**16. References**


Cell Death and Cancer, Novel Therapeutic Strategies 99

[20] Huang H, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD, Hunter T (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in

[21] Suzuki Y, Nakabayashi Y, Takahashi R (2001) Ubiquitin-protein ligase activity of Xlinked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death.

[22] Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C (2003) Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates

[25] Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber AO, Newell MK, et al. (2007) The

[26] Lavrik I, Golks A, Krammer PH (2005) Death receptor signaling. J.Cell Sci.118: 265-267. [27] Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science

[28] Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane

[29] Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell

[30] Chinnaiyan AM, Tepper CG, Seldin MF, O'Rourke K, Kischkel FC, Hellbardt S, et al. (1996) FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis

[31] Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxininduced serum factor that causes necrosis of tumors. Proc.Natl.Acad.Sci.U.S.A ;72: 3666-

[32] Schievella AR, Chen JH, Graham JR, Lin LL (1997) MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates

[33] Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, et al. (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science ;275: 1129-1132. [34] Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat.Rev.Mol.Cell Biol.11:

[35] Galluzzi L, Zamzami N, de La Motte RT, Lemaire C, Brenner C, Kroemer G (2007) Methods for the assessment of mitochondrial membrane permeabilization in apoptosis.

[36] Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and

[23] Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell ;116: 205-219. [24] Meier P, Vousden KH (2007) Lucifer's labyrinth--ten years of path finding in cell death.

vitro monoubiquitination of caspases 3 and 7. J.Biol.Chem.275: 26661-26664.

Proc.Natl.Acad.Sci.U.S.A ;98: 8662-8667.

surface death receptors. Cell ;94: 481-490.

Mol.Cell ;28: 746-754.

;305: 626-629.

3670.

700-714.

Apoptosis.12: 803-813.

therapy. Oncogene ;26: 1324-1337.

caspase activity in apoptosis. Genes Dev.17: 1487-1496.

CD95 receptor: apoptosis revisited. Cell ;129: 447-450.

permeabilization and beyond. Nat.Rev.Mol.Cell Biol.11: 621-632.

factor receptor-induced apoptosis. J.Biol.Chem.271: 4961-4965.

mitogen-activated protein kinase. J.Biol.Chem.272: 12069-12075.


[20] Huang H, Joazeiro CA, Bonfoco E, Kamada S, Leverson JD, Hunter T (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J.Biol.Chem.275: 26661-26664.

98 Apoptosis and Medicine

**16. References** 

[1] Vaux DL, Korsmeyer SJ (1999) Cell death in development. Cell ;96: 245-254.

phagocytes carry apoptotic cells to the grave. Essays Biochem.39: 105-117.

wide-ranging implications in tissue kinetics. Br.J.Cancer ;26: 239-257.

programmed lymphocyte death in vivo. J.Exp.Med.181: 1661-1672.

a requiem performed in different keys. Apoptosis.11: 889-904.

relevance in cancer. Ann.Hematol.84: 627-639.

Cell Death 2009. Cell Death.Differ.16: 3-11.

of Bcl-2 and Abl. J.Exp.Med.182: 1545-1556.

Int.Rev.Cytol.68: 251-306.

Am.J.Pathol.146: 3-15.

cell death. Physiol Rev.87: 99-163.

C. elegans. Cell ;44: 817-829.

J.Biol.Chem.284: 21777-21781.

Cycle ;6: 686-695.

70-77.

[2] Vermeulen K, Van Bockstaele DR, Berneman ZN (2005) Apoptosis: mechanisms and

[3] deCathelineau AM, Henson PM (2003) The final step in programmed cell death:

[4] Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with

[5] Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. (2009) Classification of cell death: recommendations of the Nomenclature Committee on

[6] Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis.

[7] Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere JL, Petit PX, et al. (1995) Reduction in mitochondrial potential constitutes an early irreversible step of

[8] Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. (1995) Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression

[9] Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death.

[10] Hail N, Jr., Carter BZ, Konopleva M, Andreeff M (2006) Apoptosis effector mechanisms:

[11] Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. (2012) Molecular definitions of cell death subroutines: recommendations of the

[12] Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in

[13] Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode

[14] Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science ;281: 1312-1316. [15] Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation.

[16] Kumar S (2007) Caspase function in programmed cell death. Cell Death.Differ.14: 32-43. [17] Blank M, Shiloh Y (2007) Programs for cell death: apoptosis is only one way to go. Cell

[18] Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem.J.326 ( Pt 1): 1-16. [19] Tenev T, Zachariou A, Wilson R, Ditzel M, Meier P (2005) IAPs are functionally nonequivalent and regulate effector caspases through distinct mechanisms. Nat.Cell Biol.7:

Nomenclature Committee on Cell Death 2012. Cell Death.Differ.19: 107-120.


[37] Bidere N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, et al. (2003) Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J.Biol.Chem.278: 31401-31411.

Cell Death and Cancer, Novel Therapeutic Strategies 101

[52] Vousden KH, Lu X (2002) Live or let die: the cell's response to p53. Nat.Rev.Cancer ;2:

[53] Berube C, Boucher LM, Ma W, Wakeham A, Salmena L, Hakem R, et al. (2005) Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the

[54] Janssens S, Tinel A (2012) The PIDDosome, DNA-damage-induced apoptosis and

[55] Bouchier-Hayes L, Lartigue L, Newmeyer DD (2005) Mitochondria: pharmacological

[56] Yu Q (2006) Restoring p53-mediated apoptosis in cancer cells: new opportunities for

[57] Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J.Biol.Chem.278:

[58] Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease

[59] Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death.Differ.14: 1576-1582. [60] Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families.

[61] Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y (2002) An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome cindependent activation of caspase-9 by caspase-12. J.Biol.Chem.277: 34287-34294. [62] Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, del RG, et al. (2002) Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-

[63] Jimbo A, Fujita E, Kouroku Y, Ohnishi J, Inohara N, Kuida K, et al. (2003) ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation.

[64] Fehrenbacher N, Jaattela M (2005) Lysosomes as targets for cancer therapy. Cancer

[65] Deacon EM, Pongracz J, Griffiths G, Lord JM (1997) Isoenzymes of protein kinase C: differential involvement in apoptosis and pathogenesis. Mol.Pathol.50: 124-131. [66] Kharbanda S, Saxena S, Yoshida K, Pandey P, Kaneki M, Wang Q, et al. (2000) Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response

[67] Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature

[68] Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces

[69] Gourlay CW, Ayscough KR (2005) The actin cytoskeleton: a key regulator of apoptosis

relevance and therapeutic opportunities. Nat.Rev.Drug Discov.7: 1013-1030.

Activation of caspase-12 by calpain in apoptosis. J.Cell Biol.150: 887-894.

independent intrinsic pathway. J.Biol.Chem.277: 21836-21842.

death adapter protein RAIDD. Proc.Natl.Acad.Sci.U.S.A ;102: 14314-14320.

594-604.

48872-48879.

Exp.Cell Res.283: 156-166.

to DNA damage. J.Biol.Chem.275: 322-327.

and ageing? Nat.Rev.Mol.Cell Biol.6: 583-589.

apoptosis. J.Cell Biol.124: 619-626.

Res.65: 2993-2995.

;401: 82-85.

beyond. Cell Death.Differ.19: 13-20.

cancer therapy. Drug Resist.Updat.9: 19-25.

manipulation of cell death. J.Clin.Invest ;115: 2640-2647.


[52] Vousden KH, Lu X (2002) Live or let die: the cell's response to p53. Nat.Rev.Cancer ;2: 594-604.

100 Apoptosis and Medicine

J.Biol.Chem.278: 31401-31411.

Lett.567: 111-115.

J.Biol.Chem.278: 6243-6250.

J.Biol.Chem.287: 12612-12621.

J.Biol.Chem.279: 50295-50301.

inducing factor. Science ;297: 259-263.

ped/pea-15. J.Biol.Chem.279: 46566-46572.

AIF during cell death. Cell Death.Differ.15: 1857-1864.

Proc.Natl.Acad.Sci.U.S.A ;98: 14985-14990.

[37] Bidere N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, et al. (2003) Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis.

[38] Cirman T, Oresic K, Mazovec GD, Turk V, Reed JC, Myers RM, et al. (2004) Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by

[39] Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ, Ley TJ (2001) Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK.

[40] Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell ;91: 231-241. [41] Donovan M, Cotter TG (2004) Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death. Biochim.Biophys.Acta ;1644: 133-147. [42] Belizario JE, Alves J, Occhiucci JM, Garay-Malpartida M, Sesso A (2007) A mechanistic view of mitochondrial death decision pores. Braz.J.Med.Biol.Res.40: 1011-1024. [43] Szabadkai G, Rizzuto R (2004) Participation of endoplasmic reticulum and mitochondrial calcium handling in apoptosis: more than just neighborhood? FEBS

[44] Thomenius MJ, Wang NS, Reineks EZ, Wang Z, Distelhorst CW (2003) Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3-only proteins.

[45] Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in

[46] Wang D, Liang J, Zhang Y, Gui B, Wang F, Yi X, et al. (2012) Steroid Receptor Coactivator-interacting Protein (SIP) Inhibits Caspase-independent Apoptosis by Preventing Apoptosis-inducing Factor (AIF) from Being Released from Mitochondria.

[47] Norberg E, Gogvadze V, Ott M, Horn M, Uhlen P, Orrenius S, et al. (2008) An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release

[48] Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, et al. (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-

[49] Trencia A, Fiory F, Maitan MA, Vito P, Barbagallo AP, Perfetti A, et al. (2004) Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein

[50] Cilenti L, Soundarapandian MM, Kyriazis GA, Stratico V, Singh S, Gupta S, et al. (2004) Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death.

[51] Vande WL, Wirawan E, Lamkanfi M, Festjens N, Verspurten J, Saelens X, et al. (2010) The mitochondrial serine protease HtrA2/Omi cleaves RIP1 during apoptosis of Ba/F3

cells induced by growth factor withdrawal. Cell Res.20: 421-433.

cell-free extracts: requirement for dATP and cytochrome c. Cell ;86: 147-157.

multiple papain-like lysosomal cathepsins. J.Biol.Chem.279: 3578-3587.


[70] Day CL, Puthalakath H, Skea G, Strasser A, Barsukov I, Lian LY, et al. (2004) Localization of dynein light chains 1 and 2 and their pro-apoptotic ligands. Biochem.J.377: 597-605.

Cell Death and Cancer, Novel Therapeutic Strategies 103

[89] Vanlangenakker N, Vanden Berghe T, Vandenabeele P (2012) Many stimuli pull the

[90] Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, et al. (2011) cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell

[92] Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed

[93] Dunai Z, Bauer PI, Mihalik R (2011) Necroptosis: biochemical, physiological and

[94] Martinez-Lacaci I, Garcia MP, Soto JL, Saceda M (2007) Tumour cells resistance in

[96] Hersey P, Zhang XD (2003) Overcoming resistance of cancer cells to apoptosis. J.Cell

[97] Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature ;348:

[98] Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM (1984) Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome

[99] Vaux DL, Cory S, Adams JM (1988) Bcl-2 gene promotes haemopoietic cell survival and

[100] Strasser A, Harris AW, Bath ML, Cory S (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature ;348: 331-333. [101] Strasser A, Cory S, Adams JM (2011) Deciphering the rules of programmed cell death

[102] Plati J, Bucur O, Khosravi-Far R (2011) Apoptotic cell signaling in cancer progression

[103] Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator

[104] Tagawa H, Karnan S, Suzuki R, Matsuo K, Zhang X, Ota A, et al. (2005) Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of

[105] Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. (2010) The landscape of somatic copy-number alteration across human cancers. Nature ;463:

death complex differentially regulated by cFLIP isoforms. Mol.Cell ;43: 449-463. [91] Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, et al. (2011) The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and

necrotic trigger, an overview. Cell Death.Differ.19: 75-86.

necrosis and virus-induced inflammation. Cell ;137: 1112-1123.

[95] Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell ;100: 57-70.

cooperates with c-myc to immortalize pre-B cells. Nature ;335: 440-442.

to improve therapy of cancer and other diseases. EMBO J.30: 3667-3683.

pathological aspects. Pathol.Oncol.Res.17: 791-800.

cancer therapy. Clin.Transl.Oncol.9: 13-20.

translocation. Science ;226: 1097-1099.

and therapy. Integr.Biol.(Camb.) ;3: 279-296.

the proapoptotic gene BIM. Oncogene ;24: 1348-1358.

phenotype. Science ;275: 967-969.

Physiol ;196: 9-18.

334-336.

899-905.

loss of IAPs. Mol.Cell ;43: 432-448.


[89] Vanlangenakker N, Vanden Berghe T, Vandenabeele P (2012) Many stimuli pull the necrotic trigger, an overview. Cell Death.Differ.19: 75-86.

102 Apoptosis and Medicine

Biochem.J.377: 597-605.

VDAC. Oncogene ;19: 4807-4814.

[70] Day CL, Puthalakath H, Skea G, Strasser A, Barsukov I, Lian LY, et al. (2004) Localization of dynein light chains 1 and 2 and their pro-apoptotic ligands.

[71] Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, et al. (2000) Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing

[72] Tang HL, Le AH, Lung HL (2006) The increase in mitochondrial association with actin

[73] Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG (1993) Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of

[74] Oliver FJ, Menissier-de MJ, de MG (1999) Poly(ADP-ribose) polymerase in the cellular response to DNA damage, apoptosis, and disease. Am.J.Hum.Genet.64: 1282-1288. [75] Guillouf C, Wang TS, Liu J, Walsh CE, Poirier GG, Moustacchi E, et al. (1999) Fanconi anemia C protein acts at a switch between apoptosis and necrosis in mitomycin C-

[76] Munoz-Gamez JA, Rodriguez-Vargas JM, Quiles-Perez R, Aguilar-Quesada R, Martin-Oliva D, de MG, et al. (2009) PARP-1 is involved in autophagy induced by DNA

[77] Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial

[78] Long JS, Ryan KM (2012) New frontiers in promoting tumour cell death: targeting

[79] Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in

[80] Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat.Rev.Mol.Cell Biol.10: 458-467. [81] Tanida I, Ueno T, Kominami E (2004) LC3 conjugation system in mammalian

[82] Mijaljica D, Prescott M, Devenish RJ (2011) Microautophagy in mammalian cells:

[83] Majeski AE, Dice JF (2004) Mechanisms of chaperone-mediated autophagy.

[84] Tanida I (2011) Autophagosome formation and molecular mechanism of autophagy.

[85] Yen WL, Klionsky DJ (2008) How to live long and prosper: autophagy, mitochondria,

[86] Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene ;23: 2825-2837. [87] Niikura Y, Dixit A, Scott R, Perkins G, Kitagawa K (2007) BUB1 mediation of caspase-

[88] Vitale I, Galluzzi L, Castedo M, Kroemer G (2011) Mitotic catastrophe: a mechanism for

independent mitotic death determines cell fate. J.Cell Biol.178: 283-296.

avoiding genomic instability. Nat.Rev.Mol.Cell Biol.12: 385-392.

precedes Bax translocation in apoptosis. Biochem.J.396: 1-5.

chemotherapy-induced apoptosis. Cancer Res.53: 3976-3985.

AIF: a key event in parthanatos. Exp.Neurol.218: 193-202.

apoptosis, necroptosis and autophagy. Oncogene .

less than a decade. Nat.Rev.Mol.Cell Biol.8: 931-937.

autophagy. Int.J.Biochem.Cell Biol.36: 2503-2518.

and aging. Physiology.(Bethesda.) ;23: 248-262.

Int.J.Biochem.Cell Biol.36: 2435-2444.

Antioxid.Redox.Signal.14: 2201-2214.

revisiting a 40-year-old conundrum. Autophagy.7: 673-682.

induced cell death. Exp.Cell Res.246: 384-394.

damage. Autophagy.5: 61-74.


[106] Garrison SP, Jeffers JR, Yang C, Nilsson JA, Hall MA, Rehg JE, et al. (2008) Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol.Cell Biol.28: 5391-5402.

Cell Death and Cancer, Novel Therapeutic Strategies 105

[123] Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and

[124] Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase

[125] Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in

[126] Haddad JJ, Abdel-Karim NE (2011) NF-kappaB cellular and molecular regulatory mechanisms and pathways: therapeutic pattern or pseudoregulation? Cell

[127] Hafsi S, Pezzino FM, Candido S, Ligresti G, Spandidos DA, Soua Z, et al. (2012) Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance

[128] Zitvogel L, Apetoh L, Ghiringhelli F, Andre F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success? J.Clin.Invest ;118:

[129] Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. (2012) A novel pathway combining calreticulin exposure and ATP secretion in immunogenic

[130] Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L, et al. (2008) Molecular characteristics of immunogenic cancer cell death. Cell Death.Differ.15: 3-12. [131] Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, et al. (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers

[132] Chao MP, Weissman IL, Majeti R (2012) The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr.Opin.Immunol.24: 225-

[133] Leontieva OV, Gudkov AV, Blagosklonny MV (2010) Weak p53 permits senescence

[136] Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di BS, Nardacci R, et al. (2007) Ambra1 regulates autophagy and development of the nervous system. Nature ;447:

[137] Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH, et al. (2006) Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat.Cell Biol.8:

[138] Mehrpour M, Esclatine A, Beau I, Codogno P (2010) Overview of macroautophagy

[139] Ku B, Woo JS, Liang C, Lee KH, Jung JU, Oh BH (2008) An insight into the mechanistic role of Beclin 1 and its inhibition by prosurvival Bcl-2 family proteins. Autophagy.4:

[134] Rodier F, Campisi J (2011) Four faces of cellular senescence. J.Cell Biol.192: 547-556. [135] Schmitt CA (2007) Cellular senescence and cancer treatment. Biochim.Biophys.Acta

regulation of Akt/PKB by the rictor-mTOR complex. Science ;307: 1098-1101.

pathway in cancer. Nat.Rev.Drug Discov.8: 627-644.

human cancer. Nat.Rev.Cancer ;2: 489-501.

Immunol.271: 5-14.

1991-2001.

232.

;1775: 5-20.

1121-1125.

688-699.

519-520.

(review). Int.J.Oncol.40: 639-644.

cancer cell death. EMBO J.31: 1062-1079.

and is counterbalanced by CD47. Sci.Transl.Med.2: 63ra94.

during cell cycle arrest. Cell Cycle ;9: 4323-4327.

regulation in mammalian cells. Cell Res.20: 748-762.


[123] Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science ;307: 1098-1101.

104 Apoptosis and Medicine

617-623.

646-674.

Signal.23: 1515-1527.

Cancer Res.59: 3143-3151.

by survivin targeting. Am.J.Pathol.158: 1757-1765.

Biochem.Biophys.Res.Commun.414: 445-450.

anti-cancer therapies. Front Pharmacol.3: 9.

Biol.28: 5391-5402.

Burkitt lymphoma. Blood ;116: 2531-2542.

promise. Clin.Cancer Res.16: 4496-4502.

XIAP. Cell Death.Differ.19: 42-50.

[106] Garrison SP, Jeffers JR, Yang C, Nilsson JA, Hall MA, Rehg JE, et al. (2008) Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol.Cell

[107] Richter-Larrea JA, Robles EF, Fresquet V, Beltran E, Rullan AJ, Agirre X, et al. (2010) Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in

[108] Kashkar H (2010) X-linked inhibitor of apoptosis: a chemoresistance factor or a hollow

[109] Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and

[110] Mita AC, Mita MM, Nawrocki ST, Giles FJ (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin.Cancer Res.14: 5000-5005. [111] Reichert S, Rodel C, Mirsch J, Harter PN, Tomicic MT, Mittelbronn M, et al. (2011) Survivin inhibition and DNA double-strand break repair: a molecular mechanism to

[112] Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, et al. (2000) High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene ;19:

[113] Hattori M, Sakamoto H, Satoh K, Yamamoto T (2001) DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the

[114] Li F, Altieri DC (1999) The cancer antiapoptosis mouse survivin gene: characterization of locus and transcriptional requirements of basal and cell cycle-dependent expression.

[115] Mesri M, Morales-Ruiz M, Ackermann EJ, Bennett CF, Pober JS, Sessa WC, et al. (2001) Suppression of vascular endothelial growth factor-mediated endothelial cell protection

[116] Zaffaroni N, Daidone MG (2002) Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist.Updat.5: 65-72. [117] Rufini A, Melino G (2011) Cell death pathology: the war against cancer.

[118] Li G, Ho VC (1998) p53-dependent DNA repair and apoptosis respond differently to

[119] Gabrielli B, Brooks K, Pavey S (2012) Defective cell cycle checkpoints as targets for

[120] Roos WP, Kaina B (2012) DNA damage-induced apoptosis: From specific DNA lesions

[121] Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell ;144:

[122] Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell

high- and low-dose ultraviolet radiation. Br.J.Dermatol.139: 3-10.

to the DNA damage response and apoptosis. Cancer Lett.

overcome radioresistance in glioblastoma. Radiother.Oncol.101: 51-58.

promoter region of c-erbB-2 and survivin genes. Cancer Lett.169: 155-164.


[140] Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature ;402: 672- 676.

Cell Death and Cancer, Novel Therapeutic Strategies 107

[155] Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell ;122: 927-939. [156] Maiuri MC, Le TG, Criollo A, Rain JC, Gautier F, Juin P, et al. (2007) Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J.26:

[157] Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. (2007) Autophagy suppresses tumor progression by limiting chromosomal instability. Genes

[158] Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis.

[159] Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M, et al. (2008) Regulation of autophagy by cytoplasmic p53. Nat.Cell Biol.10: 676-687. [160] Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev.20: 1-15. [161] Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation

[162] Vakkila J, Lotze MT (2004) Inflammation and necrosis promote tumour growth.

[163] Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and

[164] Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. (2005) Inhibition of macroautophagy triggers apoptosis. Mol.Cell Biol.25: 1025-1040. [165] Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the

[166] Mazure NM, Pouyssegur J (2010) Hypoxia-induced autophagy: cell death or cell

[167] Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, et al. (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of

[168] Rabinowitz JD, White E (2010) Autophagy and metabolism. Science ;330: 1344-1348. [169] Fung C, Lock R, Gao S, Salas E, Debnath J (2008) Induction of autophagy during extracellular matrix detachment promotes cell survival. Mol.Biol.Cell ;19: 797-806. [170] Kenific CM, Thorburn A, Debnath J (2010) Autophagy and metastasis: another double-

[171] Debnath J (2008) Detachment-induced autophagy during anoikis and lumen formation

[172] Yerbes R, Palacios C, Lopez-Rivas A (2011) The therapeutic potential of TRAIL

[173] Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science

BNIP3 and BNIP3L via their BH3 domains. Mol.Cell Biol.29: 2570-2581.

receptor signalling in cancer cells. Clin.Transl.Oncol.13: 839-847.

in the initiation and promotion of malignant disease. Cancer Cell ;7: 211-217.

2527-2539.

Dev.21: 1367-1381.

Genes Dev.21: 1621-1635.

Nat.Rev.Immunol.4: 641-648.

tumorigenesis. Cancer Cell ;10: 51-64.

response to hypoxic stress. Mol.Cell ;40: 294-309.

survival? Curr.Opin.Cell Biol.22: 177-180.

edged sword. Curr.Opin.Cell Biol.22: 241-245.

in epithelial acini. Autophagy.4: 351-353.

;281: 1305-1308.


[155] Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell ;122: 927-939.

106 Apoptosis and Medicine

676.

2670.

;112: 1809-1820.

Nat.Cell Biol.9: 1142-1151.

[140] Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature ;402: 672-

[141] Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

[142] Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J.Clin.Invest

[143] Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated

[144] Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis.

[145] Ionov Y, Nowak N, Perucho M, Markowitz S, Cowell JK (2004) Manipulation of nonsense mediated decay identifies gene mutations in colon cancer Cells with

[146] Kim MS, Jeong EG, Ahn CH, Kim SS, Lee SH, Yoo NJ (2008) Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite

[147] Bekri S, Adelaide J, Merscher S, Grosgeorge J, Caroli-Bosc F, Perucca-Lostanlen D, et al. (1997) Detailed map of a region commonly amplified at 11q13-->q14 in human breast

[148] Lee JW, Jeong EG, Soung YH, Nam SW, Lee JY, Yoo NJ, et al. (2006) Decreased expression of tumour suppressor Bax-interacting factor-1 (Bif-1), a Bax activator, in

[149] Coppola D, Khalil F, Eschrich SA, Boulware D, Yeatman T, Wang HG (2008) Downregulation of Bax-interacting factor-1 in colorectal adenocarcinoma. Cancer ;113: 2665-

[150] Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, et al. (2001) Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-

[151] Yang YP, Liang ZQ, Gu ZL, Qin ZH (2005) Molecular mechanism and regulation of

[152] Gozuacik D, Kimchi A (2004) Autophagy as a cell death and tumor suppressor

[153] Samuels Y, Velculescu VE (2004) Oncogenic mutations of PIK3CA in human cancers.

[154] Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G, et al. (2000) Bcl-2 downregulation causes autophagy in a caspase-independent manner in human leukemic

containing protein that associates with Bax. J.Biol.Chem.276: 20559-20565.

protein kinase and Beclin 1 in mediating autophagy. Circ.Res.100: 914-922.

Proc.Natl.Acad.Sci.U.S.A ;100: 15077-15082.

microsatellite instability. Oncogene ;23: 639-645.

carcinoma. Cytogenet.Cell Genet.79: 125-131.

gastric carcinomas. Pathology ;38: 312-315.

autophagy. Acta Pharmacol.Sin.26: 1421-1434.

mechanism. Oncogene ;23: 2891-2906.

HL60 cells. Cell Death.Differ.7: 1263-1269.

Cell Cycle ;3: 1221-1224.

instability. Hum.Pathol.39: 1059-1063.


[174] Nguyen T, Zhang XD, Hersey P (2001) Relative resistance of fresh isolates of melanoma to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Clin.Cancer Res.7: 966s-973s.

Cell Death and Cancer, Novel Therapeutic Strategies 109

[190] Chen DJ, Huerta S (2009) Smac mimetics as new cancer therapeutics. Anticancer Drugs

[191] Straub CS (2011) Targeting IAPs as an approach to anti-cancer therapy.

[192] Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-

[193] Kaelin WG, Jr. (2009) Synthetic lethality: a framework for the development of wiser

[194] Chan DA, Giaccia AJ (2011) Harnessing synthetic lethal interactions in anticancer drug

[195] Bolderson E, Richard DJ, Zhou BB, Khanna KK (2009) Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin.Cancer

[196] Dai Y, Grant S (2010) New insights into checkpoint kinase 1 in the DNA damage

[197] Calvert H, Azzariti A (2011) The clinical development of inhibitors of poly(ADP-

[198] Javle M, Curtin NJ (2011) The potential for poly (ADP-ribose) polymerase inhibitors in

[199] Imre G, Larisch S, Rajalingam K (2011) Ripoptosome: a novel IAP-regulated cell death-

[200] Safa AR, Pollok KE (2011) Targeting the Anti-Apoptotic Protein c-FLIP for Cancer

[201] Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat.Rev.Mol.Cell Biol.8: 741-752. [202] Chen N, Karantza-Wadsworth V (2009) Role and regulation of autophagy in cancer.

[203] Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L, et al. (2007) Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA

[204] Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A (2008) Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res.68: 1485-1494. [205] Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ (2005) Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to

[206] Esparis-Ogando A, Ocana A, Rodriguez-Barrueco R, Ferreira L, Borges J, Pandiella A (2008) Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-

[207] Ropero S, Menendez JA, Vazquez-Martin A, Montero S, Cortes-Funes H, Colomer R (2004) Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in

[208] Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. (2011) Pancreatic cancers

to overcome Bcr-Abl-mediated drug resistance. Blood ;110: 313-322.

trastuzumab resistance of breast cancer cells. Cancer Res.65: 11118-11128.

overexpressing breast cancer cells. Ann.Oncol.19: 1860-1869.

require autophagy for tumor growth. Genes Dev.25: 717-729.

breast carcinoma. Breast Cancer Res.Treat.86: 125-137.

kappaB, inflammation and cancer. Nat.Rev.Cancer ;10: 561-574.

response signaling network. Clin.Cancer Res.16: 376-383.

ribose) polymerase. Ann.Oncol.22 Suppl 1: i53-i59.

cancer therapy. Ther.Adv.Med.Oncol.3: 257-267.

signalling platform. J.Mol.Cell Biol.3: 324-326.

Therapy. Cancers.(Basel) ;3: 1639-1671.

Biochim.Biophys.Acta ;1793: 1516-1523.

;20: 646-658.

Res.15: 6314-6320.

Curr.Top.Med.Chem.11: 291-316.

cancer therapeutics. Genome Med.1: 99.

discovery. Nat.Rev.Drug Discov.10: 351-364.


[190] Chen DJ, Huerta S (2009) Smac mimetics as new cancer therapeutics. Anticancer Drugs ;20: 646-658.

108 Apoptosis and Medicine

apoptosis. Clin.Cancer Res.7: 966s-973s.

sword. Nat.Rev.Immunol.3: 745-756.

Future.Oncol.3: 263-271.

Death.Dis.1: e108.

;435: 677-681.

10967-10971.

as effector molecule. Nat.Immunol.1: 489-495.

domain protein FADD. J.Biol.Chem.279: 7925-7933.

apoptosis and autophagy. Cell Death.Dis.1: e76.

FEBS J.275: 1925-1936.

1475-1483.

paradigms for cancer therapy. Oncogene ;30: 1-20.

onset, progression and therapy. Nat.Rev.Cancer ;8: 782-798.

[174] Nguyen T, Zhang XD, Hersey P (2001) Relative resistance of fresh isolates of melanoma to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced

[175] Pavet V, Portal MM, Moulin JC, Herbrecht R, Gronemeyer H (2011) Towards novel

[176] Hetschko H, Voss V, Seifert V, Prehn JH, Kogel D (2008) Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL-induced apoptosis.

[177] Johnstone RW, Frew AJ, Smyth MJ (2008) The TRAIL apoptotic pathway in cancer

[178] Speirs CK, Hwang M, Kim S, Li W, Chang S, Varki V, et al. (2011) Harnessing the cell

[179] Martinez-Lostao L, Marzo I, Anel A, Naval J (2012) Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer. Biochem.Pharmacol.83:

[180] Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged

[181] Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP

[182] Vanden Berghe T, van LG, Saelens X, Van GM, Brouckaert G, Kalai M, et al. (2004) Differential signaling to apoptotic and necrotic cell death by Fas-associated death

[183] Tarhini AA, Kirkwood JM (2007) Oblimersen in the treatment of metastatic melanoma.

[184] Heidari N, Hicks MA, Harada H (2010) GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of

[185] McCoy F, Hurwitz J, McTavish N, Paul I, Barnes C, O'Hagan B, et al. (2010) Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK. Cell

[186] Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature

[187] van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces

[188] Cragg MS, Harris C, Strasser A, Scott CL (2009) Unleashing the power of inhibitors of

[189] Carrington EM, Vikstrom IB, Light A, Sutherland RM, Londrigan SL, Mason KD, et al. (2010) BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc.Natl.Acad.Sci.U.S.A ;107:

apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell ;10: 389-399.

oncogenic kinases through BH3 mimetics. Nat.Rev.Cancer ;9: 321-326.

death pathway for targeted cancer treatment. Am.J.Cancer Res.1: 43-61.


[209] Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev.25: 460-470.

**Chapter 5** 

© 2012 Marchal et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Marchal et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Apoptosis as a Therapeutic Target** 

**Novel Strategies and Futures Perspectives** 

María A. García, Esther Carrasco, Alberto Ramírez, Gema Jiménez,

Apoptosis is an essential part of the normal development. The homeostatic balance between cell proliferation and cell death rate is critical for maintaining normal physiological processes. Aberrant regulation of apoptotic cell death mechanisms is one of the hallmarks of cancer development and progression, and many cancer cells exhibit significant resistance to apoptosis signalling [1]. Triggering of apoptosis can be achieved via the activation of two distinct molecular pathways, the extrinsic or death receptor pathway or via the intrinsic or mitochondrial apoptotic cascades. Both pathways lead to the hierarchical activation of a family of cysteine proteases called caspases [2], that cleave a series of cellular substrates which induce changes including chromatin condensation, internucleosomal DNA fragmentation, membrane blebbing and cell shrinkage [3]. Extrinsic pathway is activated from outside the cell by proapoptotic ligands that interact with specialized cell surface death receptors, including CD95 and TNF-related apoptosis-inducing ligand (TRAIL) receptors [4]. After binding to receptors apoptosis is triggered by the intracellular formation of a death-inducing signalling complex (DISC) that consists of FAS-associated death domain (FADD) and procaspase-8 and 10 [5,6]. As a result, this protein complex activates procaspase-8 and 10 inside itself, hence triggering procaspase-3 to execute the apoptosis process [7]. The mitochondria (intrinsic) pathway is activated from inside the cell by severe cell stress, such as DNA or cytoskeletal damage, inducing mitochondrial outer membrane permeabilization and transcription or post-translational activation of BH3-only proapoptotic B-cell leukemia/lymphoma 2 (Bcl-2) family proteins [4]. This permeabilization allows the release of apoptogenic proteins, including cytochrome c and second mitochondria-derived

Joaquín Campos, Houria Boulaiz and Juan Antonio Marchal

**in Cancer and Cancer Stem Cells:** 

Elena López-Ruiz, Macarena Perán, Manuel Picón,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48267

**1. Introduction** 

