Abstract
Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancer-targeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumor-specific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human α-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aits S, Gustafsson L, Hallgren O, Brest P, Gustafsson M, Trulsson M et al. (2009). HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. Int J Cancer 124: 1008–1019.
Alemany R, Balague C, Curiel DT . (2000). Replicative adenoviruses for cancer therapy. Nat Biotechnol 18: 723–727.
Altucci L, Rossin A, Hirsch O, Nebbioso A, Vitoux D, Wilhelm E et al. (2005). Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res 65: 8754–8765.
Altucci L, Rossin A, Raffelsberger W, Reitmair A, Chomienne C, Gronemeyer H . (2001). Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 7: 680–686.
Backendorf C, Visser AE, de Boer AG, Zimmerman R, Visser M, Voskamp P et al. (2008). Apoptin: therapeutic potential of an early sensor of carcinogenic transformation. Annu Rev Pharmacol Toxicol 48: 143–169.
Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U et al. (2006). Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 24: 4738–4745.
Belyanskaya LL, Ziogas A, Hopkins-Donaldson S, Kurtz S, Simon HU, Stahel R et al. (2008). TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8. Lung Cancer 60: 355–365.
Berdis AJ . (2008). DNA polymerases as therapeutic targets. Biochemistry 47: 8253–8260.
Bergers G, Benjamin LE . (2003). Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3: 401–410.
Bernardi R, Scaglioni PP, Bergmann S, Horn HF, Vousden KH, Pandolfi PP . (2004). PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat Cell Biol 6: 665–672.
Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G . (2007). Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol 39: 1416–1431.
Blundell TL, Jhoti H, Abell C . (2002). High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 1: 45–54.
Cai X, Cullen BR . (2007). The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13: 313–316.
Castets M, Coissieux MM, Delloye-Bourgeois C, Bernard L, Delcros JG, Bernet A et al. (2009). Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis. Dev Cell 16: 614–620.
Chen HX, Cleck JN . (2009). Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6: 465–477.
Clarke N, Jimenez-Lara AM, Voltz E, Gronemeyer H . (2004). Tumor suppressor IRF-1 mediates retinoid and interferon anticancer signaling to death ligand TRAIL. EMBO J 23: 3051–3060.
Cortes J, Jabbour E, Daley GQ, O'Brien S, Verstovsek S, Ferrajoli A et al. (2007). Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer 110: 1295–1302.
Costa FF . (2008). Non-coding RNAs, epigenetics and complexity. Gene 410: 9–17.
Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ . (2002). Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 168: 1356–1361.
Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S et al. (2008). Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68: 5049–5058.
de Stanchina E, Querido E, Narita M, Davuluri RV, Pandolfi PP, Ferbeyre G et al. (2004). PML is a direct p53 target that modulates p53 effector functions. Mol Cell 13: 523–535.
Demetri GD, von MM, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ et al. (2002). Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347: 472–480.
Desgrosellier JS, Cheresh DA . (2010). Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10: 9–22.
Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M et al. (2002). Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295: 1079–1082.
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P et al. (2008). Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26: 5705–5712.
Dorer DE, Nettelbeck DM . (2009). Targeting cancer by transcriptional control in cancer gene therapy and viral oncolysis. Adv Drug Deliv Rev 61: 554–571.
Druker B . (2001). Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia. Semin Hematol 38: 9–14.
Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC . (2005). Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45: 495–528.
Duringer C, Hamiche A, Gustafsson L, Kimura H, Svanborg C . (2003). HAMLET interacts with histones and chromatin in tumor cell nuclei. J Biol Chem 278: 42131–42135.
Eager R, Harle L, Nemunaitis J . (2008). Ad-MDA-7; INGN 241: a review of preclinical and clinical experience. Expert Opin Biol Ther 8: 1633–1643.
Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin KM, Jeremias I . (2003). TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. Oncogene 22: 3842–3852.
Ekmekcioglu S, Mumm JB, Udtha M, Chada S, Grimm EA . (2008). Killing of human melanoma cells induced by activation of class I interferon-regulated signaling pathways via MDA-7/IL-24. Cytokine 43: 34–44.
Ellerhorst JA, Prieto VG, Ekmekcioglu S, Broemeling L, Yekell S, Chada S et al. (2002). Loss of MDA-7 expression with progression of melanoma. J Clin Oncol 20: 1069–1074.
Emdad L, Lebedeva IV, Su ZZ, Gupta P, Sauane M, Dash R et al. (2009). Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24. Cancer Biol Ther 8: 391–400.
Esquela-Kerscher A, Trang P, Wiggins JF, Patrawala L, Cheng A, Ford L et al. (2008). The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7: 759–764.
Esteller M . (2008). Epigenetics in cancer. N Engl J Med 358: 1148–1159.
Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L et al. (2007). Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 12: 457–466.
Feinberg AP, Tycko B . (2004). The history of cancer epigenetics. Nat Rev Cancer 4: 143–153.
Feinberg AP, Vogelstein B . (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301: 89–92.
Ferrara N, Hillan KJ, Gerber HP, Novotny W . (2004). Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3: 391–400.
Flygare JA, Fairbrother WJ . (2010). Small-molecule pan-IAP antagonists: a patent review. Expert Opin Ther Pat 20: 251–267.
Fraga MF, Esteller M . (2005). Towards the human cancer epigenome: a first draft of histone modifications. Cell Cycle 4: 1377–1381.
Fukuhara H, Homma Y, Todo T . (2009). Oncolytic virus therapy for prostate cancer. Int J Urol 17: 20–30.
Fukuhara H, Martuza RL, Rabkin SD, Ito Y, Todo T . (2005). Oncolytic herpes simplex virus vector g47delta in combination with androgen ablation for the treatment of human prostate adenocarcinoma. Clin Cancer Res 11: 7886–7890.
Fulda S . (2009). Inhibitor of apoptosis proteins in hematological malignancies. Leukemia 23: 467–476.
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R et al. (2004). A census of human cancer genes. Nat Rev Cancer 4: 177–183.
Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW et al. (1983). The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11: 6883–6894.
Garofalo M, Di LG, Romano G, Nuovo G, Suh SS, Ngankeu A et al. (2009). miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16: 498–509.
Georgakis GV, Li Y, Humphreys R, Andreeff M, O'Brien S, Younes M et al. (2005). Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death. Br J Haematol 130: 501–510.
Goldschneider D, Mehlen P . (2010). Dependence receptors: a new paradigm in cell signaling and cancer therapy. Oncogene 29: 1865–1882.
Gopal YN, Arora TS, Van Dyke MW . (2007). Parthenolide specifically depletes histone deacetylase 1 protein and induces cell death through ataxia telangiectasia mutated. Chem Biol 14: 813–823.
Gopalan B, Litvak A, Sharma S, Mhashilkar AM, Chada S, Ramesh R . (2005). Activation of the Fas-FasL signaling pathway by MDA-7/IL-24 kills human ovarian cancer cells. Cancer Res 65: 3017–3024.
Granchi C, Bertini S, Macchia M, Minutolo F . (2010). Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem 17: 672–697.
Grant S, Easley C, Kirkpatrick P . (2007). Vorinostat. Nat Rev Drug Discov 6: 21–22.
Greco FA, Bonomi P, Crawford J, Kelly K, Oh Y, Halpern W et al. (2008). Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer 61: 82–90.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. (2007). Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158.
Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M et al. (1998). Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391: 815–818.
Grothey A, Galanis E . (2009). Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 6: 507–518.
Guan Y, Gerhard B, Hogge DE . (2003). Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 101: 3142–3149.
Guelen L, Paterson H, Gaken J, Meyers M, Farzaneh F, Tavassoli M . (2004). TAT-apoptin is efficiently delivered and induces apoptosis in cancer cells. Oncogene 23: 1153–1165.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138: 645–659.
Gustafsson L, Aits S, Onnerfjord P, Trulsson M, Storm P, Svanborg C . (2009). Changes in proteasome structure and function caused by HAMLET in tumor cells. PloS One 4: e5229.
Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AK, Svanborg C . (2004). Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med 350: 2663–2672.
Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS et al. (2005). The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 105: 4163–4169.
Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC et al. (2007). An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110: 4427–4435.
Hakansson A, Zhivotovsky B, Orrenius S, Sabharwal H, Svanborg C . (1995). Apoptosis induced by a human milk protein. Proc Natl Acad Sci USA 92: 8064–8068.
Hallgren O, Aits S, Brest P, Gustafsson L, Mossberg AK, Wullt B et al. (2008). Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Adv Exp Med Biol 606: 217–240.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Harper N, Farrow SN, Kaptein A, Cohen GM, MacFarlane M . (2001). Modulation of tumor necrosis factor apoptosis-inducing ligand-induced NF-kappa B activation by inhibition of apical caspases. J Biol Chem 276: 34743–34752.
Hasegawa H, Yamada Y, Harasawa H, Tsuji T, Murata K, Sugahara K et al. (2005). Sensitivity of adult T-cell leukaemia lymphoma cells to tumour necrosis factor-related apoptosis-inducing ligand. Br J Haematol 128: 253–265.
Hassane DC, Guzman ML, Corbett C, Li X, Abboud R, Young F et al. (2008). Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood 111: 5654–5662.
He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A et al. (1998). Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet 18: 126–135.
Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al. (2009). Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23: 1054–1061.
Holoch PA, Griffith TS . (2009). TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol 625: 63–72.
Holyoake TL, Jiang X, Jorgensen HG, Graham S, Alcorn MJ, Laird C et al. (2001). Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97: 720–728.
Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A et al. (2008). A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 14: 3450–3455.
Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV et al. (2001). Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 20: 7051–7063.
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L et al. (1988). Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72: 567–572.
Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, Goodfellow PJ et al. (2009). Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 69: 9038–9046.
Idogawa M, Sasaki Y, Suzuki H, Mita H, Imai K, Shinomura Y et al. (2009). A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells. Clin Cancer Res 15: 3725–3732.
Insinga A, Minucci S, Pelicci PG . (2005). Mechanisms of selective anticancer action of histone deacetylase inhibitors. Cell Cycle 4: 741–743.
Insinga A, Monestiroli S, Ronzoni S, Carbone R, Pearson M, Pruneri G et al. (2004). Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J 23: 1144–1154.
Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS et al. (2009). Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6: 327–338.
Janne PA, Gray N, Settleman J . (2009). Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8: 709–723.
Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB . (1995). Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11: 2477–2486.
Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR et al. (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6: 564–567.
Kamashev D, Vitoux D, De The H . (2004). PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med 199: 1163–1174.
Kantarjian HM, Cortes J . (2006). New strategies in chronic myeloid leukemia. Int J Hematol 83: 289–293.
Kantarjian HM, Talpaz M, Giles F, O'Brien S, Cortes J . (2006). New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 145: 913–923.
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC et al. (2008). K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359: 1757–1765.
Kasuya H, Takeda S, Nomoto S, Nakao A . (2005). The potential of oncolytic virus therapy for pancreatic cancer. Cancer Gene Ther 12: 725–736.
Kawasaki BT, Hurt EM, Kalathur M, Duhagon MA, Milner JA, Kim YS et al. (2009). Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: an integrated molecular profiling approach. Prostate 69: 827–837.
Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al. (2000). A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 6: 879–885.
Kirn D . (2000). Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 19: 6660–6669.
Klose RJ, Bird AP . (2006). Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31: 89–97.
Knight ZA, Lin H, Shokat KM . (2010). Targeting the cancer kinome through polypharmacology. Nat Rev Cancer 10: 130–137.
Kogan SC . (2009). Curing APL: differentiation or destruction? Cancer Cell 15: 7–8.
Kohler C, Hakansson A, Svanborg C, Orrenius S, Zhivotovsky B . (1999). Protease activation in apoptosis induced by MAL. Exp Cell Res 249: 260–268.
Landry MC, Robert A, Lavoie JN . (2006). Alternative cell death pathways: lessons learned from a viral protein. Bull Cancer 93: 921–930.
Lane AA, Chabner BA . (2009). Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27: 5459–5468.
Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B et al. (2001). Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7: 383–385.
le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N et al. (2008). Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or-intolerant accelerated-phase chronic myelogenous leukemia. Blood 111: 1834–1839.
Lebedeva IV, Emdad L, Su ZZ, Gupta P, Sauane M, Sarkar D et al. (2007). mda-7/IL-24, novel anticancer cytokine: focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review). Int J Oncol 31: 985–1007.
Leong S, Cohen RB, Gustafson DL, Langer CJ, Camidge DR, Padavic K et al. (2009). Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol 27: 4413–4421.
Lessene G, Czabotar PE, Colman PM . (2008). BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7: 989–1000.
Leverkus M, Neumann M, Mengling T, Rauch CT, Brocker EB, Krammer PH et al. (2000). Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 60: 553–559.
Li JH, Kirkiles-Smith NC, McNiff JM, Pober JS . (2003). TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells. J Immunol 171: 1526–1533.
Li S, Brignole C, Marcellus R, Thirlwell S, Binda O, McQuoid MJ et al. (2009a). The adenovirus E4orf4 protein induces G2/M arrest and cell death by blocking protein phosphatase 2A activity regulated by the B55 subunit. J Virol 83: 8340–8352.
Li S, Szymborski A, Miron MJ, Marcellus R, Binda O, Lavoie JN et al. (2009b). The adenovirus E4orf4 protein induces growth arrest and mitotic catastrophe in H1299 human lung carcinoma cells. Oncogene 28: 390–400.
Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF et al. (2006). KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66: 3992–3995.
Lin HK, Bergmann S, Pandolfi PP . (2004). Cytoplasmic PML function in TGF-beta signalling. Nature 431: 205–211.
Lin RJ, Nagy L, Inoue S, Shao W, Miller Jr WH, Evans RM . (1998). Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391: 811–814.
Liu TC, Galanis E, Kirn D . (2007). Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol 4: 101–117.
Liu TC, Kirn D . (2008). Gene therapy progress and prospects cancer: oncolytic viruses. Gene Therapy 15: 877–884.
Luo J, Solimini NL, Elledge SJ . (2009). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136: 823–837.
Lurje G, Nagashima F, Zhang W, Yang D, Chang HM, Gordon MA et al. (2008). Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res 14: 7884–7895.
Maddika S, Booy EP, Johar D, Gibson SB, Ghavami S, Los M . (2005). Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. J Cell Sci 118: 4485–4493.
Maddika S, Mendoza FJ, Hauff K, Zamzow CR, Paranjothy T, Los M . (2006). Cancer-selective therapy of the future: apoptin and its mechanism of action. Cancer Biol Ther 5: 10–19.
Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F . (2009). Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 158: 1–9.
Masui H, Moroyama T, Mendelsohn J . (1986). Mechanism of antitumor activity in mice for anti-epidermal growth factor receptor monoclonal antibodies with different isotypes. Cancer Res 46: 5592–5598.
Mehlen P, Guenebeaud C . (2010). Netrin-1 and its dependence receptors as original targets for cancer therapy. Curr Opin Oncol 22: 46–54.
Mehlen P, Puisieux A . (2006). Metastasis: a question of life or death. Nat Rev Cancer 6: 449–458.
Melnick A, Licht JD . (1999). Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.
Mitrus I, Missol-Kolka E, Plucienniczak A, Szala S . (2005). Tumour therapy with genes encoding apoptin and E4orf4. Anticancer Res 25: 1087–1090.
Mitsiades CS, Treon SP, Mitsiades N, Shima Y, Richardson P, Schlossman R et al. (2001). TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 98: 795–804.
Mom CH, Verweij J, Oldenhuis CN, Gietema JA, Fox NL, Miceli R et al. (2009). Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res 15: 5584–5590.
Morel J, Audo R, Hahne M, Combe B . (2005). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem 280: 15709–15718.
Mossberg AK, Wullt B, Gustafsson L, Mansson W, Ljunggren E, Svanborg C . (2007). Bladder cancers respond to intravesical instillation of HAMLET (human alpha-lactalbumin made lethal to tumor cells). Int J Cancer 121: 1352–1359.
Motoki K, Mori E, Matsumoto A, Thomas M, Tomura T, Humphreys R et al. (2005). Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Clin Cancer Res 11: 3126–3135.
Naka T, Sugamura K, Hylander BL, Widmer MB, Rustum YM, Repasky EA . (2002). Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patient's colon tumors grown in SCID mice. Cancer Res 62: 5800–5806.
Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C et al. (2008). Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 14: 1333–1342.
Nasr R, Lallemand-Breitenbach V, Zhu J, Guillemin MC, de The H . (2009). Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure. Clin Cancer Res 15: 6321–6326.
Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al. (2005). Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 11: 77–84.
Nesterov A, Ivashchenko Y, Kraft AS . (2002). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in normal prostate epithelial cells. Oncogene 21: 1135–1140.
Newsom-Davis T, Prieske S, Walczak H . (2009). Is TRAIL the holy grail of cancer therapy? Apoptosis 14: 607–623.
Nitsch R, Bechmann I, Deisz RA, Haas D, Lehmann TN, Wendling U et al. (2000). Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356: 827–828.
Noteborn MH . (2009). Proteins selectively killing tumor cells. Eur J Pharmacol 625: 165–173.
Nuesch JP, Bar S, Rommelaere J . (2008). Viral proteins killing tumor cells: new weapons in the fight against cancer. Cancer Biol Ther 7: 1374–1376.
Nuesch JP, Rommelaere J . (2006). NS1 interaction with CKII alpha: novel protein complex mediating parvovirus-induced cytotoxicity. J Virol 80: 4729–4739.
Nuesch JP, Rommelaere J . (2007). A viral adaptor protein modulating casein kinase II activity induces cytopathic effects in permissive cells. Proc Natl Acad Sci USA 104: 12482–12487.
O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B et al. (2007). Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25: 1114–1120.
Ovcharenko D, Kelnar K, Johnson C, Leng N, Brown D . (2007). Genome-scale microRNA and small interfering RNA screens identify small RNA modulators of TRAIL-induced apoptosis pathway. Cancer Res 67: 10782–10788.
Ozoren N, Kim K, Burns TF, Dicker DT, Moscioni AD, El-Deiry WS . (2000). The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 60: 6259–6265.
Pallasch CP, Patz M, Park YJ, Hagist S, Eggle D, Claus R et al. (2009). miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood 114: 3255–3264.
Pavet V, Beyrath J, Pardin C, Morizot A, Lechner MC, Briand JP et al. (2010). Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer Res 70: 1101–1110.
Peng DJ, Sun J, Wang YZ, Tian J, Zhang YH, Noteborn MH et al. (2007). Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor. Cancer Gene Ther 14: 66–73.
Persson H, Kvist A, Vallon-Christersson J, Medstrand P, Borg A, Rovira C . (2009). The non-coding RNA of the multidrug resistance-linked vault particle encodes multiple regulatory small RNAs. Nat Cell Biol 11: 1268–1271.
Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett R et al. (2007). Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 13: 6187–6194.
Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C et al. (2005). HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 92: 1430–1441.
Qin J, Chaturvedi V, Bonish B, Nickoloff BJ . (2001). Avoiding premature apoptosis of normal epidermal cells. Nat Med 7: 385–386.
Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . (2008). Efficient tumour formation by single human melanoma cells. Nature 456: 593–598.
Rana TM . (2007). Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8: 23–36.
Ravi R, Bedi GC, Engstrom LW, Zeng Q, Mookerjee B, Gelinas C et al. (2001). Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB. Nat Cell Biol 3: 409–416.
Rohn JL, Noteborn MH . (2004). The viral death effector Apoptin reveals tumor-specific processes. Apoptosis 9: 315–322.
Sarkar D, Dent P, Curiel DT, Fisher PB . (2008). Acquired and innate resistance to the cancer-specific apoptosis-inducing cytokine, mda-7/IL-24: not insurmountable therapeutic problems. Cancer Biol Ther 7: 109–112.
Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M et al. (2008). Identification of cells initiating human melanomas. Nature 451: 345–349.
Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM et al. (2005). The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 115: 2159–2168.
Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A et al. (2009). Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461: 809–813.
Shankaranarayanan P, Rossin A, Khanwalkar H, Alvarez S, Alvarez R, Jacobson A et al. (2009). Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by no. Cancer Cell 16: 220–231.
Shanker M, Gopalan B, Patel S, Bocangel D, Chada S, Ramesh R et al. (2007). Vitamin E succinate in combination with mda-7 results in enhanced human ovarian tumor cell killing through modulation of extrinsic and intrinsic apoptotic pathways. Cancer Lett 254: 217–226.
Shi Y, Whetstine JR . (2007). Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25: 1–14.
Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J et al. (2007). Molecular definition of breast tumor heterogeneity. Cancer Cell 11: 259–273.
Shipley JL, Butera JN . (2009). Acute myelogenous leukemia. Exp Hematol 37: 649–658.
Shtivelman E, Lifshitz B, Gale RP, Canaani E . (1985). Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315: 550–554.
Sieger KA, Mhashilkar AM, Stewart A, Sutton RB, Strube RW, Chen SY et al. (2004). The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 9: 355–367.
Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N et al. (2001). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 193: 661–670.
Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ et al. (1998). Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339: 1341–1348.
Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M . (2009). The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4: 1568–1582.
Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L et al. (2000). PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci USA 97: 12216–12221.
Steele AJ, Jones DT, Ganeshaguru K, Duke VM, Yogashangary BC, North JM et al. (2006). The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 20: 1073–1079.
Sun J, Yan Y, Wang XT, Liu XW, Peng DJ, Wang M et al. (2009). PTD4-apoptin protein therapy inhibits tumor growth in vivo. Int J Cancer 124: 2973–2981.
Sun Y, Wu J, Aboukameel A, Banerjee S, Arnold AA, Chen J et al. (2008). Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. Cancer Biol Ther 7: 1418–1426.
Svanborg C, Agerstam H, Aronson A, Bjerkvig R, Duringer C, Fischer W et al. (2003). HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. Adv Cancer Res 88: 1–29.
Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al. (2001). Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7: 94–100.
Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H et al. (2002). Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195: 161–169.
Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE et al. (2004). Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 199: 437–448.
Tan ML, Ooi JP, Ismail N, Moad AIH, Muhammad TST . (2009). Programmed cell death pathways and current antitumor targets. Pharm Res 26: 1547–1559.
Tennant DA, Duran RV, Gottlieb E . (2010). Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10: 267–277.
Thibert C, Fombonne J . (2010). Dependence receptors: mechanisms of an announced death. Cell Cycle 9: 2085–2091.
Thorburn A, Behbakht K, Ford H . (2008). TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them. Drug Resist Updat 11: 17–24.
Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic K et al. (2007). Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 25: 1390–1395.
Trarbach T, Moehler M, Heinemann V, Kohne CH, Przyborek M, Schulz C et al. (2010). Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102: 506–512.
Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D et al. (2006). TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 25: 7434–7439.
Tsimberidou AM, Tirado-Gomez M, Andreeff M, O'Brien S, Kantarjian H, Keating M et al. (2006). Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma 47: 1062–1068.
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B et al. (2007). Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25: 1658–1664.
van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. (2005). High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 11: 6520–6527.
Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M, Vucic D et al. (2005). Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem 280: 40599–40608.
Vasudevan S, Tong Y, Steitz JA . (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science 318: 1931–1934.
Vilimanovich U, Bumbasirevic V . (2008). TRAIL induces proliferation of human glioma cells by c-FLIPL-mediated activation of ERK1/2. Cell Mol Life Sci 65: 814–826.
Volkmann X, Fischer U, Bahr MJ, Ott M, Lehner F, Macfarlane M et al. (2007). Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver. Hepatology 46: 1498–1508.
Wakelee HA, Patnaik A, Sikic BI, Mita M, Fox NL, Miceli R et al. (2010). Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol 21: 376–381.
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M et al. (1999). Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5: 157–163.
Wang M, Liang P . (2005). Interleukin-24 and its receptors. Immunology 114: 166–170.
Warrell Jr RP, de The H, Wang ZY, Degos L . (1993). Acute promyelocytic leukemia. N Engl J Med 329: 177–189.
Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL et al. (2005). Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37: 853–862.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ et al. (2007). The genomic landscapes of human breast and colorectal cancers. Science 318: 1108–1113.
Xu WS, Parmigiani RB, Marks PA . (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26: 5541–5552.
Yamashita N, Osato M, Huang L, Yanagida M, Kogan SC, Iwasaki M et al. (2005). Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. Br J Haematol 131: 495–507.
Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M et al. (2008). Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 14: 135–145.
Yarden Y, Ullrich A . (1988). Growth factor receptor tyrosine kinases. Annu Rev Biochem 57: 443–478.
Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ et al. (2001). AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA 98: 10398–10403.
Zeisig BB, Kwok C, Zelent A, Shankaranarayanan P, Gronemeyer H, Dong S et al. (2007). Recruitment of RXR by homotetrameric RARalpha fusion proteins is essential for transformation. Cancer Cell 12: 36–51.
Zerafa N, Westwood JA, Cretney E, Mitchell S, Waring P, Iezzi M et al. (2005). Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol 175: 5586–5590.
Zhang J, Yang PL, Gray NS . (2009). Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9: 28–39.
Zhang L, Fang B . (2005). Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12: 228–237.
Zhang L, Ren X, Alt E, Bai X, Huang S, Xu Z et al. (2010). Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis. Nature 464: 1058–1061.
Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M et al. (2007). FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25: 3712–3718.
Zhenchuk A, Lotfi K, Juliusson G, Albertioni F . (2009). Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol 78: 1351–1359.
Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB et al. (2009). Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8: 806–823.
Acknowledgements
Work in our laboratory is supported by Agence Nationale de la Recherche (ANR-07-PCVI-0031-01), the European Commission (LSHC-CT-2005-518417 ‘Epitron,’ HEALTH-F4-2007-200767 ‘Apo-Sys,’ H Gronemeyer laboratory), La Ligue Contre le Cancer (H Gronemeyer, laboratoire labellisée; MMP postdoctoral fellow) and Fondation pour la Recherche Médicale (JCM master fellow).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Pavet, V., Portal, M., Moulin, J. et al. Towards novel paradigms for cancer therapy. Oncogene 30, 1–20 (2011). https://doi.org/10.1038/onc.2010.460
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.460
Keywords
This article is cited by
-
Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses
Nature Biomedical Engineering (2018)
-
Dual role of DR5 in death and survival signaling leads to TRAIL resistance in cancer cells
Cell Death & Disease (2017)
-
Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species
Investigational New Drugs (2017)
-
Anti-tumor activity of SL4 against breast cancer cells: induction of G2/M arrest through modulation of the MAPK-dependent p21 signaling pathway
Scientific Reports (2016)
-
Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells
Cell Death & Disease (2014)
