Transcript of VIVEK SINGH M.Sc. 3 rd sem Centre of Biotechnology Uniersity of allahabad ANOIKIS 1 “LOSS OF...
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- 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)
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- 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
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- 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
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- 4
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- Two pathway of anoikis The intrinsic pathway perturbation of
mitochondria. The extrinsic pathway- the triggering of cell surface
death receptor. 5
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- 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.
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- 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
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- 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
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- S.K. Alahari, P.J. Reddig, R.L. Juliano, Biological aspects of
signal transduction by cell adhesion receptors. 9
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- 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
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- 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
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- The molecular signature of cell survival in physiological
conditions 13
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- 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
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- 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
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- 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.
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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.
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- 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.
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- EPITHELIAL MESENCHYMAL TRANSITION(EMT) 25
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- ANOIKIS RESISTANCE 26
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- 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.
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- ROLE OF miRNA IN INDUCTION OF ANOIKIS RESISTANCE 28
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- 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.
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- 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
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- 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.
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- 35 Transformed cells employ different strategies to compensate
for, or circumvent, the anoikis signals and thus become anchorage
independent.
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- 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
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- 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).
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- 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.
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- 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).
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- 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.
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- 41 (1) death receptor mediated pathway, (2) ECM-integrin cell
survival pathway and (3) mitochondrial mediated pathway.
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- 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.
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- 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.
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