vivek singh m.sc. 3 rd sem centre of biotechnology uniersity of allahabad anoikis 1 “loss of...

VIVEK SINGH M.Sc. 3 rd sem Centre of Biotechnology Uniersity of allahabad ANOIKIS 1 LOSS OF HOME (Given by Frisch & Ruoslathi, 1997; Frisch & Screton,2001)

INTRODUCTION Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix. A greek word meaning loss of home or homelessness. Integrin receptors, mediates of cell-ECM integration, not only proide physical links with the cytoskeleton but also transduce signal from the ECM to the cell, mandatory for several cellular process including migration, proliferation & survival. Anoikis first described in epithelial & endothelial cells can be viewed as physiologically relevant process which insures development & tissue homeostasis. Anoikis acts as defence for the organism by preventing detached cells re-adhesion to new matrices in incorrect location & their dysplastic growth. Failure to executes the anoikis program could result in adherent cells surviving under suspension condition or proliferating at ectopic sites where the ECM protein are different from original ones.this deregulation in anoikis execution is emerging as a hallmark of cancer cells & contributes to formation of metastasis in distant organ. 2

CONTINUED The initiation & execution of anoikis is mediated by different pathway, all of which converge into activation of caspases & dowmstream molecular pathways, culminating in the activation of endonucleases, DNA fragmentation & cell death. The protein of Bcl-2 family are key players of both these process. The Bcl-2 family can be devided into three groups. 1-the antiapoptotic proteins, including Bcl-2, Bcl-XL & myeloid cell leukemia sequence 1(MCL-1). 2-The multidomain pro-apoptotic proteins Bax, Bak, Bok. 3-the proapoptotic BH-3 only protein counting Bid, Bad,Bim,Bik,Bmf,Noxa Puma,Hrk. 3

Two pathway of anoikis The intrinsic pathway perturbation of mitochondria. The extrinsic pathway- the triggering of cell surface death receptor. 5

THE INTRINSIC PATHWAY The intrinsic pathway is triggered in response to several intracellular signal, including DNA damage & ER stress, where mitochondria play central role with regard to control of apoptosis. The pro-apoptotic BH-3 only proteins act as critical players during the intrinsic cascade of anoikis program. Bid & Bim are activated by detachement of cells from ECM & rapidly promotes the assembly of Bax-Bak oligomers within outer mitochondrial membrane(OMM). These members of the BH-3 only protein. Bim is sequestered in the dynein cytoskeletal complexes until cell detachement induces release of Bim from these stuctures & causes its translocation to mitochondria. Loss of cell adhesion also causes Bim accumulation, through the inhibting of its proteasomal degradation initiated by an extracellular signal regulated kinase(ERK) & phosphoinositide-3-oh kinase(P13K)/Akt- mediated phosphorylation of Bim, elicted upon integrin engagement. 6

CONTINUED Another group of BH-3 only proteins are termed sensitizers & include Bad, Bik,Bmf,Noxa,Puma & Hrk. The sensitizers BH-3 only proteins are unable to directly activate Bax & Bak oligomerisation & contribute to cell death through the inactivation of anti-apoptotic function of Bcl-2 by competing for its BH-3 binding domain, thus freeing activators BH-3 only proteins to induce Bax, Bak oligomer formation. Bcl-2 is the master antiapoptotic members of the family which avoids mitochondrial dysfunction. Noxa & Puma are transcriptionally regulated by P53& have been implicated in fibroblast anoikis. In epithelial cells the Bcl-2 modifying factor(bmf) behaves as sentinelable to register damage at the cytoskeleton & to convey death signals. Upon cell detachment, Bmf is released from its previous interaction with the myosin5th motor complex & accumulates in the mitochondria,where it neutralizes Bcl-2 leading to cytochrome-C release & anoikis execution. 7

THE EXTRINSIC PATHWAY The extrinsic pathway is initiated by ligand binding of members of tumor necrosis factor receptor(TNFR) superfamily of death receptor such as Fas receptor{TNFR} superfamily of death receptor such as Fas receptor. TNFR1 & TNF-related apoptosis inducing ligand (TRAIL) receptor -1& 2resulting in the formation of death inducing signalling complex {DISC}. Caspase-8 Activation result in the the cleavage & activation of Bid, which in its truncated form(t-Bid) can prmote mitochondrial cyt-c release & assembly of apoptosome thus linking the extrinsic pathway to intrinsic one. Recent evidence reported that upon cell detachment from ECM, a mitochondrial protein named Bit-1 is released to cytoplasm & act as pro-apoptotic mediator inducing a caspase independent form of apoptosis. Change in cell shape can induce extrinsic anoikis. Indeed cell rounding following detachment could lead to induced proximity of Fas receptor resulting in their activation. 8

S.K. Alahari, P.J. Reddig, R.L. Juliano, Biological aspects of signal transduction by cell adhesion receptors. 9

PROTECTION FROM ANOIKIS IN PHYSIOLOGICAL CONDITION 1-CELL ADHESION TO ECM Epithelial cells are protected by anoikis when they are adherent on permissive ECM proteins. Role of integrins in suppression apoptosis in attached cells by elicting anti-apoptotic & prosurvival signal from ECM. Integrins are categorised depending on their or subunit composition. Integrins have different abilties to protect cell from apoptosis & anoikis by utilisation of diverse signalling pathway. Their downstream pathways or molecules are different & include FAK( focal adhesion kinase), src kinase, integrins linked kinase(ILK), P13K/Akt & mitogen activated protein kinase (MAPK). Activation or overexpression of these signalling molecules have been shown to interfere with anoikis, some of these molecule have been found to be upregulated or activated in malignant cells. FAK is one of the most important integrin signallig molecules recruited into focal adhesions upon cell-ECM contact, which affect multiple critical cellular process such as cell survival, proliferation, motility,& differentiation. 11

CONTINUED P13K is one of the FAK activated proteins which in turn recruits & activates its downstream target protein kinaseB( PKB/Akt). Akt prevents the release of cytC from mitochondria by phosphorylating the pro- apoptotic protein Bad on Ser136, causing the release of Bcl-2 & directly inhibits the caspase cascade by phosphorylating the procaspase-9. Akt can also activate the nuclear factor KB(NFkB) survival pathway by phosphorylating & inhibting IkB( inhibiting subunit if NFkB) through IkB kinase(IKK). The MAPK pathway is another signalling cascade triggered by FAK activation. The Src-mediated phosphorylation of FAK on Tyr925, which creates binding site for the Grb2 adaptor protein, leading to activation of the MAPK pathway. ILKis another key players in integrin-mediated signal transduction to anoikis protection, upon cell ECM adhesion, ILK, inteacts with integrin receptors & phosphorylates its target PKB/Akt on ser473, therby stimulating its activity. Overexpression of active active FAK or ILK blocks anoikis in suspended cells, therby supporting role of these kinase in anoikis protection. Caveolin-1-mediated binding of integrin to the adaptor protein Shc, which leads to FAK INDEPENDENT activation of MAPK & consequently to escape from anoikis as well as cell cycle progression through cyclinD1 accumulation. 12

The molecular signature of cell survival in physiological conditions 13

2- LACK OF ADHESION DURING CELL MIGRATION The second physiological process in which cells needs to escape from anoikis is the temporary displacement of focal contacts during cell migration. Intrgrins engagement within focal contacts & concamitant activation of several receptor tyrosine kinase(RTKs) including Met, which is often the initiating event for mesenchymal motility leads to p13k activation & grants for concamitant prosurvival signalling. In addition this leads to P13K-dependent activation of Rac-1 & cdc42 at the leading edge of the cell which co-ordinate actin polymerisation. The alternative motility style is the amoeboid migration which cells to glide through,rather than degrade,ECM barriers through a weakening of focal contacts. During amoeboid motility the pro-survival signals are ensured by the strong activation of Rho family of Gtpases. Rho-g has been reported toregulate the suression of anoikis in a P13K- independent manner. The amoeboid movement is also exploited by non-professional adhering cells; among which hematopoetic stem cels & leukocytes. 14

CONTINUED T-lymphocytes & oter leukocytes mive in protease independent manner across matrix barriers through adaptation of the cell shape & squeezingthrough narrow space. The movement of these cells is driven by weak interactions with ECM, therby permitting high velocities. Nonadhering cells are protected from anoikis by anti-apoptotic signal elicited by several cytokines including Interleukin-2(IL-2), IL-7, IL-15 & interferon- which selectively abrogates induction of proapoptotic BH-3 only proteins. Quiescent T-cells the withdrawl of survival factors, leads to Bim accumulation & Bcl-XL downregulation & final commitment to apoptosis. 15

3-CELL-CELL CONTACTS Cell-cell contacts are mainly mediated by cadherins a family of membrane proteins allowing homotypic or hetrotypic calcium dependent cell-2 anchorage. Blockage of E-cadherins binding induces anoikis,while overexpression of -catenin a downstream regulator of cadherins signalling, elicits anoikis resistant in epithelial cell. N-cadherins signalling mainly promotes survival in P13K/Akt-dependent fashion. Cadherins may also affect cell survival through indirect association with integrins. Some integrins like 2 1 & 3 can be localised at cell-2 contacts & can mediate survival signal despite loss of ECM adhesion. Recent research highlighted that in adhesion to cadherins, intercellular adhesion mediated by other cell surface molecules as P- & L- selectin & NCAM, play an important role in cell survival via the activation of intracellular signalling molecule. 16

3-DETACHEMENT INDUCED AUTOPHAGY Autophagy may provide a temporary survival mechanism which delay the onset of apoptosis, thus giving cell chance survive & reactivate once they reattach to ECM. During autophagy, cells package cellular proteins & organelles within the autophagosome. The vesicles are then catabolised by lysosomes & degraded products are utilised by the cell in order to create new proteins. Induction of autophagy is driven by the activation of proteins that sense cellular metabolic stress; such as AMP activated protein kinase (AMPK). AMPK activates the canonical autophagic pathway through ATG6 & ATG8, thereby sustaining ATP levels & delaying anoikis. The functional players of such integration are BECLIN-1 an autophagic protein acknowledged to modulate the anti-apoptotic role of Bcl-2 & Bcl-XL & MAPK. Autophagy can also be induced by ECM detachment- induced oxidative stress. this oxidative stress-mediated induction of autophagy has been fomed to be controlled by activity of the RNA activated protein kinase like endoplasmic reticulum(ER). Inturn PERK phosphorylates& activates eukaryotic translation initiation factor 2 , thus inducing transcription & translation of the ATG proteins required for autophagy & sustaining survival detachment. 17

The potential dual role of entosis. When epithelial cells lose their attachment to the ECM, cells can undergo, instead of anoikis, the process of entosis, which is favored by forces that are associated with adherens junctions. In this intermediate state, where one cell is inside another, an important decision can be made: the internalized cell can either die or be released from the host cell, and potentially reattach to ECM, pointing to a protective role of entosis. 18

ANOIKIS RESISTANCE IN CANCER CELLS Cancer cells rapidly develop to several mechanisms to resist to anoikis & exploit them to progress towards malignancy & spread metastases to distant organ. Cancer cell achieve resistance to anoikis through- 1. A specific switch in their integrins, thereby adapting to the metastatic site, 2. Undergoing to epithelial mesenchymal transition (EMT). 3. Exploiting a constitutive activation of pro-survival signaling due to intrinsic or environmental factors, as well as 4. Deregulating & adapting their metabolism, mainly through WARBURG metabolism or autophagy. 19

1- INTEGRINS SWITCH Deregulation of integrins & changes in their expression profile can contribute to cancer cell growth or metastatic dissemination. By changing the intagrins repertoire exprssion, cancer cells can overcome anoikis, during both the initial phase of oncogenic transformation & metastatic colonisation of other organs or tissues. In human intestinal carcinoma cells, downregulation of v 3 integrin expression protects suspended cells from death, suggesting that this contributes to acquisition of an anoikis resistant phenotype. The contribution of v 3 intrgrins in acquisition of anoikis resistant/migratory cancer cell lines. Normal prostrate epithelial cells & androgen sensitive LNCaP prostrate cancer cell line did not express v3 integrin which result otherwise expressed on androgen resistant PC3 cancer cell line. Transition from normal cells to hyperproliferative as well as cancerous phenotype is associated with high expression levels of pro-survival v6 integrin. This switch strongly contributes to acqistion of an anoikis resistant phenotype. Integrin 6 expression is also significantly upregulated in numerous carcinomas including head & necks cancer & breast cancers. 20

CONTINUED In normal cells, integrin 6 is expressed during development from subset of epithelial cell, kidney, lung & skin but became undetacheable in adult normal cells. Overexpression of the 6 subunit into poorly invasive oral squamous cell carcinoma stimulate migration & secretion of metalloproteinase-3 (MMP-3) that in turn stimulate cell invasion. Overexpression of 4 integrin causes a consitutive activation of P13K inducing anoikis resistance & a strong increase of breast cancer cell invasiveness, while 4 knockdown promotes apoptosis. 21

2- CONSTITUTIE ACTIVATION OF ANTI-APOPTOTIC PATHWAY P13K/Akt is one the most important signaling pathway involved in pro-survival features, as it integrates most of the signals derived from integrins & growth factors receptors. Akt is essential to regulate several cellular functions such as cell survival & cell growth, & its aberrant or constitutive activation strongly contributes to sustain cancer growth. Sustained pro-survival Akt activation can be achieved as consequence of- 1. Overexpression or constitutive activation of several receptor protein tyrosine kinases, 2. Activating Ras mutations, 3. Loss of the phosphatase & tensin homolog(PTEN) function via gene mutation, deletion or promoter methylation, 4. Alteration of P13K activity, 5. Amplification of Akt genes or overexpression. 22

CONTINUED 23 Akt activation can modulate activity of transcription factors tha control the expression of pro & anti-apoptotic genes or direct phosphorylation of pro-apoptotic proteins, such as Bad & procaspase-9, inhibiting their expression. Akt activates the transcription factors that upregulate antiapoptoticgenes such as IKK. Akt negatively the transcription factors that promote the expression of death genes such as forkhead transcription factors,FKHR,FKHRL1 & AFX. Sustained Akt activation occurs by upregulation of N-cadherin expression. Switch from E-cadherin to N-cadherin is a common features of cancerous epithelial cells that undergo EMT. N-cadherin recruits P13K which in turn activates Akt & induces anoikis resistance. Activation of P13K/Akt signaling pathway is most common mechanism to achieve anoikis resistance in cancer cell & PTEN is its most important negative regulator. Downregulation of PTEN induces anoikis resistance & malignancy. Activation of Src due to its cysteine oxidation plays an important role in the induction of anoikis resistance in aggressive prostrate cancer unndergoing consititutive oxdative stress mainly acting on EGFR prosurvival signaling. In pancreatic cancer cell neuropilin-1 increases MAPK signaling & expression of the anti-apoptotic regulator Mcl-1 thereby enhancing survival of cancer cell in suspension.

3-EPITHELIAL MESENCHYMAL TRANSITION(EMT) 24 EMT is phsiological process that allows epithelial cells to remodel cytoskeleton release the linkage with vicinal cells & acquire a motile phenotype. This phenomenon is usually activated during wound healing, inflamation or embryogenesis. EMT has also been described for cancer cells allowing them todetach from neighboring cells, overcoming anoikis & to move from their primary location & invades other tissues. During EMT cancer cells activate epigenetic pathways that lead to the downregulation of cell-cell adhesion molecules such as E- cadherins & catenin & at the same time to the expression of mesenchymal markers such as vimentin, fibronectin -smooth muscle actin (SNA), N-cadherins as well as to the activation of MMPs. Key players involved in EMT induction are transcription factors such as Snail, ZEB1/2, Twist, NF-Kb & HIF1/2. they are often aberrantly expressed in cancer cells & share the ability to decrease E- CADHERIN expression, while increasing the expression of mesenchymal markers. Twist promotes survival upregulating the level of anti-apoptotic Bcl-2 protein, similar mechanism has been described for snail-1 which has found upregulated in primary human breast carcinomas & breast tumors. ZEB-1 transcription factors has been associated to anchorage independent growth of lung cancer cells, contributing to EMT & malignancy. ZEB-1 expression causes an increases of vimentin & decrease of E-cadherin & semaphorin 3F expression events that contribute to activation of Akt pathway, therby promoting anoikis resistance.

EPITHELIAL MESENCHYMAL TRANSITION(EMT) 25

ANOIKIS RESISTANCE 26

3- microRNAs 27 MicroRNA(miR) are noncoding RNA that post translationally regulates gene expression miR directly involved in negative EMT regulation & acquistion of anoikis resistance. miR200 family is most acknowledged to be involved in regulation of epithelial phenotype. The family includes miR-200a,-200b,-200c,-141,-429, most of these repress ZEB1/2 upregulating E-cadherin expression &driving mesenchymal epithelial transition. miR-200C downregulation is the activation signaling pathways that stimulate cell motility, EMT & anoikis resistance. miR-200Aa promotes anoikis resistance through regulation of anti-apoptotic protein YAP-1 with clear correlation with metastasis diffusion in pateints with breast cancer. miR-210 has been correlated to the transcriptional program engaged by hypoxia. This miR has been found expressed in many tumors & its contribution to inhibition of pro-apoptotic signaling in an hypoxic environment. miR-155 targets the tumor protein p53 inducible nuclear protein1(TP53INP1) a positive regulator of p53-mediated apoptosis.downregulation of TP53INP1 by miR-155 atenuates apoptotic pathway, promoting cell survival. miR-26 is downregulated in human esophageal adenocarcinoma cells leading to increased Rb1 expression levels & causing E2F1 inhibition, thereby inducing cell cycle arrest.

ROLE OF miRNA IN INDUCTION OF ANOIKIS RESISTANCE 28

5- REGULATION OF ANOIKIS RESISTANCE DUE TO OXIDATIVE STRESS OR HYPOXIA 29 EMT engagement &p53 inactivation may contribute to ROS production. Exposure of lung carcinoma & melanoma cells to subtoxic doses of hydrogen peroxide significantly upregulates cav-1 which by activating Akt pathway, leads to anoikis resistance & anchorage-independent growth. Exposure of human lung carcinoma cells to subtoxic doses of cis-platin, chronically increases intracellular ROS levels & cav-1 expression leading to anokis resistance. Activated growth factor receptors increases intracellular ROS production by activating enzymes such as NADPH oxidas(NOX) & lipooxygense. ROS modulates activation of Akt & MAPK signaling pathway as well as activity of redox- sensitive transcription factors (NF-Kb, HIF-1/2, P53 etc) thus contribtuing to sustain autocrine loops.

6-AVOIDING ANOIKIS BY MODULATING ENERGETIC METABOLISM 31 Upon cell detachment ErbB2 overexpression is enough to restore glucose uptake through P13K/Akt pathway activation, quench ROS increasing NADPH production rescuing cell from anoikis. Cancer cell metabolise high glucose level through glycolysis but most of pyruvate obtained is transformed into lactate instead of being oxidised in mitochondria a phenomenon described by WARBURG EFFECT

CANCER CELLS EXPLOIT ANOIKIS RESISTANCE IN THEIR LONG METASTATIC ROUTE 33 Long metastatic route can be mainly categorised into these steps: 1. Carcinogenesis in primary site, 2. Sustained proliferative signaling & hyperproliferation of cancer mass, 3. Generation of hypoxic environment inside the cancer bulk, 4. Sustained angiogenesis/lymphanogiogenesis to recostitute the adequate supply of oxygen & nutreints, 5. Cross-talk with component of new microenvironment including parenchymalstromal, endothelial & inflamatory cells, 6. Migration through the extracellular matrix & invasiveness, 7. Intravasation into bloodstream, 8. Cell survival in the blood & lymphatic vessels, 9. Extravasation from the circulation into the surrounding tissues of distant organs, 10. Prepartion of the metastatic niche in which cancer cells should adapt,& 11. Growth of the invading cells in the new site.

35 Transformed cells employ different strategies to compensate for, or circumvent, the anoikis signals and thus become anchorage independent.

THERAPEUTIC VALUE: OVERCOMING ANOIKIS RESISTANCE IN METASTATIC TUMORS 36 1. Novel quinazoline based compounds 2. PPAR- inhibitor 3. TrkB inhibitor 4. SRC inhibitor 5. Talin resisting anoikisN

1.NOVEL QUINAZOLINE BASED COMPOUNDS 37 Clinically available quinazoline-based 1-adenoreceptor antagonists, DOXAZOSIN& TERAZOSIN exert potent antitumor growyh effects via induction of apoptosis in prostrate epithelial, smooth muscle & endothelial cells. Drugs proceed via a 1-adenoreceptor-independent mechanism mediated by receptor mediated apoptosis involving death inducing signaling complex (DISC) formation /caspase-8 activation & inhibition of Akt activation. (Keledjian et al., 2005; Keledjian and Kyprianou, 2003;Rennebeck et al., 2005). The two lead compounds, DZ-3 and DZ-50, are shown to be effective at inhibiting epithelial and endothelial cell survival by targeting the Akt survival pathway and preventing angiogenesis. DZ-50 reduces tumor cell adhesion to the ECM by promoting anoikis and inhibits tumor growth and neovascularization in vivo. The parent compound, doxazosin induces cell death via the death receptor mediated apoptotic signaling and inhibition of Akt survival signaling (Garrison and Kyprianou, 2006). These quinazoline-derived drugs may have therapeutic potential in preventing distant metastasis via inducing anoikis in tumor epithelial as well as endothelial cells (targeting vascularity).

2. PPAR- INHIBITOR 38 Peroxisome proliferator-activated receptor-gamma (PPAR-c) belongs to the nuclear hormone receptor family; a protein mainlyexpressed in adipose tissue, plays a central role in adipocyte differentiationandinsulin sensitivity (DesvergneandWahli,1999). recently PPAR-c is implicated as a putative therapeutic target for cancer in a variety of tumors due to its ability to inhibit tumor cell growth (Martelli et al., 2002; Panigrahy et al., 2003). Inhibition of PPAR-c-induced anoikis in squamous carcinoma and hepatocellular carcinoma (Schaefer et al., 2005) via suppressing integrin a5 expression and blocking FAK signaling.

3. TrkB INHIBITOR 39 Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in tumor cell growth and survival signaling. Inhibitors of Trk receptor kinases hold considerable therapeutic promise in enabling targeted anti-tumor strategies. The Pan-Trk inhibitors have been used in tumor xenograft and transplantation models and suppressed the xenograft growth in a number of cancer models including neuroblastoma, medulloblastoma, prostatic and pancreatic cancer cell lines. Trk inhibitors have already been used in phase I clinical trials (Marshall et al., 2005; Undevia et al., 2004). They appear to be tolerated well, but fail to elicit a tumor response in a limited number of patients suffering from mostly solid tumors. Phase II clinical trials are currently under way, which may bring additional data on the suitability of Trks as anti-cancer therapeutic targets (Desmet and Peeper, 2006).

3. SRC INHIBITOR 40 The Src family of kinases is currently being investigated as valuable therapeutic targets for cancer treatment. Dasatinib treatment effectively inhibits both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant cancer (Park et al., 2008). Dasatinib suppresses cell adhesion, migration, and invasion of cancer cells by blocking the kinase activities of the SFKs, Lyn, and Src, in cancer cells at low concentrations. 4. TALIN RESISTING ANOIKIS Talin1, an integrin-activator in patients with high risk for metastasis, early targeting with specific inhibitor-based chemotherapy may benefit patient long-term survival by reversing anoikis resistance and ultimately suppressing the tumor metastatic spread, prior to its initiation.

41 (1) death receptor mediated pathway, (2) ECM-integrin cell survival pathway and (3) mitochondrial mediated pathway.

FUTURE ASPECTS 42 A better understanding of the molecular mechanisms involved in anoikis resistance would assit in the development of anticancer drug to eradicate circulating tumors cells & prevent tumor metastasis. It will also be interesting to systematically compare the effects of the various integrins types in anoikis, in the hope of understanding how tumors cells might evade anoikis by expressing certain integrins. To analyze the transcriptional mechanisms by which the epithelial transcription program is established in order to understand anoikis more fully.

CONCLUSIONS 43 In normal tissue, adhesion to appropriate extracellular matrix proteins is essential for survival, & loss of this adhesion induces cell death which has been termed anoikis. If cell acquires oncogenic signals that are able to overcome this machinery, they gain the ability to survive outside their normal environment in the absence of adhesion to the ECM. This process is an important step within the metastatic progression of epithelial cancers, in that resistance to anoikis allows cells to survive within the circulatory & lymphatic systems. The ability to survive & proliferate in the absense of adhesion to the ECM allows the cancer cells to disseminate from primary tumors sites to ectopic locations. Understanding the molecular mechanisms by which cancer cells escape signals to die in non-adherent states is important in understanding the process by which cancer can spread to distant sites away from the primary tumors, as well as potentially allowing for the design of therapeutics to inhibit the spread of the disease.

REFERENCES 44 S.M. Frisch, E. Ruoslahti, Integrins and anoikis,Curr. Opin. Cell Biol. 9 (5) (1997) 701706. E. Ruoslahti, J.C. Reed, Anchorage dependence, integrins, and apoptosis, Cell 77 (4) (1994) 477478. S.K. Alahari, P.J. Reddig, R.L. Juliano, Biological aspects of signal transduction by cell adhesion receptors, Int. Rev. Cytol. 220 (2002) 145184. S. Attwell, C. Roskelley, S. Dedhar, The integrin-linked kinase (ILK) suppresses anoikis, Oncogene 19 (2000) 38113815. E. Avizienyte, M.C. Frame, Src and FAK signalling controls adhesion fate and the epithelial-to- mesenchymal transition, Curr. Opin. Cell Biol. 17 (2005) 542547. Aoudjit, F., Vuori, K., 2001. Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis. J. Cell Biol. 152, 633643. Clincaltrials.gov.. Desmet, C.J., Peeper, D.S., 2006. The neurotrophic receptor TrkB: a drug target in anti-cancer therapy? Cell Mol. Life Sci. 63, 755759. Desvergne, B., Wahli, W., 1999. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20, 649688. A. Barrallo-Gimeno, M.A. Nieto, The Snail genes as inducers of cell movement and survival: implications in development and cancer, Development 132 (2005) 31513161.

vivek singh m.sc. 3 rd sem centre of biotechnology uniersity of allahabad anoikis 1 “loss of...

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