steps and estimates of renal carcinoma initiating cells. Journal of Clinical Oncology, 32:5 s, suppl; abstr 11127.
25. Mimeault, M., & Batra, S. K. (2013). Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. Journal of Cellular and Molecular Medicine, 17(1), 30–54.
26. Li, Z., & Rich, J. N. (2010). Hypoxia and hypoxia inducible factors in cancer stem cell maintenance. Current Topics in Microbiology and Immunology, 345, 21–30.
27. Mazumdar, J., Dondeti, V., & Simon, M. C. (2009). Hypoxia-inducible factors in stem cells and cancer. Journal of Cellular and Molecular Medicine, 13(11–12), 4319–4328.
28. Heddleston, J. M., Li, Z., Lathia, J. D., Bao, S., Hjelmeland, A. B., & Rich, J. N. (2010). Hypoxia inducible factors in cancer stem cells. British Journal of Cancer, 102(5), 789–795.
29. Keith, B., & Simon, M. C. (2007). Hypoxia-inducible factors, stem cells, and cancer. Cell, 129(3), 465–472.
30. Grosse-Gehling, P., Fargeas, C. A., Dittfeld, C., et al. (2013). CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. Journal of Pathology, 229(3), 355–378.
31. Angelotti, M. L., Lazzeri, E., Lasagni, L., & Romagnani, P. (2010). Only anti-CD133 antibodies recognizing the CD133/1 or the CD133/2 epitopes can identify human renal progenitors. Kidney International, 78(6), 620–621. author reply 621.
32. Kemper, K., Sprick, M. R., de Bree, M., et al. (2010). The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Research, 70(2), 719–729.
33. Bruno, S., Bussolati, B., Grange, C., et al. (2006). CD133+ renal progenitor cells contribute to tumor angiogenesis. American Journal of Pathology, 169(6), 2223–2235.
34. Caplan, A. I., & Bruder, S. P. (2001). Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends in Molecular Medicine, 7(6), 259–264.
35. Bussolati, B., Brossa, A., & Camussi, G. (2011). Resident stem cells and renal carcinoma. International Journal of Nephrology, 2011, 286985.
36. Bussolati, B., Bruno, S., Grange, C., et al. (2005). Isolation of renal progenitor cells from adult human kidney. American Journal of Pathology, 166(2), 545–555.
37. Lindgren, D., Boström, A. K., Nilsson, K., et al. (2011). Isolation and characterization of progenitor-like cells from human renal proximal tubules. American Journal of Pathology, 178(2), 828–837.
38. Sallustio, F., De Benedictis, L., Castellano, G., et al. (2010). TLR2 plays a role in the activation of human resident renal stem/progenitor cells. FASEB Journal, 24(2), 514–525.
39. Ronconi, E., Sagrinati, C., Angelotti, M. L., et al. (2009). Regeneration of glomerular podocytes by human renal progenitors. Journal of the American Society of Nephrology, 20(2), 322–332.
40. Sagrinati, C., Netti, G. S., Mazzinghi, B., et al. (2006). Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. Journal of the American Society of Nephrology, 17(9), 2443–2456.
41. Bussolati, B., Moggio, A., Collino, F., et al. (2012). Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through Oct4/miR-145 balance. American Journal of Physiology. Renal Physiology, 302(1), F116–128.
42. Ivanova, L., Hiatt, M. J., Yoder, M. C., Tarantal, A. F., & Matsell, D. G. (2010). Ontogeny of CD24 in the human kidney. Kidney International, 77(12), 1123–1131.
43. Lazzeri, E., Crescioli, C., Ronconi, E., et al. (2007). Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. Journal of the American Society of Nephrology, 18(12), 3128–3138.
44. Duff, S. E., Li, C., Garland, J. M., & Kumar, S. (2003). CD105 is important for angiogenesis: evidence and potential applications. FASEB Journal, 17(9), 984–992.
45. Dallas, N. A., Samuel, S., Xia, L., et al. (2008). Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clinical Cancer Research, 14(7), 1931–1937.
46. Li, C., Issa, R., Kumar, P., et al. (2003). CD105 prevents apoptosis in hypoxic endothelial cells. Journal of Cell Science, 116(Pt 13), 2677–2685.
47. Bussolati, B., Bruno, S., Grange, C., Ferrando, U., & Camussi, G. (2008). Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB Journal, 22(10), 3696–3705.
48. Hu, D., Wang, X., Mao, Y., & Zhou, L. (2012). Identification of CD105 (endoglin)-positive stem-like cells in rhabdoid meningioma. Journal of Neuro-Oncology, 106(3), 505–517.
49. Gibbs, C. P., Kukekov, V. G., Reith, J. D., et al. (2005). Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia, 7(11), 967–976.
50. Ricci-Vitiani, L., Pallini, R., Biffoni, M., et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468(7325), 824–828.
51. Xiong, Y. Q., Sun, H. C., Zhang, W., et al. (2009). Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clinical Cancer Research, 15(15), 4838–4846.
52. Alvero, A. B., Fu, H. H., Holmberg, J., et al. (2009). Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells, 27(10), 2405–2413.
53. Bussolati, B., Grange, C., Sapino, A., & Camussi, G. (2009). Endothelial cell differentiation of human breast tumour stem/progenitor cells. Journal of Cellular and Molecular Medicine, 13(2), 309–319.
54. Grange, C., Tapparo, M., Collino, F., et al. (2011). Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Research, 71(15), 5346–5356.
55. Lindoso, R. S., Collino, F., & Camussi, G. (2015). Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells. Oncotarget, 6(10), 7959–7969.
56. Gassenmaier, M., Chen, D., Buchner, A., et al. (2013). CXC chemokine receptor 4 is essential for maintenance of renal cell carcinoma-initiating cells and predicts metastasis. Stem Cells, 31(8), 1467–1476.
57. Nishizawa, S., Hirohashi, Y., Torigoe, T., et al. (2012). HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells. Cancer Research, 72(11), 2844–2854.
58. Zhong, Y., Guan, K., Guo, S., et al. (2010). Spheres derived from the human SK-RC-42 renal cell carcinoma cell line are enriched in cancer stem cells. Cancer Letters, 299(2), 150–160.
59. Lichner, Z., Saleh, C., Subramaniam, V., Seivwright, A., Prud’homme, G. J., & Yousef, G. M. (2015). miR-17 inhibition enhances the formation of kidney cancer spheres with stem cell/ tumor initiating cell properties. Oncotarget, 6(8), 5567–5581.
60. Wu, C., & Alman, B. A. (2008). Side population cells in human cancers. Cancer Letters, 268(1), 1–9.
61. Addla, S. K., Brown, M. D., Hart, C. A., Ramani, V. A., & Clarke, N. W. (2008). Characterization of the Hoechst 33342 side population from normal and malignant human renal epithelial cells. American Journal of Physiology. Renal Physiology, 295(3), F680–687.
62. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., & Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine, 183(4), 1797–1806.
63. Broadley, K. W., Hunn, M. K., Farrand, K. J., et al. (2011). Side population is not necessary or sufficient for a cancer stem cell phenotype in glioblastoma multiforme. Stem Cells, 29(3), 452–461.
64. Golebiewska, A., Brons, N. H., Bjerkvig, R., & Niclou, S. P. (2011). Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell, 8(2), 136–147.
65. Oates, J. E., Grey, B. R., Addla, S. K., et al. (2009). Hoechst 33342 side population identification is a conserved and unified mechanism in urological cancers. Stem Cells and Development, 18(10), 1515–1522.
66. Huang, B., Huang, Y. J., Yao, Z. J., et al. (2013). Cancer stem cell-like side population cells in clear cell renal cell carcinoma cell line 769P. PLoS ONE, 8(7), e68293.
67. Lu, J., Cui, Y., Zhu, J., He, J., Zhou, G., & Yue, Z. (2013). Biological characteristics of Rh123 stem-like cells in a side population of 786-O renal carcinoma cells. Oncology Letters, 5(6), 1903–1908.
68. Hughes, C., Liew, M., Sachdeva, A., et al. (2010). SR-FTIR spectroscopy of renal epithelial carcinoma side population cells displaying stem cell-like characteristics. Analyst, 135(12), 3133–3141.
69. Marcato, P., Dean, C. A., Giacomantonio, C. A., & Lee, P. W. (2011). Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle, 10(9), 1378–1384.
70. Debeb, B. G., Zhang, X., Krishnamurthy, S., et al. (2010). Characterizing cancer cells with cancer stem cell-like features in 293 T human embryonic kidney cells. Molecular Cancer, 9, 180.
71. Wang, L., Park, P., Zhang, H., La Marca, F., & Lin, C. Y. (2011). Characterization of renal tumor-initiating cells in human renal carcinoma cell lines. Cancer Research, 71, 8 suppl; abstr 293.
72. Ueda, K., Ogasawara, S., Akiba, J., et al. (2013). Aldehyde dehydrogenase 1 identifies cells with cancer stem cell-like properties in a human renal cell carcinoma cell line. PLoS ONE, 8(10), e75463.
73. Shukrun, R., Pode Shakked, N., & Dekel, B. (2014). Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example. Pediatric Nephrology, 29(5), 815–823.
74. Benigni, A., Morigi, M., & Remuzzi, G. (2010). Kidney regeneration. Lancet, 375(9722), 1310–1317.
75. Gupta, S., & Rosenberg, M. E. (2008). Do stem cells exist in the adult kidney? American Journal of Nephrology, 28(4), 607–613.
76. Bruno, S., Bussolati, B., Grange, C., et al. (2009). Isolation and characterization of resident mesenchymal stem cells in human glomeruli. Stem Cells and Development, 18(6), 867–880.
77. Metsuyanim, S., Harari-Steinberg, O., Buzhor, E., et al. (2009). Expression of stem cell markers in the human fetal kidney. PLoS ONE, 4(8), e6709.
78. Cantley, L. G. (2005). Adult stem cells in the repair of the injured renal tubule. Nature Clinical Practice Nephrology, 1(1), 22–32.
79. da Silva Meirelles, L., Chagastelles, P. C., & Nardi, N. B. (2006). Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science, 119(Pt 11), 2204–2213.
80. Gupta, S., Verfaillie, C., Chmielewski, D., et al. (2006). Isolation and characterization of kidney-derived stem cells. Journal of the American Society of Nephrology, 17(11), 3028–3040.
81. Park, H. C., Yasuda, K., Kuo, M. C., et al. (2010). Renal capsule as a stem cell niche. American Journal of Physiology. Renal Physiology, 298(5), F1254–1262.
82. D’Alterio, C., Cindolo, L., Portella, L., et al. (2010). Differential role of CD133 and CXCR4 in renal cell carcinoma. Cell Cycle, 9(22), 4492–4500.
83. Kim, K., Ihm, H., Ro, J. Y., & Cho, Y. M. (2011). High-level expression of stem cell marker CD133 in clear cell renal cell carcinoma with favorable prognosis. Oncology Letters, 2(6), 1095–1100.
84. Canis, M., Lechner, A., Mack, B., et al. (2013). CD133 induces tumour-initiating properties in HEK293 cells. Tumour Biology, 34(1), 437–443.
85. Galleggiante, V., Rutigliano, M., Sallustio, F., et al. (2014). CTR2 identifies a population of cancer cells with stem cell-like features in patients with clear cell renal cell carcinoma. Journal of Urology, 192(6), 1831–1841.
86. Varna, M., Gapihan, G., Feugeas, J. P., et al. (2015). Stem cells increase in numbers in perinecrotic areas in human renal cancer. Clinical Cancer Research, 21(4), 916–924.
87. Vogetseder, A., Picard, N., Gaspert, A., Walch, M., Kaissling, B., & Le Hir, M. (2008). Proliferation capacity of the renal proximal tubule involves the bulk of differentiated epithelial cells. American Journal of Physiology. Cell Physiology, 294(1), C22–28.
88. Vogetseder, A., Karadeniz, A., Kaissling, B., & Le Hir, M. (2005). Tubular cell proliferation in the healthy rat kidney. Histochemistry and Cell Biology, 124(2), 97–104.
89. Vogetseder, A., Palan, T., Bacic, D., Kaissling, B., & Le Hir, M. (2007). Proximal tubular epithelial cells are generated by division of differentiated cells in the healthy kidney. American Journal of Physiology. Cell Physiology, 292(2), C807–813.
90. Humphreys, B. D., Valerius, M. T., Kobayashi, A., et al. (2008). Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell, 2(3), 284–291.
91. Humphreys, B. D., Czerniak, S., DiRocco, D. P., Hasnain, W., Cheema, R., & Bonventre, J. V. (2011). Repair of injured proximal tubule does not involve specialized progenitors. Proceedings of the National Academy of Sciences of the United States of America, 108(22), 9226–9231.
92. Bonventre, J. V. (2003). Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. Journal of the American Society of Nephrology, 14(suppl 1), S55–61.
93. Witzgall, R., Brown, D., Schwarz, C., & Bonventre, J. V. (1994). Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. The Journal of Clinical Investigation, 93(5), 2175–2188.
94. Mani, S. A., Guo, W., Liao, M. J., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704–715.
95. Imgrund, M., Gröne, E., Gröne, H. J., et al. (1999). Re-expression of the developmental gene Pax-2 during experimental acute tubular necrosis in mice 1. Kidney International, 56(4), 1423–1431.
96. Humphreys, B. D., & Bonventre, J. V. (2008). Mesenchymal stem cells in acute kidney injury. Annual Review of Medicine, 59, 311–325.
97. Galiè, M., Konstantinidou, G., Peroni, D., et al. (2008). Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Oncogene, 27(18), 2542–2551.
98. Aractingi, S., Kanitakis, J., Euvrard, S., et al. (2005). Skin carcinoma arising from donor cells in a kidney transplant recipient. Cancer Research, 65(5), 1755–1760.
99. Barozzi, P., Luppi, M., Facchetti, F., et al. (2003). Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors. Nature Medicine, 9(5), 554–561.
100. Boix, R., Sanz, C., Mora, M., et al. (2009). Primary renal cell carcinoma in a transplanted kidney: genetic evidence of recipient origin. Transplantation, 87(7), 1057–1061.
101. Houghton, J., Stoicov, C., Nomura, S., et al. (2004). Gastric cancer originating from bone marrow-derived cells. Science, 306(5701), 1568–1571.
102. Gedye, C., Sirskyj, D., Lobo, N. C., et al. (2013). VHL-mutant renal cell carcinomas contain cancer cells with mesenchymal phenotypes. Journal of Clinical Oncology, 31, suppl; abstr 4568.
103. Li, H., Fan, X., Kovi, R. C., et al. (2007). Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: a model of age-related tumorigenesis in mice. Cancer Research, 67(22), 10889–10898.
104. Kurose, K., Gilley, K., Matsumoto, S., Watson, P. H., Zhou, X. P., & Eng, C. (2002). Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genetics, 32(3), 355–357.
105. Hu, M., Yao, J., Cai, L., et al. (2005). Distinct epigenetic changes in the stromal cells of breast cancers. Nature Genetics, 37(8), 899–905.
106. Pelham, R. J., Rodgers, L., Hall, I., et al. (2006). Identification of alterations in DNA copy number in host stromal cells during tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 103(52), 19848–19853.
107. Bertout, J. A., Patel, S. A., & Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature Reviews Cancer, 8(12), 967–975.
108. Brezis, M., & Rosen, S. (1995). Hypoxia of the renal medulla--its implications for disease. The New England Journal of Medicine, 332(10), 647–655.
109. Höckel, M., & Vaupel, P. (2001). Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. Journal of the National Cancer Institute, 93(4), 266–276.
110. Vaupel, P., & Harrison, L. (2004). Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. The Oncologist, 9(suppl 5), 4–9.
111. Vaupel, P., & Mayer, A. (2007). Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews, 26(2), 225–239.
112. Harris, A. L. (2002). Hypoxia--a key regulatory factor in tumour growth. Nature Reviews Cancer, 2(1), 38–47.
113. Jaakkola, P., Mole, D. R., Tian, Y. M., et al. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292(5516), 468–472.
114. Kaelin, W. G., Jr. (2004). The Von Hippel-Lindau tumor suppressor gene and kidney cancer. Clinical Cancer Research, 10(18 Pt 2), 6290S–6295S.
115. Kim, W. Y., & Kaelin, W. G. (2004). Role of VHL gene mutation in human cancer. Journal of Clinical Oncology, 22(24), 4991–5004.
116. Kim, W. Y., & Kaelin, W. G., Jr. (2006). Molecular pathways in renal cell carcinoma--rationale for targeted treatment. Seminars in Oncology, 33(5), 588–595.
117. Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews Cancer, 3(10), 721–732.
118. Latif, F., Tory, K., Gnarra, J., et al. (1993). Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 260(5112), 1317–1320.
119. Kaelin, W. G., Jr., & Maher, E. R. (1998). The VHL tumour-suppressor gene paradigm. Trends in Genetics, 14(10), 423–426.
120. Ivan, M., Kondo, K., Yang, H., et al. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science, 292(5516), 464–468.
121. Maxwell, P. H., Wiesener, M. S., Chang, G. W., et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399(6733), 271–275.
122. Richards, F. M. (2001). Molecular pathology of von Hippel Lindau disease and the VHL tumour suppressor gene. Expert Reviews in Molecular Medicine, 2001, 1–27.
123. Carroll, V. A., & Ashcroft, M. (2006). Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Research, 66(12), 6264–6270.
124. Kaelin, W. G., Jr. (2007). The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clinical Cancer Research, 13(2 Pt 2), 680s–684s.
125. Pouysségur, J., Dayan, F., & Mazure, N. M. (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 441(7092), 437–443.
126. Hill, R. P., Marie-Egyptienne, D. T., & Hedley, D. W. (2009). Cancer stem cells, hypoxia and metastasis. Seminars in Radiation Oncology, 19(2), 106–111.
127. Makino, Y., Cao, R., Svensson, K., et al. (2001). Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature, 414(6863), 550–554.
128. Seizinger, B. R., Rouleau, G. A., Ozelius, L. J., et al. (1988). Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature, 332(6161), 268–269.
129. Knudson, A. G., Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America, 68(4), 820–823.
130. Iliopoulos, O., Kibel, A., Gray, S., & Kaelin, W. G., Jr. (1995). Tumour suppression by the human von Hippel- Lindau gene product. Nature Medicine, 1(8), 822–826.
131. Foster, K., Prowse, A., van den Berg, A., et al. (1994). Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Human Molecular Genetics, 3(12), 2169–2173.
132. Brauch, H., Weirich, G., Brieger, J., et al. (2000). VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Research, 60(7), 1942–1948.
133. Shuin, T., Kondo, K., Torigoe, S., et al. (1994). Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Research, 54(11), 2852–2855.
134. Gnarra, J. R., Lerman, M. I., Zbar, B., & Linehan, W. M. (1995). Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. Seminars in Oncology, 22(1), 3–8.
135. Banks, R. E., Tirukonda, P., Taylor, C., et al. (2006). Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Research, 66(4), 2000–2011.
136. Herman, J. G., Latif, F., Weng, Y., et al. (1994). Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 91(21), 9700–9704.
137. Fiorentini, G., Aliberti, C., Benea, G., et al. (2009). Effects of Molecularly Targeting Hypoxia in Oncology. In G. Baronzio, G. Fiorentini, & C. R. Cogle (Eds.), Cancer Microenvironment and Therapeutic Implications (pp. 117–135). Netherlands: Springer.
138. Pietras, A., Johnsson, A. S., & Påhlman, S. (2010). The HIF-2α-driven pseudo-hypoxic phenotype in tumor aggressiveness, differentiation, and vascularization. Current Topics in Microbiology and Immunology, 345, 1–20.
139. Gordan, J. D., & Simon, M. C. (2007). Hypoxia-inducible factors: central regulators of the tumor phenotype. Current Opinion in Genetics & Development, 17(1), 71–77.
140. Wilson, W. R., & Hay, M. P. (2011). Targeting hypoxia in cancer therapy. Nature Reviews Cancer, 11(6), 393–410.
141. Liao, D., & Johnson, R. S. (2007). Hypoxia: a key regulator of angiogenesis in cancer. Cancer and Metastasis Reviews, 26(2), 281–290.
142. Kaelin, W. G., Jr. (2008). The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nature Reviews Cancer, 8(11), 865–873.
143. Barnhart, B. C., & Simon, M. C. (2007). Metastasis and stem cell pathways. Cancer and Metastasis Reviews, 26(2), 261–271.
144. Ezashi, T., Das, P., & Roberts, R. M. (2005). Low O2 tensions and the prevention of differentiation of hES cells. Proceedings of the National Academy of Sciences of the United States of America, 102(13), 4783–4788.
145. Carreau, A., El Hafny-Rahbi, B., Matejuk, A., Grillon, C., & Kieda, C. (2011). Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. Journal of Cellular and Molecular Medicine, 15(6), 1239–1253.
146. Grayson, W. L., Zhao, F., Izadpanah, R., Bunnell, B., & Ma, T. (2006). Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs. Journal of Cellular Physiology, 207(2), 331–339.
147. Morrison, S. J., Csete, M., Groves, A. K., Melega, W., Wold, B., & Anderson, D. J. (2000). Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. The Journal of Neuroscience, 20(19), 7370–7376.
148. Mohyeldin, A., Garzón-Muvdi, T., & Quiñones-Hinojosa, A. (2010). Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell, 7(2), 150–161.
149. Mao, Q., Zhang, Y., Fu, X., et al. (2013). A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy. Journal of Cancer Research and Clinical Oncology, 139(2), 211–222.
150. Das, B., Tsuchida, R., Malkin, D., Koren, G., Baruchel, S., & Yeger, H. (2008). Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells, 26(7), 1818–1830.
151. Seidel, S., Garvalov, B. K., Wirta, V., et al. (2010). A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain, 133(Pt 4), 983–995.
152. Pietras, A., Gisselsson, D., Ora, I., et al. (2008). High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. Journal of Pathology, 214(4), 482–488.
153. Pietras, A., Hansford, L. M., Johnsson, A. S., et al. (2009). Hif-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 106(39), 16805–16810.
154. Li, Z., Bao, S., Wu, Q., et al. (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell, 15(6), 501–513.
155. McCord, A. M., Jamal, M., Shankavaram, U. T., Lang, F. F., Camphausen, K., & Tofilon, P. J. (2009). Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro. Molecular Cancer Research, 7(4), 489–497.
156. Soeda, A., Park, M., Lee, D., et al. (2009). Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene, 28(45), 3949–3959.
157. Platet, N., Liu, S. Y., Atifi, M. E., et al. (2007). Influence of oxygen tension on CD133 phenotype in human glioma cell cultures. Cancer Letters, 258(2), 286–290.
158. Heddleston, J. M., Li, Z., McLendon, R. E., Hjelmeland, A. B., & Rich, J. N. (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle, 8(20), 3274–3284.
159. Dang, C. V., Kim, J. W., Gao, P., & Yustein, J. (2008). The interplay between MYC and HIF in cancer. Nature Reviews Cancer, 8(1), 51–56.
160. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A., & Simon, M. C. (2007). HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell, 11(4), 335–347.
161. Koshiji, M., Kageyama, Y., Pete, E. A., Horikawa, I., Barrett, J. C., & Huang, L. E. (2004). HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO Journal, 23(9), 1949–1956.
162. Gordan, J. D., Lal, P., Dondeti, V. R., et al. (2008). HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell, 14(6), 435–446.
163. Bertout, J. A., Majmundar, A. J., Gordan, J. D., et al. (2009). HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14391–14396.
164. Covello, K. L., Kehler, J., Yu, H., et al. (2006). HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes and Development, 20(5), 557–570.
165. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.
166. Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T., & Yamanaka, S. (2009). Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell, 5(3), 237–241.
167. Mathieu, J., Zhang, Z., Zhou, W., et al. (2011). HIF induces human embryonic stem cell markers in cancer cells. Cancer Research, 71(13), 4640–4652.
168. Hama, A., Codogno, P., & Mehrpour, M. (2014). Cancer stem cells and autophagy: facts and perspectives. Journal of Cancer Stem Cell Research, 2, e1005.
169. Chen, Y., De Marco, M. A., Graziani, I., et al. (2007). Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Research, 67(17), 7954–7959.
170. Bedogni, B., Warneke, J. A., Nickoloff, B. J., Giaccia, A. J., & Powell, M. B. (2008). Notch1 is an effector of Akt and hypoxia in melanoma development. The Journal of Clinical Investigation, 118(11), 3660–3670.
171. Hu, Y. Y., Fu, L. A., Li, S. Z., et al. (2014). Hif-1α and Hif-2α differentially regulate Notch signaling through competitive interaction with the intracellular domain of Notch receptors in glioma stem cells. Cancer Letters, 349(1), 67–76.
172. Gustafsson, M. V., Zheng, X., Pereira, T., et al. (2005). Hypoxia requires notch signaling to maintain the undifferentiated cell state. Developmental Cell, 9(5), 617–628.
173. D’Uva, G., Bertoni, S., Lauriola, M., et al. (2013). Beta-Catenin/HuR Post-transcriptional machinery governs cancer stem cell features in response to hypoxia. PLoS ONE, 8(11), e80742.
174. Mazumdar, J., O’Brien, W. T., Johnson, R. S., et al. (2010). O2 regulates stem cells through Wnt/β-catenin signalling. Nature Cell Biology, 12(10), 1007–1013.
175. Kaidi, A., Williams, A. C., & Paraskeva, C. (2007). Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nature Cell Biology, 9(2), 2010–2017.
176. Comerford, K. M., Wallace, T. J., Karhausen, J., Louis, N. A., Montalto, M. C., & Colgan, S. P. (2002). Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Research, 62(12), 3387–3394.
177. Nishi, H., Nakada, T., Kyo, S., Inoue, M., Shay, J. W., & Isaka, K. (2004). Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT). Molecular Cell. Biology, 24(13), 6076–6083.
178. Zhang, Y., Wang, H., Zhang, J., Lv, J., & Huang, Y. (2013). Positive feedback loop and synergistic effects between hypoxia-inducible factor-2a and stearoyl–CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma. Cancer Science, 104(4), 416–422.
179. Toschi, A., Lee, E., Gadir, N., Ohh, M., & Foster, D. A. (2008). Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. The Journal of Biological Chemistry, 283(50), 34495–34499.
180. Noto, A., Raffa, S., De Vitis, C., et al. (2013). Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells. Cell Death and Disease, 4, e947.
181. Kim, R. J., Park, J. R., Roh, K. J., et al. (2013). High aldehyde dehydrogenase activity enhances stem cell features in breast cancer cells by activating hypoxia-inducible factor-2α. Cancer Letters, 333(1), 18–31.
182. Tiezzi, D. G., Clagnan, W. S., Mandarano, L. R., et al. (2013). Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer. Clinics (São Paulo, Brazil), 68(5), 592–598.
183. Jögi, A., Øra, I., Nilsson, H., et al. (2002). Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proceedings of the National Academy of Sciences of the United States of America, 99(10), 7021–7026.
184. Helczynska, K., Kronblad, A., Jögi, A., et al. (2003). Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Research, 63(7), 1441–1444.
185. Liang, D., Ma, Y., Liu, J., et al. (2012). The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells. BMC Cancer, 12, 201.
186. Zhang, H., Wu, H., Zheng, J., et al. (2013). Transforming growth factor β1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma. Stem Cells, 31(3), 433–446.
187. Kumar, S. M., Liu, S., Lu, H., et al. (2012). Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene, 31(47), 4898–4911.
188. Jögi, A., Vaapil, M., Johansson, M., & Påhlman, S. (2012). Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors. Upsala Journal of Medical Sciences, 117(2), 217–224.
189. Axelson, H., Fredlund, E., Ovenberger, M., Landberg, G., & Påhlman, S. (2005). Hypoxia-induced dedifferentiation of tumor cells—a mechanism behind heterogeneity and aggressiveness of solid tumors. Seminars in Cell and Developmental Biology, 16(4–5), 554–563.
190. Marie-Egyptienne, D. T., Lohse, I., & Hill, R. P. (2013). Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Letters, 341(1), 63–72.
191. Polyak, K., & Weinberg, R. A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Reviews Cancer, 9(4), 265–273.
192. Scheel, C., & Weinberg, R. A. (2012). Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Seminars in Cancer Biology, 22(5–6), 396–403.
193. Singh, A., & Settleman, J. (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene, 29(34), 4741–4751.
194. Dave, B., Mittal, V., Tan, N. M., & Chang, J. C. (2012). Epithelial-mesenchymal transition, cancer stem cells and treatment resistance. Breast Cancer Research, 14(1), 202.
195. Thiery, J. P., Acloque, H., Huang, R. Y. J., & Nieto, M. A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139(5), 871–890.
196. Jiang, J., Tang, Y. L., & Liang, X. H. (2011). EMT: a new vision of hypoxia promoting cancer progression. Cancer Biology & Therapy, 11(8), 714–723.
197. Morais, C., Johnson, D. W., Vesey, D. A., & Gobe, G. C. (2013). Functional significance of erythropoietin in renal cell carcinoma. BMC Cancer, 13, 14.
198. Hammers, H. J., Verheul, H. M., Salumbides, B., et al. (2010). Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Molecular Cancer Therapeutics, 9(6), 1525–1535.
199. Krishnamachary, B., Zagzag, D., Nagasawa, H., et al. (2006). Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Research, 66(5), 2725–2731.
200. Esteban, M. A., Tran, M. G., Harten, S. K., et al. (2006). Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Research, 66(7), 3567–3575.
201. Evans, A. J., Russell, R. C., Roche, O., et al. (2007). VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Molecular and Cellular Biology, 27(1), 157–169.
202. Huang, J., Yao, X., Zhang, J., et al. (2013). Hypoxia-induced downregulation of miR-30c promotes epithelial-mesenchymal transition in human renal cell carcinoma. Cancer Science, 104(12), 1609–1617.
203. Russell, R. C., & Ohh, M. (2007). The role of VHL in the regulation of E-cadherin: a new connection in an old pathway. Cell Cycle, 6(1), 56–59.
204. Sun, C., Song, H., Zhang, H., et al. (2012). CD133 expression in renal cell carcinoma (RCC) is correlated with nuclear hypoxia-inducing factor 1α (HIF-1α). Journal of Cancer Research and Clinical Oncology, 138(10), 1619–1624.
205. Valluru, M., Staton, C. A., Reed, M. W. R., & Brown, N. J. (2011). Transforming growth factor-β and endoglin signaling orchestrate wound healing. Frontiers in Physiology, 2, 89.
206. Barbara, N. P., Wrana, J. L., & Letarte, M. (1999). Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. The Journal of Biological Chemistry, 274(2), 584–594.
207. Oxmann, D., Held-Feindt, J., Stark, A. M., Hattermann, K., Yoneda, T., & Mentlein, R. (2008). Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype. Oncogene, 27(25), 3567–3575.
208. Pardali, E., van der Schaft, D. W., Wiercinska, E., et al. (2011). Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma. Oncogene, 30(3), 334–345.
209. Sulzmaier, F. J., Jean, C., & Schlaepfer, D. D. (2014). FAK in cancer: mechanistic findings and clinical applications. Nature Reviews Cancer, 14(9), 598–610.
210. Yao, X. H., Ping, Y. F., & Bian, X. W. (2011). Contribution of cancer stem cells to tumor vasculogenic mimicry. Protein & Cell, 2(4), 266–272.
211. Fan, Y. L., Zheng, M., Tang, Y. L., & Liang, X. H. (2013). A new perspective of vasculogenic mimicry: EMT and cancer stem cells (Review). Oncology Letters, 6(5), 1174–1180.
212. Bussolati, B., Grange, C., & Camussi, G. (2011). Tumor exploits alternative strategies to achieve vascularization. FASEB Journal, 25(9), 2874–2882.
213. Zhang, Y., Sun, B., Zhao, X., et al. (2013). Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma. Journal of Surgical Oncology, 108(6), 414–419.
214. Pérez-Gómez, E., Del Castillo, G., Juan Francisco, S., López-Novoa, J. M., Bernabéu, C., & Quintanilla, M. (2010). The role of the TGF-β coreceptor endoglin in cancer. The Scientific World Journal, 10, 2367–2384.
215. Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E. J., & Krek, W. (2003). Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature, 425(6955), 307–311.
216. Zagzag, D., Krishnamachary, B., Yee, H., et al. (2005). 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 Research, 65(14), 6178–6188.
217. Knebelmann, B., Ananth, S., Cohen, H. T., & Sukhatme, V. P. (1998). Transforming growth factor alpha is a target for the von Hippel-Lindau tumor suppressor. Cancer Research, 58(2), 226–231.
218. de Paulsen, N., Brychzy, A., Fournier, M. C., et al. (2001). Role of transforming growth factor-alpha in von Hippel--Lindau (VHL)(−/−) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 98(4), 1387–1392.
219. Wykoff, C. C., Sotiriou, C., Cockman, M. E., et al. (2004). Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene. British Journal of Cancer, 90(6), 1235–1243.
220. Baba, M., Hirai, S., Yamada-Okabe, H., et al. (2003). Loss of von Hippel-Lindau protein causes cell density dependent deregulation of cyclin D1 expression through hypoxia inducible factor. Oncogene, 22(18), 2728–2738.
221. Bindra, R. S., Vasselli, J. R., Stearman, R., Linehan, W. M., & Klausner, R. D. (2002). VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Research, 62(11), 3014–3019.
222. Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., et al. (2006). Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell, 10(5), 413–423.
223. Noguera, R., Fredlund, E., Piqueras, M., et al. (2009). HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization. Clinical Cancer Research, 15(23), 7130–7136.
224. Helczynska, K., Larsson, A. M., Holmquist-Mengelbier, L., et al. (2008). Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Research, 68(22), 9212–9220.
225. Giatromanolaki, A., Koukourakis, M. I., Sivridis, E., et al. (2001). Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. British Journal of Cancer, 85(6), 881–890.
226. Kim, W. Y., Perera, S., Zhou, B., et al. (2009). HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. The Journal of Clinical Investigation, 119(8), 2160–2170.
227. Yang, M. H., Wu, M. Z., Chiou, S. H., et al. (2008). Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nature Cell Biology, 10(3), 295–305.
228. Hoffmann, A. C., Mori, R., Vallbohmer, D., et al. (2008). High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia, 10(7), 674–679.
229. Shen, C., & Kaelin, W. G., Jr. (2013). The VHL/HIF axis in clear cell renal carcinoma. Seminars in Cancer Biology, 23(1), 18–25.
230. Acker, T., Diez-Juan, A., Aragones, J., et al. (2005). Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer Cell, 8(2), 131–141.
231. Bangoura, G., Liu, Z. S., Qian, Q., Jiang, C. Q., Yang, G. F., & Jing, S. (2007). Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World Journal of Gastroenterology, 13(23), 3176–3182.
232. Franovic, A., Holterman, C. E., Payette, J., & Lee, S. (2009). Human cancers converge at the HIF-2alpha oncogenic axis. Proceedings of the National Academy of Sciences of the United States of America, 106(50), 21306–21311.
233. Mandriota, S. J., Turner, K. J., Davies, D. R., et al. (2002). HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell, 1(5), 459–468.
234. Kondo, K., Klco, J., Nakamura, E., Lechpammer, M., & Kaelin, W. G., Jr. (2002). Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell, 1(3), 237–246.
235. Kondo, K., Kim, W. Y., Lechpammer, M., & Kaelin, W. G., Jr. (2003). Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biology, 1(3), E83.
236. Covello, K. L., Simon, M. C., & Keith, B. (2005). Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Research, 65(6), 2277–2286.
237. Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S., Linehan, W. M., & Klausner, R. D. (2002). The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell, 1(3), 247–255.
238. Raval, R. R., Lau, K. W., Tran, M. G., et al. (2005). Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and Cellular Biology, 25(13), 5675–5686.
239. Zimmer, M., Doucette, D., Siddiqui, N., & Iliopoulos, O. (2004). Inhibition of hypoxia-inducible factor is sufficient for growth suppression of Vhl−/− tumors. Molecular Cancer Research, 2(2), 89–95.
240. Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003). Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Molecular and Cellular Biology, 23(24), 9361–9374.
241. Brown, J. M., & Wilson, W. R. (2004). Exploiting tumour hypoxia in cancer treatment. Nature Reviews Cancer, 4(6), 437–447.
242. Baldewijns, M. M. (2010). VHL and HIF signalling in renal cell carcinogenesis. Journal of Pathology, 221(2), 125–138.
243. Gilbertson, R. J., & Rich, J. N. (2007). Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nature Reviews Cancer, 7(10), 733–736.
244. Czarnecka, A. M., & Szczylik, C. (2013). Renal cell carcinoma cancer stem cells as therapeutic targets. Current Signal Transduction Therapy, 8(3), 203–209.
245. Bielecka, Z. F., Czarnecka, A. M., & Szczylik, C. (2014). Genomic analysis as the first step toward personalized treatment in renal cell carcinoma. Frontiers in Oncology, 4, 194.
246. Kanesvaran, R., & Tan, M. H. (2014). Targeted therapy for renal cell carcinoma: the next lap. Journal of Carcinogenesis, 13, 3.
247. Crea, F., Duhagon, M. A., Farrar, W. L., & Danesi, R. (2011). Pharmacogenomics and cancer stem cells: a changing landscape? Trends in Pharmacological Sciences, 32(8), 487–494.
248. Azzi, S., Bruno, S., Giron-Michel, J., et al. (2011). Differentiation therapy: targeting human renal cancer stem cells with interleukin 15. Journal of the National Cancer Institute, 103(24), 1884–1898.
249. Ziebarth, A. J., Nowsheen, S., Steg, A. D., et al. (2013). Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer. Clinical Cancer Research, 19(1), 170–182.
250. Fried, L. E., & Arbiser, J. L. (2009). Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxidants & Redox Signaling, 11(5), 1139–1148.
251. Li, W., Wang, Q., Su, Q., et al. (2014). Honokiol suppresses renal cancer cells’ metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling. Molecules and Cells, 37(5), 383–388.
252. Banerjee, P., Basu, A., Arbiser, J. L., & Pal, S. (2013). The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. Cancer Letters, 338(2), 292–299.
253. von Roemeling, C. A., Marlow, L. A., Wei, J. J., et al. (2013). Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clinical Cancer Research, 19(9), 2368–2380.
254. Sourbier, C., Srivastava, G., Ghosh, M. C., et al. (2012). Targeting HIF2α translation with Tempol in VHL-deficient clear cell renal cell carcinoma. Oncotarget, 3(11), 1472–1482.
255. Buczek, M., Escudier, B., Bartnik, E., Szczylik, C., & Czarnecka, A. (2014). Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: from the patient’s bed to molecular mechanisms. Biochimica et Biophysica Acta, 1845(1), 31–41.
256. Porta, C., Szczylik, C., & Escudier, B. (2012). Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: a critical review. Critical Reviews in Oncology/Hematology, 82(3), 323–337.
257. Joosten, S. C., Hamming, L., Soetekouw, P. M., et al. (2014). Resistance to sunitinib in renal cell carcinoma: from molecular mechanisms to predictive markers and future perspectives. Biochimica et Biophysica Acta, 1855(1), 1–16.
258. Ravaud, A., & Gross-Goupil, M. (2012). Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma. Cancer Treatment Reviews, 38(8), 996–1003.
259. Bergers, G., & Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nature Reviews Cancer, 8(8), 592–603.
260. Rini, B. I., & Atkins, M. B. (2009). Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncology, 10(10), 992–1000.
261. D’Alterio, C., Portella, L., & Ottaiano, A. (2012). High CXCR4 expression correlates with sunitinib poor response in metastatic renal cancer. Current Cancer Drug Targets, 12(6), 693–702.
262. Conley, S. J., Gheordunescu, E., Kakarala, P., et al. (2012). Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 2784–2789.
263. Shen, R., Ye, Y., Chen, L., Yan, Q., Barsky, S. H., & Gao, J. X. (2008). Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS ONE, 3(2), e1652.
264. Brossa, A., Grange, C., Mancuso, L., et al. (2015). Sunitinib but not VEGF blockade inhibits cancer stem cell endothelial differentiation. Oncotarget, 6(13), 11295–11309.
265. Bousquet, G., & Janin, A. (2015). Reactive resistance to anti-angiogenic drugs. Aging (Albany NY), 7(5), 282–283.
266. Kieda, C., El Hafny-Rahbi, B., Collet, G., et al. (2013). Stable tumor vessel normalization with pO2 increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment. Journal of Molecular Medicine (Berlin, Germany), 91(7), 883–899.
267. Collet, G., Lamerant-Fayel, N., Tertil, M., et al. (2014). Hypoxia-regulated overexpression of soluble VEGFR2 controls angiogenesis and inhibits tumor growth. Molecular Cancer Therapeutics, 13(1), 165–178.
268. Lin, F., Wang, N., & Zhang, T. C. (2012). The role of endothelial-mesenchymal transition in development and pathological process. International Union of Biochemistry and Molecular Biology Life, 64(9), 717–723.