Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas
Abstract
:1. Introduction
1.1. Hypoxia-Inducible Factors
1.2. HIFs and Soft Tissue Sarcoma
1.3. HIFs as Independent Prognosticators in Soft Tissue and Bone Sarcomas
2. HIFs: Mediators of Sarcoma Progression, Metastasis, and Therapy Resistance
2.1. HIFs as Regulators of Sarcomagenesis
2.1.1. Rhabdomyosarocoma
2.1.2. Kaposi’s Sarcoma
2.1.3. Gastroinstestinal Tumor
2.1.4. Liposarcoma
2.1.5. Ewing’s Sarcoma
2.2. HIFs as Regulators of Metastasis
2.3. HIFs as Regulators of Therapy Resistance
3. Agents Targeting HIFs
4. Conclusions
References
- Majmundar, A.J.; Wong, W.J.; Simon, M.C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 2010, 40, 294–309. [Google Scholar] [CrossRef]
- Bertout, J.A.; Patel, S.A.; Simon, M.C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 2008, 8, 967–975. [Google Scholar] [CrossRef]
- Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 2003, 3, 721–732. [Google Scholar] [CrossRef]
- Nordsmark, M.; Alsner, J.; Keller, J.; Nielsen, O.S.; Jensen, O.M.; Horsman, M.R.; Overgaard, J. Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations. Br. J. Cancer 2001, 84, 1070–1075. [Google Scholar] [CrossRef]
- Brizel, D.M.; Scully, S.P.; Harrelson, J.M.; Layfield, L.J.; Bean, J.M.; Prosnitz, L.R.; Dewhirst, M.W. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996, 56, 941–943. [Google Scholar]
- Keith, B.; Johnson, R.S.; Simon, M.C. HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 2011, 12, 9–22. [Google Scholar]
- Xia, X.; Lemieux, M.E.; Li, W.; Carroll, J.S.; Brown, M.; Liu, X.S.; Kung, A.L. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc. Natl. Acad. Sci. USA 2009, 106, 4260–4265. [Google Scholar]
- Heikkila, M.; Pasanen, A.; Kivirikko, K.I.; Myllyharju, J. Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cell Mol. Life Sci. 2011, 68, 3885–3901. [Google Scholar] [CrossRef]
- Pouyssegur, J.; Dayan, F.; Mazure, N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006, 441, 437–443. [Google Scholar] [CrossRef]
- Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29. [Google Scholar] [CrossRef]
- Semenza, G.L. Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 2012, 33, 207–214. [Google Scholar] [CrossRef]
- Wu, M.Z.; Tsai, Y.P.; Yang, M.H.; Huang, C.H.; Chang, S.Y.; Chang, C.C.; Teng, S.C.; Wu, K.J. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol. Cell 2011, 43, 811–822. [Google Scholar] [CrossRef]
- Crosby, M.E.; Devlin, C.M.; Glazer, P.M.; Calin, G.A.; Ivan, M. Emerging roles of microRNAs in the molecular responses to hypoxia. Curr. Pharm. Des. 2009, 15, 3861–3866. [Google Scholar] [CrossRef]
- Detwiller, K.Y.; Fernando, N.T.; Segal, N.H.; Ryeom, S.W.; D’Amore, P.A.; Yoon, S.S. Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A. Cancer Res. 2005, 65, 5881–5889. [Google Scholar] [CrossRef]
- Semenza, G.L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010, 29, 625–634. [Google Scholar] [CrossRef]
- Aebersold, D.M.; Burri, P.; Beer, K.T.; Laissue, J.; Djonov, V.; Greiner, R.H.; Semenza, G.L. Expression of hypoxia-inducible factor-1alpha: A novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001, 61, 2911–2916. [Google Scholar]
- Birner, P.; Gatterbauer, B.; Oberhuber, G.; Schindl, M.; Rossler, K.; Prodinger, A.; Budka, H.; Hainfellner, J.A. Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: Its impact on prognosis and on neoangiogenesis. Cancer 2001, 92, 165–171. [Google Scholar] [CrossRef]
- Enatsu, S.; Iwasaki, A.; Shirakusa, T.; Hamasaki, M.; Nabeshima, K.; Iwasaki, H.; Kuroki, M. Expression of hypoxia-inducible factor-1 alpha and its prognostic significance in small-sized adenocarcinomas of the lung. Eur. J. Cardiothorac. Surg. 2006, 29, 891–895. [Google Scholar] [CrossRef]
- Fillies, T.; Werkmeister, R.; van Diest, P.J.; Brandt, B.; Joos, U.; Buerger, H. HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer 2005, 5, 84. [Google Scholar] [CrossRef] [Green Version]
- Hoffmann, A.C.; Mori, R.; Vallbohmer, D.; Brabender, J.; Klein, E.; Drebber, U.; Baldus, S.E.; Cooc, J.; Azuma, M.; Metzger, R.; et al. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia 2008, 10, 674–679. [Google Scholar]
- Lidgren, A.; Hedberg, Y.; Grankvist, K.; Rasmuson, T.; Vasko, J.; Ljungberg, B. The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma. Clin. Cancer Res. 2005, 11, 1129–1135. [Google Scholar]
- Chen, C.; Ma, Q.; Ma, X.; Liu, Z.; Liu, X. Association of elevated HIF-2alpha levels with low Beclin 1 expression and poor prognosis in patients with chondrosarcoma. Ann. Surg. Oncol. 2011, 18, 2364–2372. [Google Scholar] [CrossRef]
- Chen, C.; Zhou, H.; Wei, F.; Jiang, L.; Liu, X.; Liu, Z.; Ma, Q. Increased levels of hypoxia-inducible factor-1alpha are associated with Bcl-xL expression, tumor apoptosis, and clinical outcome in chondrosarcoma. J. Orthop. Res. 2011, 29, 143–151. [Google Scholar] [CrossRef]
- Huang, J.H.; Lee, F.S.; Pasha, T.L.; Sammel, M.D.; Karakousis, G.; Xu, G.; Fraker, D.; Zhang, P.J. Analysis of HIF-1alpha and its regulator, PHD2, in retroperitoneal sarcomas: Clinico-Pathologic implications. Cancer Biol. Ther. 2010, 9, 303–311. [Google Scholar] [CrossRef]
- Shintani, K.; Matsumine, A.; Kusuzaki, K.; Matsubara, T.; Satonaka, H.; Wakabayashi, T.; Hoki, Y.; Uchida, A. Expression of hypoxia-inducible factor (HIF)-1alpha as a biomarker of outcome in soft-tissue sarcomas. Virchows Arch. 2006, 449, 673–681. [Google Scholar] [CrossRef]
- Hoffmann, A.C.; Danenberg, K.D.; Taubert, H.; Danenberg, P.V.; Wuerl, P. A three-gene signature for outcome in soft tissue sarcoma. Clin. Cancer Res. 2009, 15, 5191–5198. [Google Scholar] [CrossRef]
- Zhong, H.; de Marzo, A.M.; Laughner, E.; Lim, M.; Hilton, D.A.; Zagzag, D.; Buechler, P.; Isaacs, W.B.; Semenza, G.L.; Simons, J.W. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999, 59, 5830–5835. [Google Scholar]
- Kilic, M.; Kasperczyk, H.; Fulda, S.; Debatin, K.M. Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. Oncogene 2007, 26, 2027–2038. [Google Scholar] [CrossRef]
- Das, B.; Tsuchida, R.; Malkin, D.; Koren, G.; Baruchel, S.; Yeger, H. Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 2008, 26, 1818–1830. [Google Scholar] [CrossRef]
- Wan, X.; Shen, N.; Mendoza, A.; Khanna, C.; Helman, L.J. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia 2006, 8, 394–401. [Google Scholar] [CrossRef]
- Rey, S.; Semenza, G.L. Hypoxia-Inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc. Res. 2010, 86, 236–242. [Google Scholar] [CrossRef]
- Jham, B.C.; Ma, T.; Hu, J.; Chaisuparat, R.; Friedman, E.R.; Pandolfi, P.P.; Schneider, A.; Sodhi, A.; Montaner, S. Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi’s sarcoma. PLoS One 2011, 6, e19103. [Google Scholar]
- Cai, Q.; Murakami, M.; Si, H.; Robertson, E.S. A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi’s sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia. J. Virol. 2007, 81, 10413–10423. [Google Scholar]
- Cai, Q.L.; Knight, J.S.; Verma, S.C.; Zald, P.; Robertson, E.S. EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog. 2006, 2, e116. [Google Scholar] [CrossRef]
- Corless, C.L.; Barnett, C.M.; Heinrich, M.C. Gastrointestinal stromal tumours: Origin and molecular oncology. Nat. Rev. Cancer 2011, 11, 865–878. [Google Scholar]
- Antonescu, C.R.; Viale, A.; Sarran, L.; Tschernyavsky, S.J.; Gonen, M.; Segal, N.H.; Maki, R.G.; Socci, N.D.; DeMatteo, R.P.; Besmer, P. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin. Cancer Res. 2004, 10, 3282–3290. [Google Scholar] [CrossRef]
- Yun, Z.; Maecker, H.L.; Johnson, R.S.; Giaccia, A.J. Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: A mechanism for regulation of adipogenesis by hypoxia. Dev. Cell 2002, 2, 331–341. [Google Scholar] [CrossRef]
- Lin, Q.; Lee, Y.J.; Yun, Z. Differentiation arrest by hypoxia. J. Biol. Chem. 2006, 281, 30678–30683. [Google Scholar] [CrossRef]
- Kim, Y.; Lin, Q.; Zelterman, D.; Yun, Z. Hypoxia-Regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res. 2009, 69, 9271–9280. [Google Scholar] [CrossRef]
- Aryee, D.N.; Niedan, S.; Kauer, M.; Schwentner, R.; Bennani-Baiti, I.M.; Ban, J.; Muehlbacher, K.; Kreppel, M.; Walker, R.L.; Meltzer, P.; et al. Hypoxia modulates EWS-FLI1 transcriptional signature and enhances the malignant properties of Ewing’s sarcoma cells in vitro. Cancer Res. 2010, 70, 4015–4023. [Google Scholar] [CrossRef]
- Knowles, H.J.; Schaefer, K.L.; Dirksen, U.; Athanasou, N.A. Hypoxia and hypoglycaemia in Ewing’s sarcoma and osteosarcoma: Regulation and phenotypic effects of Hypoxia-Inducible Factor. BMC Cancer 2010, 10, 372. [Google Scholar] [CrossRef]
- Mayer, A.; Hoeckel, M.; von Wallbrunn, A.; Horn, L.C.; Wree, A.; Vaupel, P. HIF-Mediated hypoxic response is missing in severely hypoxic uterine leiomyomas. Adv. Exp. Med. Biol. 2010, 662, 399–405. [Google Scholar] [CrossRef]
- Francis, P.; Namlos, H.M.; Muller, C.; Eden, P.; Fernebro, J.; Berner, J.M.; Bjerkehagen, B.; Akerman, M.; Bendahl, P.O.; Isinger, A.; et al. Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: Hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics 2007, 8, 73. [Google Scholar]
- Mito, J.K.; Riedel, R.F.; Dodd, L.; Lahat, G.; Lazar, A.J.; Dodd, R.D.; Stangenberg, L.; Eward, W.C.; Hornicek, F.J.; Yoon, S.S.; et al. Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma. PLoS One 2009, 4, e8075. [Google Scholar] [CrossRef]
- Skubitz, K.M.; Francis, P.; Skubitz, A.P.; Luo, X.; Nilbert, M. Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas. Cancer 2012, 118, 4235–4243. [Google Scholar] [CrossRef]
- Sullivan, R.; Graham, C.H. Hypoxia-Driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007, 26, 319–331. [Google Scholar] [CrossRef]
- Krishnamachary, B.; Berg-Dixon, S.; Kelly, B.; Agani, F.; Feldser, D.; Ferreira, G.; Iyer, N.; LaRusch, J.; Pak, B.; Taghavi, P.; et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003, 63, 1138–1143. [Google Scholar]
- Erler, J.T.; Bennewith, K.L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q.T.; Chi, J.T.; Jeffrey, S.S.; Giaccia, A.J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006, 440, 1222–1226. [Google Scholar] [CrossRef]
- Lu, X.; Yan, C.H.; Yuan, M.; Wei, Y.; Hu, G.; Kang, Y. In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer. Cancer Res. 2010, 70, 3905–3914. [Google Scholar] [CrossRef]
- Muller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M.E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S.N.; et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410, 50–56. [Google Scholar] [CrossRef]
- Erler, J.T.; Bennewith, K.L.; Cox, T.R.; Lang, G.; Bird, D.; Koong, A.; Le, Q.T.; Giaccia, A.J. Hypoxia-Induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 2009, 15, 35–44. [Google Scholar] [CrossRef]
- Denny, W.A. Hypoxia-Activated prodrugs in cancer therapy: Progress to the clinic. Future Oncol. 2010, 6, 419–428. [Google Scholar]
- Bertout, J.A.; Majmundar, A.J.; Gordan, J.D.; Lam, J.C.; Ditsworth, D.; Keith, B.; Brown, E.J.; Nathanson, K.L.; Simon, M.C. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc. Natl. Acad. Sci. USA 2009, 106, 14391–14396. [Google Scholar] [CrossRef]
- Moeller, B.J.; Dreher, M.R.; Rabbani, Z.N.; Schroeder, T.; Cao, Y.; Li, C.Y.; Dewhirst, M.W. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005, 8, 99–110. [Google Scholar] [CrossRef]
- Yoon, S.S.; Duda, D.G.; Karl, D.L.; Kim, T.M.; Kambadakone, A.R.; Chen, Y.L.; Rothrock, C.; Rosenberg, A.E.; Nielsen, G.P.; Kirsch, D.G.; et al. Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 2011, 81, 1081–1090. [Google Scholar] [CrossRef]
- Rohwer, N.; Dame, C.; Haugstetter, A.; Wiedenmann, B.; Detjen, K.; Schmitt, C.A.; Cramer, T. Hypoxia-Inducible factor 1alpha determines gastric cancer chemosensitivity via modulation of p53 and NF-kappaB. PLoS One 2010, 5, e12038. [Google Scholar]
- Hao, J.; Song, X.; Song, B.; Liu, Y.; Wei, L.; Wang, X.; Yu, J. Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells. Cancer Gene Ther. 2008, 15, 449–455. [Google Scholar] [CrossRef]
- Sullivan, R.; Pare, G.C.; Frederiksen, L.J.; Semenza, G.L.; Graham, C.H. Hypoxia-Induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol. Cancer Ther. 2008, 7, 1961–1973. [Google Scholar] [CrossRef]
- Generali, D.; Buffa, F.M.; Berruti, A.; Brizzi, M.P.; Campo, L.; Bonardi, S.; Bersiga, A.; Allevi, G.; Milani, M.; Aguggini, S.; et al. Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer. J. Clin. Oncol. 2009, 27, 227–234. [Google Scholar] [CrossRef]
- Nakamura, J.; Kitajima, Y.; Kai, K.; Hashiguchi, K.; Hiraki, M.; Noshiro, H.; Miyazaki, K. HIF-1alpha is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. Int. J. Cancer 2010, 127, 1158–1171. [Google Scholar]
- Unruh, A.; Ressel, A.; Mohamed, H.G.; Johnson, R.S.; Nadrowitz, R.; Richter, E.; Katschinski, D.M.; Wenger, R.H. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 2003, 22, 3213–3220. [Google Scholar] [CrossRef] [Green Version]
- Zhao, F.; Mancuso, A.; Bui, T.V.; Tong, X.; Gruber, J.J.; Swider, C.R.; Sanchez, P.V.; Lum, J.J.; Sayed, N.; Melo, J.V.; et al. Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming. Oncogene 2010, 29, 2962–2972. [Google Scholar] [CrossRef]
- Wilson, W.R.; Hay, M.P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 2011, 11, 393–410. [Google Scholar] [CrossRef]
- Rapisarda, A.; Melillo, G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat. Rev. Clin. Oncol. 2012, 9, 378–390. [Google Scholar] [CrossRef]
- Zhang, H.; Qian, D.Z.; Tan, Y.S.; Lee, K.; Gao, P.; Ren, Y.R.; Rey, S.; Hammers, H.; Chang, D.; Pili, R.; et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA 2008, 105, 19579–19586. [Google Scholar] [CrossRef]
- Ganjoo, K.N.; Cranmer, L.D.; Butrynski, J.E.; Rushing, D.; Adkins, D.; Okuno, S.H.; Lorente, G.; Kroll, S.; Langmuir, V.K.; Chawla, S.P. A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. Oncology 2011, 80, 50–56. [Google Scholar] [CrossRef]
- Ganjoo, K.N. New developments in targeted therapy for soft tissue sarcoma. Curr. Oncol. Rep. 2010, 12, 261–265. [Google Scholar] [CrossRef]
- Moyer, M.W. Targeting hypoxia brings breath of fresh air to cancer therapy. Nat. Med. 2012, 18, 636–637. [Google Scholar] [CrossRef]
- Ma, W.W.; Adjei, A.A. Novel agents on the horizon for cancer therapy. CA Cancer J. Clin. 2009, 59, 111–137. [Google Scholar] [CrossRef]
- Greenberger, L.M.; Horak, I.D.; Filpula, D.; Sapra, P.; Westergaard, M.; Frydenlund, H.F.; Albaek, C.; Schroder, H.; Orum, H. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol. Cancer Ther. 2008, 7, 3598–3608. [Google Scholar] [CrossRef]
- Terzuoli, E.; Puppo, M.; Rapisarda, A.; Uranchimeg, B.; Cao, L.; Burger, A.M.; Ziche, M.; Melillo, G. Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion. Cancer Res. 2010, 70, 6837–6848. [Google Scholar] [CrossRef]
- Sapra, P.; Kraft, P.; Pastorino, F.; Ribatti, D.; Dumble, M.; Mehlig, M.; Wang, M.; Ponzoni, M.; Greenberger, L.M.; Horak, I.D. Potent and sustained inhibition of HIF-1alpha and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis 2011, 14, 245–253. [Google Scholar] [CrossRef]
- Chawla, S.P.; Staddon, A.P.; Baker, L.H.; Schuetze, S.M.; Tolcher, A.W.; D’Amato, G.Z.; Blay, J.Y.; Mita, M.M.; Sankhala, K.K.; Berk, L.; et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J. Clin. Oncol. 2012, 30, 78–84. [Google Scholar] [CrossRef]
- Isaacs, J.S.; Jung, Y.J.; Mimnaugh, E.G.; Martinez, A.; Cuttitta, F.; Neckers, L.M. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J. Biol. Chem. 2002, 277, 29936–29944. [Google Scholar]
- Lee, K.; Qian, D.Z.; Rey, S.; Wei, H.; Liu, J.O.; Semenza, G.L. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA 2009, 106, 2353–2358. [Google Scholar]
- Keedy, V.L. Treating metastatic soft-tissue or bone sarcomas—Potential role of ridaforolimus. Oncol. Targets Ther. 2012, 5, 153–160. [Google Scholar]
- Mita, M.M.; Poplin, E.; Britten, C.D.; Tap, W.D.; Rubin, E.H.; Scott, B.B.; Berk, L.; Rivera, V.M.; Loewy, J.W.; Dodion, P.; et al. Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma. Ann. Oncol. 2013, 24, 1104–1111. [Google Scholar] [CrossRef]
- Rapisarda, A.; Shoemaker, R.H.; Melillo, G. Antiangiogenic agents and HIF-1 inhibitors meet at the crossroads. Cell Cycle 2009, 8, 4040–4043. [Google Scholar] [CrossRef]
- Krohn, K.A.; Link, J.M.; Mason, R.P. Molecular imaging of hypoxia. J. Nucl. Med. 2008, 49, 129S–148S. [Google Scholar] [CrossRef]
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Sadri, N.; Zhang, P.J. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas. Cancers 2013, 5, 320-333. https://doi.org/10.3390/cancers5020320
Sadri N, Zhang PJ. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas. Cancers. 2013; 5(2):320-333. https://doi.org/10.3390/cancers5020320
Chicago/Turabian StyleSadri, Navid, and Paul J. Zhang. 2013. "Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas" Cancers 5, no. 2: 320-333. https://doi.org/10.3390/cancers5020320