Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression.
References
[1]
Majmundar, A.J.; Wong, W.J.; Simon, M.C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 2010, 40, 294–309, doi:10.1016/j.molcel.2010.09.022.
[2]
Bertout, J.A.; Patel, S.A.; Simon, M.C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 2008, 8, 967–975, doi:10.1038/nrc2540.
[3]
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 2003, 3, 721–732, doi:10.1038/nrc1187.
[4]
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, doi:10.1054/bjoc.2001.1728.
[5]
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.
[6]
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.
[7]
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.
[8]
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, doi:10.1007/s00018-011-0679-5.
[9]
Pouyssegur, J.; Dayan, F.; Mazure, N.M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006, 441, 437–443, doi:10.1038/nature04871.
[10]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29, doi:10.3322/caac.20138.
[11]
Semenza, G.L. Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 2012, 33, 207–214, doi:10.1016/j.tips.2012.01.005.
[12]
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, doi:10.1016/j.molcel.2011.07.012.
[13]
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, doi:10.2174/138161209789649367.
[14]
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, doi:10.1158/0008-5472.CAN-04-4078.
[15]
Semenza, G.L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010, 29, 625–634, doi:10.1038/onc.2009.441.
[16]
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.
[17]
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, doi:10.1002/1097-0142(20010701)92:1<165::AID-CNCR1305>3.0.CO;2-F.
[18]
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, doi:10.1016/j.ejcts.2006.03.027.
[19]
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, doi:10.1186/1471-2407-5-84.
[20]
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.
[21]
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.
[22]
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, doi:10.1245/s10434-011-1587-5.
[23]
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, doi:10.1002/jor.21193.
[24]
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, doi:10.4161/cbt.9.4.10744.
[25]
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, doi:10.1007/s00428-006-0304-4.
[26]
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, doi:10.1158/1078-0432.CCR-08-2534.
[27]
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.
[28]
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, doi:10.1038/sj.onc.1210008.
[29]
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, doi:10.1634/stemcells.2007-0724.
[30]
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, doi:10.1593/neo.05820.
[31]
Rey, S.; Semenza, G.L. Hypoxia-Inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc. Res. 2010, 86, 236–242, doi:10.1093/cvr/cvq045.
[32]
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.
[33]
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.
[34]
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, doi:10.1371/journal.ppat.0020116.
[35]
Corless, C.L.; Barnett, C.M.; Heinrich, M.C. Gastrointestinal stromal tumours: Origin and molecular oncology. Nat. Rev. Cancer 2011, 11, 865–878.
[36]
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, doi:10.1158/1078-0432.CCR-03-0715.
[37]
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, doi:10.1016/S1534-5807(02)00131-4.
[38]
Lin, Q.; Lee, Y.J.; Yun, Z. Differentiation arrest by hypoxia. J. Biol. Chem. 2006, 281, 30678–30683, doi:10.1074/jbc.C600120200.
[39]
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, doi:10.1158/0008-5472.CAN-09-1605.
[40]
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, doi:10.1158/0008-5472.CAN-09-4333.
[41]
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, doi:10.1186/1471-2407-10-372.
[42]
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, doi:10.1007/978-1-4419-1241-1_58.
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, doi:10.1371/journal.pone.0008075.
[45]
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, doi:10.1002/cncr.26733.
[46]
Sullivan, R.; Graham, C.H. Hypoxia-Driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007, 26, 319–331, doi:10.1007/s10555-007-9062-2.
[47]
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.
[48]
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, doi:10.1038/nature04695.
[49]
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, doi:10.1158/0008-5472.CAN-09-3739.
[50]
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, doi:10.1038/35065016.
[51]
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, doi:10.1016/j.ccr.2008.11.012.
[52]
Denny, W.A. Hypoxia-Activated prodrugs in cancer therapy: Progress to the clinic. Future Oncol. 2010, 6, 419–428.
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, doi:10.1016/j.ccr.2005.06.016.
[55]
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, doi:10.1016/j.ijrobp.2010.07.024.
[56]
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.
[57]
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, doi:10.1038/cgt.2008.4.
[58]
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, doi:10.1158/1535-7163.MCT-08-0198.
[59]
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, doi:10.1200/JCO.2007.13.7083.
[60]
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.
[61]
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, doi:10.1038/sj.onc.1206385.
[62]
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, doi:10.1038/onc.2010.67.
[63]
Wilson, W.R.; Hay, M.P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 2011, 11, 393–410, doi:10.1038/nrc3064.
[64]
Rapisarda, A.; Melillo, G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat. Rev. Clin. Oncol. 2012, 9, 378–390, doi:10.1038/nrclinonc.2012.64.
[65]
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, doi:10.1073/pnas.0809763105.
[66]
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, doi:10.1159/000327739.
[67]
Ganjoo, K.N. New developments in targeted therapy for soft tissue sarcoma. Curr. Oncol. Rep. 2010, 12, 261–265, doi:10.1007/s11912-010-0107-2.
[68]
Moyer, M.W. Targeting hypoxia brings breath of fresh air to cancer therapy. Nat. Med. 2012, 18, 636–637, doi:10.1038/nm0512-636b.
[69]
Ma, W.W.; Adjei, A.A. Novel agents on the horizon for cancer therapy. CA Cancer J. Clin. 2009, 59, 111–137, doi:10.3322/caac.20003.
[70]
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, doi:10.1158/1535-7163.MCT-08-0510.
[71]
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, doi:10.1158/0008-5472.CAN-10-1075.
[72]
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, doi:10.1007/s10456-011-9209-1.
[73]
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, doi:10.1200/JCO.2011.35.6329.
[74]
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.
[75]
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.
[76]
Keedy, V.L. Treating metastatic soft-tissue or bone sarcomas—Potential role of ridaforolimus. Oncol. Targets Ther. 2012, 5, 153–160.
[77]
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, doi:10.1093/annonc/mds602.
[78]
Rapisarda, A.; Shoemaker, R.H.; Melillo, G. Antiangiogenic agents and HIF-1 inhibitors meet at the crossroads. Cell Cycle 2009, 8, 4040–4043, doi:10.4161/cc.8.24.10145.
[79]
Krohn, K.A.; Link, J.M.; Mason, R.P. Molecular imaging of hypoxia. J. Nucl. Med. 2008, 49, 129S–148S, doi:10.2967/jnumed.107.045914.
