Hypoxia, notch signalling, and prostate cancer

Nature Reviews Urology

Volumn 10, Issue 7, 2013, Pages 405-413

  Marignol, Laure ^a   Rivera Figueroa, Karla ^b   Lynch, Thomas ^c   Hollywood, Donal ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c ST JAMES S HOSPITAL   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; ANDROSTANOLONE; BETA CATENIN; CARBONATE DEHYDRATASE IX; HERMES ANTIGEN; HYPOXIA INDUCIBLE FACTOR; JAGGED1; NOTCH RECEPTOR; NOTCH2 RECEPTOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN P53; TRANSCRIPTION FACTOR HES 1;

ADENOID CYSTIC CARCINOMA; ANDROGEN DEPRIVATION THERAPY; ANTIANDROGEN THERAPY; APOPTOSIS; BREAST CANCER; CANCER PROGNOSIS; CANCER STEM CELL; CELL FATE; CELL GROWTH; CELL INVASION; CELL MIGRATION; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; DISEASE COURSE; HUMAN; HYPOXIA; IMMUNOCHEMISTRY; IN SITU HYBRIDIZATION; IONIZING RADIATION; MALIGNANT MESOTHELIOMA; MICROCIRCULATION; NONHUMAN; OVARY CANCER; OVERALL SURVIVAL; PRIORITY JOURNAL; PROSTATE ADENOCARCINOMA; PROSTATE CANCER; PROSTATIC INTRAEPITHELIAL NEOPLASIA; PROTEIN EXPRESSION; RADIOSENSITIVITY; REVIEW; S PHASE CELL CYCLE CHECKPOINT; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; UTERINE CERVIX CANCER;

ANIMALS; CELL HYPOXIA; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; MALE; NEOVASCULARIZATION, PATHOLOGIC; PROSTATIC NEOPLASMS; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION;

EID: 84880317936     PISSN: 17594812     EISSN: 17594820     Source Type: Journal    
DOI: 10.1038/nrurol.2013.110     Document Type: Review

References (144)

1. Chiba, S. Notch signaling in stem cell systems. Stem Cells 24, 2437-2447 (2006 (Pubitemid 44674304)
2. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: Cell fate control and signal integration in development. Science 284, 770-776 (1999 (Pubitemid 29291335)
3. South, A. P., Cho, R. J. & Aster, J. C. The double-edged sword of Notch signaling in cancer. Semin. Cell Dev. Biol. 23, 458-464 (2012
4. Hu, Y. Y., Zheng, M. H., Zhang, R., Liang, Y. M. & Han, H. Notch signaling pathway and cancer metastasis. Adv. Exp. Med. Biol. 727, 186-198 (2012
5. Shao, H., Huang, Q. & Liu, Z. J. Targeting Notch signaling for cancer therapeutic intervention. Adv. Pharmacol. 65, 191-234 (2012
6. Wang, X. D. et al. Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Dev. Biol. 290, 66-80 (2006
7. Villaronga, M. A., Bevan, C. L. & Belandia, B. Notch signaling: A potential therapeutic target in prostate cancer. Curr. Cancer Drug Targets. 8, 566-580 (2008
8. Marignol, L., Coffey, M., Lawler, M. & Hollywood, D. Hypoxia in prostate cancer: A powerful shield against tumour destruction? Cancer Treat Rev. 34, 313-327 (2008
9. Zhong, H. et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59, 5830-5835 (1999
10. Lekas, A. et al. The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and angiogenesis markers in hyperplastic and malignant prostate tissue. Anticancer Res. 26, 2989-2993 (2006 (Pubitemid 44161791)
11. Gustafsson, M. V. et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617-628 (2005 (Pubitemid 41555144)
12. Scorey, N. et al. Notch signalling and voltage-gated Na+ channel activity in human prostate cancer cells: Independent modulation of in vitro motility. Prostate Cancer Prostatic Dis. 9, 399-406 (2006 (Pubitemid 44843133)
13. Shou, J., Ross, S., Koeppen, H., de Sauvage, F. J. & Gao, W. Q. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res. 61, 7291-7297 (2001 (Pubitemid 32951774)
14. Sethi, S., Macoska, J., Chen, W. & Sarkar, F. H. Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am. J. Transl. Res. 3, 90-99 (2010
15. Whelan, J. T., Kellogg, A., Shewchuk, B. M., Hewan-Lowe, K. & Bertrand, F. E. Notch-1 signaling is lost in prostate adenocarcinoma and promotes PTEN gene expression. J. Cell Biochem. 107, 992-1001 (2009
16. Mamaeva, O. A., Kim, J., Feng, G. & McDonald, J. M. Calcium/calmodulin-dependent kinase II regulates notch-1 signaling in prostate cancer cells. J. Cell Biochem. 106, 25-32 (2009
17. Chen, L. et al. P53-induced microRNA-107 inhibits proliferation of glioma cells and down-regulates the expression of CDK6 and Notch-2. Neurosci. Lett. 534, 327-332 (2013
18. Florena, A. M. et al. Associations between Notch-2, Akt-1 and HER2/neu expression in invasive human breast cancer: A tissue microarray immunophenotypic analysis on 98 patients. Pathobiology 74, 317-322 (2007 (Pubitemid 350273702)
19. Ungerback, J., Elander, N., Grunberg, J., Sigvardsson, M. & Soderkvist, P. The Notch-2 gene is regulated by Wnt signaling in cultured colorectal cancer cells. PLoS ONE 6, e17957 (2011
20. Parr, C., Watkins, G. & Jiang, W. G. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int. J. Mol. Med. 14, 779-786 (2004
21. Reichrath, S. et al. Notch- and vitamin D signaling in 1,25(OH)2D3-resistant glioblastoma multiforme (GBM) cell lines. J. Steroid Biochem. Mol. Biol. 121, 420-424 (2010
22. Ding, L. C. et al. Notch-4 contributes to the metastasis of salivary adenoid cystic carcinoma. Oncol. Rep. 24, 363-368 (2010
23. Sansone, P. et al. p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25, 807-815 (2007 (Pubitemid 46354241)
24. Studebaker, A. W. et al. Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res. 68, 9087-9095 (2008
25. Yeasmin, S. et al. Expression of nuclear Notch3 in cervical squamous cell carcinomas and its association with adverse clinical outcomes. Gynecol. Oncol. 117, 409-416 (2010
26. Chen, X. et al. Jagged1 expression regulated by Notch3 and Wnt/beta-catenin signaling pathways in ovarian cancer. Oncotarget 1, 210-218 (2010
27. Jung, S. G. et al. Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma. Cancer Sci. 101, 1977-1983 (2010
28. Santagata, S. et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 64, 6854-6857 (2004 (Pubitemid 39330990)
29. Ross, A. E. et al. Gene expression pathways of high grade localized prostate cancer. Prostate http://dx.doi.org/10.1002/pros.21373
30. Sharad, S. et al. Prostate cancer gene expression signature of patients with high body mass index. Prostate Cancer Prostatic Dis. 14, 22-29 (2011
31. Reedijk, M. et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 65, 8530-8537 (2005 (Pubitemid 41330622)
32. Reedijk, M. Notch signaling and breast cancer. Adv. Exp. Med. Biol. 727, 241-257 (2012
33. Yao, K. et al. Notch-1 and notch-4 receptors as prognostic markers in breast cancer. Int. J. Surg. Pathol. 19, 607-613 (2011
34. Sulis, M. L. et al. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 112, 733-740 (2008
35. O'Neil, J. et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J. Exp. Med. 204, 1813-1824 (2007 (Pubitemid 47236319)
36. Koh, M. S., Ittmann, M., Kadmon, D., Thompson, T. C. & Leach, F. S. CDC4 gene expression as potential biomarker for targeted therapy in prostate cancer. Cancer Biol. Ther. 5, 78-83 (2006 (Pubitemid 43234982)
37. Yu, X., Wang, Y., DeGraff, D. J., Wills, M. L. & Matusik, R. J. Wnt/beta-catenin activation promotes prostate tumor progression in a mouse model. Oncogene 30, 1868-1879 (2011
38. Kim, H. et al. Delta-Catenin promotes E-cadherin processing and activates beta-catenin-mediated signaling: Implications on human prostate cancer progression. Biochim. Biophys. Acta 1822, 509-521 (2012
39. Jin, Y. H. et al. Beta-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochim. Biophys. Acta 1793, 290-299 (2009
40. Patrawala, L. et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 65, 6207-6219 (2005 (Pubitemid 40994406)
41. Gulino, A., Di Marcotullio, L. & Screpanti, I. The multiple functions of Numb. Exp. Cell Res. 316, 900-906 (2010
42. Pece, S., Confalonieri, S. P. R. R. & Di Fiore, P. P. NUMB-ing down cancer by more than just a NOTCH. Biochim. Biophys. Acta 1815, 26-43 (2011
43. Westhoff, B. et al. Alterations of the Notch pathway in lung cancer. Proc. Natl Acad. Sci. USA 106, 22293-22298 (2009
44. Pece, S. et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J. Cell Biol. 167, 215-221 (2004 (Pubitemid 39435065)
45. Pear, W. S. & Simon, M. C. Lasting longer without oxygen: The influence of hypoxia on Notch signaling. Cancer Cell 8, 435-437 (2005 (Pubitemid 41773445)
46. Yong, T., Sun, A., Henry, M. D., Meyers, S. & Davis, J. N. Down regulation of CSL activity inhibits cell proliferation in prostate and breast cancer cells. J. Cell Biochem. 112, 2340-2351 (2011
47. Rehman, A. O. & Wang, C. Y. Notch signaling in the regulation of tumor angiogenesis. Trends Cell Biol. 16, 293-300 (2006 (Pubitemid 43884979)
48. Zheng, X. et al. Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc. Natl Acad. Sci. USA 105, 3368-3373 (2008 (Pubitemid 351723559)
49. Chen, J., Imanaka, N., Chen, J. & Griffin, J. D. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br. J. Cancer 102, 351-360 (2010
50. Pietras, A., von Stedingk, K., Lindgren, D., Pahlman, S. & Axelson, H. JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation. Mol. Cancer Res. 9, 626-636 (2011
51. Xing, F. et al. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075-4086 (2011
52. Chen, Y. et al. Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res. 67, 7954-7959 (2007 (Pubitemid 47395124)
53. Eliasz, S. et al. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29, 2488-2498 (2010
54. Bedogni, B., Warneke, J. A., Nickoloff, B. J., Giaccia, A. J. & Powell, M. B. Notch1 is an effector of Akt and hypoxia in melanoma development. J. Clin. Invest. 118, 3660-3670 (2008
55. Graziani, I. et al. Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res. 68, 9678-9685 (2008
56. Danza, G. et al. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Mol. Cancer Res. 10, 230-238 (2012
57. Zhang, Y. et al. Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells. Int. J. Cancer 119, 2071-2077 (2006 (Pubitemid 44423663)
58. Zolzer, F. & Streffer, C. Increased radiosensitivity with chronic hypoxia in four human tumor cell lines. Int. J. Radiat. Oncol. Biol. Phys. 54, 910-920 (2002
59. Alimirah, F., Panchanathan, R., Davis, F. J., Chen, J. & Choubey, D. Restoration of p53 expression in human cancer cell lines upregulates the expression of Notch1: Implications for cancer cell fate determination after genotoxic stress. Neoplasia 9, 427-434 (2007 (Pubitemid 46799986)
60. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391-396 (2000 (Pubitemid 30131884)
61. Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat. Med. 13, 1203-1210 (2007 (Pubitemid 47530629)
62. Guo, S., Liu, M. & Gonzalez-Perez, R. R. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim. Biophys. Acta 1815, 197-213 (2011
63. Keith, B. & Simon, M. C. Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465-472 (2007 (Pubitemid 46660978)
64. Panchision, D. M. The role of oxygen in regulating neural stem cells in development and disease. J. Cell Physiol. 220, 562-568 (2009
65. Seidel, S. et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133, 983-995 (2010
66. Alison, M. R., Lin, W. R., Lim, S. M. & Nicholson, L. J. Cancer stem cells: In the line of fire. Cancer Treat. Rev. 38, 589-598 (2012
67. Greer, S. N., Metcalf, J. L., Wang, Y. & Ohh, M. The updated biology of hypoxia-inducible factor. EMBO J. 31, 2448-2460 (2012
68. Wang, Y., Liu, Y., Malek, S. N., Zheng, P. & Liu, Y. Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8, 399-411 (2011
69. Lam, B. S. & Adams, G. B. Blocking HIF1alpha activity eliminates hematological cancer stem cells. Cell Stem Cell 8, 354-356 (2011
70. Farnie, G. & Clarke, R. B. Mammary stem cells and breast cancer- - role of Notch signalling. Stem Cell Rev. 3, 169-175 (2007 (Pubitemid 350129719)
71. van Leenders, G. J. et al. Activation of c-MET induces a stem-like phenotype in human prostate cancer. PLoS ONE 6, e26753 (2011
72. Litvinov, I. V. et al. Low-calcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells. Cancer Res. 66, 8598-8607 (2006 (Pubitemid 44449174)
73. Vallejo, D. M., Caparros, E. & Dominguez, M. Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells. EMBO J. 30, 756-769 (2011
74. Domingo-Domenech, J. et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 22, 373-388 (2012
75. Mathieu, J. et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 71, 4640-4652 (2011
76. Anderson, K. M., Guinan, P. & Rubenstein, M. The effect of normoxia and hypoxia on a prostate (PC-3) CD44/CD41 cell side fraction. Anticancer Res. 31, 487-494 (2011
77. Mimeault, M. & Batra, S. K. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J. Cell. Mol. Med. 17, 30-54 (2013
78. Bakin, R. E., Gioeli, D., Sikes, R. A., Bissonette, E. A. & Weber, M. J. Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res. 63, 1981-1989 (2003 (Pubitemid 36460867)
79. Park, S. Y. et al. Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res. 66, 5121-5129 (2006
80. Powell, S. M. et al. Mechanisms of androgen receptor repression in prostate cancer. Biochem. Soc. Trans. 34, 1124-1127 (2006 (Pubitemid 46769002)
81. Reiter, R. E. et al. Coamplification of prostate stem cell antigen (PSCA) and MYC in locally advanced prostate cancer. Genes Chromosomes Cancer 27, 95-103 (2000
82. Belandia, B. et al. Hey1, a mediator of notch signaling, is an androgen receptor corepressor. Mol. Cell Biol. 25, 1425-1436 (2005 (Pubitemid 40204919)
83. Armas, O. A. et al. Clinical and pathobiological effects of neoadjuvant total androgen ablation therapy on clinically localized prostatic adenocarcinoma. Am. J. Surg. Pathol. 18, 979-991 (1994 (Pubitemid 24301720)
84. Polito, M., Muzzonigro, G., Minardi, D. & Montironi, R. Effects of neoadjuvant androgen deprivation therapy on prostatic cancer. Eur. Urol. 30 (Suppl. 1), 26-39 (1996
85. Mazzucchelli, R. et al. Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients. Prostate 45, 72-79 (2000
86. Horii, K. et al. Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells. Mol. Cancer Res. 5, 383-391 (2007 (Pubitemid 46707000)
87. Comstock, C. E. & Knudsen, K. E. The complex role of AR signaling after cytotoxic insult: Implications for cell-cycle-based chemotherapeutics. Cell Cycle 6, 1307-1313 (2007 (Pubitemid 47327962)
88. Hess-Wilson, J. K., Daly, H. K., Zagorski, W. A., Montville, C. P. & Knudsen, K. E. Mitogenic action of the androgen receptor sensitizes prostate cancer cells to taxane-based cytotoxic insult. Cancer Res. 66, 11998-12008 (2006 (Pubitemid 46094214)
89. Escuin, D., Kline, E. R. & Giannakakou, P. Both microtubule- stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1alpha accumulation and activity by disrupting microtubule function. Cancer Res. 65, 9021-9028 (2005 (Pubitemid 41377394)
90. Forde, J. C. et al. Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro. Cancer Biol. Ther. 11, 421-428 (2011
91. Forde, J. C. et al. Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells. Urol. Oncol. 30, 912-919 (2010
92. Dent, P., Yacoub, A., Fisher, P. B., Hagan, M. P. & Grant, S. MAPK pathways in radiation responses. Oncogene 22, 5885-5896 (2003 (Pubitemid 37176709)
93. McKenna, W. G. & Muschel, R. J. Targeting tumor cells by enhancing radiation sensitivity. Genes Chromosomes Cancer 38, 330-338 (2003 (Pubitemid 37466934)
94. McKenna, W. G., Muschel, R. J., Gupta, A. K., Hahn, S. M. & Bernhard, E. J. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 22, 5866-5875 (2003 (Pubitemid 37176707)
95. Mungamuri, S. K., Yang, X., Thor, A. D. & Somasundaram, K. Survival signaling by Notch1: LMammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 66, 4715-4724 (2006
96. Nefedova, Y., Cheng, P., Alsina, M., Dalton, W. S. & Gabrilovich, D. I. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103, 3503-3510 (2004 (Pubitemid 38525684)
97. Ye, Q. F. et al. siRNA-mediated silencing of Notch-1 enhances docetaxel induced mitotic arrest and apoptosis in prostate cancer cells. Asian Pac. J. Cancer Prev. 13, 2485-2489 (2012
98. Allal, A. S. et al. Radioresistance-related proteins in rectal cancer. Proteomics 4, 2261-2269 (2004 (Pubitemid 39025326)
99. May, M., Siegsmund, M., Hammermann, F., Loy, V. & Gunia, S. Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy. Scand. J. Urol. Nephrol. 41, 375-381 (2007 (Pubitemid 350034696)
100. Koukourakis, M. I., Giatromanolaki, A., Sivridis, E., Gatter, K. C. & Harris, A. L. High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamous cell head-neck cancer (HNSCC). Angiogenesis 16, 343-351 (2012
101. Yu, S., Zhang, R., Liu, F., Hu, H. & Wang, H. Down-regulation of Notch signaling by a gamma-secretase inhibitor enhances the radiosensitivity of nasopharyngeal carcinoma cells. Oncol. Rep. 26, 1323-1328 (2011
102. Liu, S. K. et al. Delta-like ligand 4-notch blockade and tumor radiation response. J. Natl Cancer Inst. 103, 1778-1798 (2011
103. Ponnurangam, S. et al. Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Mol. Cancer Ther. 11, 963-972 (2012
104. Ji, Q. et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE 4, e6816 (2009
105. Wang, J. et al. Notch promotes radioresistance of glioma stem cells. Stem Cells 28, 17-28 (2010
106. Krause, M., Yaromina, A., Eicheler, W., Koch, U. & Baumann, M. Cancer stem cells: Targets and potential biomarkers for radiotherapy. Clin. Cancer Res. 17, 7224-7229 (2011
107. Anderson, L. M. & Gibbons, G. H. Notch: A mastermind of vascular morphogenesis. J. Clin. Invest. 117, 299-302 (2007 (Pubitemid 46203955)
108. Gridley, T. Notch signaling in vascular development and physiology. Development 134, 2709-2718 (2007 (Pubitemid 47305050)
109. Jain, R. K. Determinants of tumor blood flow: A review. Cancer Res. 48, 2641-2658 (1988
110. Roberts, W. G. et al. Host microvasculature influence on tumor vascular morphology and endothelial gene expression. Am. J. Pathol. 153, 1239-1248 (1998 (Pubitemid 28465847)
111. Kakolyris, S. et al. Assessment of vascular maturation in non-small cell lung cancer using a novel basement membrane component, LH39: Correlation with p53 and angiogenic factor expression. Cancer Res. 59, 5602-5607 (1999 (Pubitemid 29526480)
112. Steinberg, F., Konerding, M. A. & Streffer, C. The vascular architecture of human xenotransplanted tumors: Histological, morphometrical, and ultrastructural studies. J. Cancer Res. Clin. Oncol. 116, 517-524 (1990 (Pubitemid 20359916)
113. Pallares, J. et al. Study of microvessel density and the expression of the angiogenic factors VEGF, bFGF and the receptors Flt-1 and FLK-1 in benign, premalignant and malignant prostate tissues. Histol. Histopathol. 21, 857-865 (2006 (Pubitemid 44082728)
114. Bostwick, D. G. & Iczkowski, K. A. Microvessel density in prostate cancer: Prognostic and therapeutic utility. Semin. Urol. Oncol. 16, 118-123 (1998 (Pubitemid 28394936)
115. Sinha, A. A. et al. Microvessel density as a molecular marker for identifying high-grade prostatic intraepithelial neoplasia precursors to prostate cancer. Exp. Mol. Pathol. 77, 153-159 (2004 (Pubitemid 39209299)
116. Halvorsen, O. J., Haukaas, S., Hoisaeter, P. A. & Akslen, L. A. Independent prognostic importance of microvessel density in clinically localized prostate cancer. Anticancer Res. 20, 3791-3799 (2000 (Pubitemid 32002277)
117. Bono, A. V. et al. Microvessel density in prostate carcinoma. Prostate Cancer Prostatic Dis. 5, 123-127 (2002 (Pubitemid 34777895)
118. Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res. 49, 6449-6465 (1989 (Pubitemid 20008770)
119. Wheeler, R. H. et al. Tumor blood flow and systemic shunting in patients receiving intraarterial chemotherapy for head and neck cancer. Cancer Res. 46, 4200-4204 (1986 (Pubitemid 16075931)
120. Padera, T. P. et al. Pathology: Cancer cells compress intratumour vessels. Nature 427, 695 (2004 (Pubitemid 38294577)
121. Sivridis, E., Giatromanolaki, A. & Koukourakis, M. I. The vascular network of tumours-what is it not for? J. Pathol. 201, 173-180 (2003
122. Morrow, D. et al. Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo. Am. J. Physiol. Cell Physiol. 292, C488-C496 (2007 (Pubitemid 46115157)
123. Morrow, D. et al. Cyclic strain inhibits Notch receptor signaling in vascular smooth muscle cells in vitro. Circ. Res. 96, 567-575 (2005 (Pubitemid 40463466)
124. Jain, R. K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820-10825 (1998 (Pubitemid 28413152)
125. Baluk, P., Hashizume, H. & McDonald, D. M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15, 102-111 (2005 (Pubitemid 40127638)
126. Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610-2621 (2006 (Pubitemid 44511625)
127. Thurston, G., Noguera-Troise, I. & Yancopoulos, G. D. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat. Rev. Cancer 7, 327-331 (2007 (Pubitemid 46652486)
128. Sainson, R. C. & Harris, A. L. Anti-Dll4 therapy: Can we block tumour growth by increasing angiogenesis? Trends Mol. Med. 13, 389-395 (2007 (Pubitemid 47385383)
129. Al Haj Zen, A. et al. Inhibition of delta-like-4-mediated signaling impairs reparative angiogenesis after ischemia. Circ. Res. 107, 283-293 (2010
130. Liu, R. et al. Inhibition of Notch signaling by Dll4-Fc promotes reperfusion of acutely ischemic tissues. Biochem. Biophys. Res. Commun. 418, 173-179 (2012
131. Li, J. L. et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 67, 11244-11253 (2007
132. Diez, H. et al. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp. Cell Res. 313, 1-9 (2007 (Pubitemid 44958449)
133. Zeng, Q. et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8, 13-23 (2005 (Pubitemid 40991811)
134. Martinive, P. et al. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: Implications for anticancer therapies. Cancer Res. 66, 11736-11744 (2006 (Pubitemid 46094185)
135. Patel, N. S. et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res. 65, 8690-8697 (2005 (Pubitemid 41377356)
136. Groth, C. & Fortini, M. E. Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Semin. Cell Dev. Biol. 23, 465-472 (2012
137. Bin Hafeez, B. et al. Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin. Cancer Res. 15, 452-459 (2009
138. Wang, Z. et al. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J. Cell Biochem. 109, 726-736 (2010
139. Wang, Z. et al. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J. Cell Biochem. 112, 78-88 (2011
140. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell 137, 216-233 (2009
141. Kong, D. et al. Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment. Am. J. Transl. Res. 4, 14-23 (2012
142. Krop, I. et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J. Clin. Oncol. 30, 2307-2313 (2012
143. Tolcher, A. W. et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J. Clin. Oncol. 30, 2348-2353 (2012
144. Schott, A. F. et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin. Cancer Res. 19, 1512-1524 (2013