Download role of integrins in cancer development

konferencijos medžiaga
ROLE OF INTEGRINS IN CANCER DEVELOPMENT – THERAPEUTIC
IMPLICATIONS
Integrinų vaidmuo vėžio atsiradime ir jo gydYme
Jerzy Lazowski
Polish Society of Oncology Pharmacists, Warsaw (Poland)
Lenkijos onkologijos farmacininkų draugija, Varšuva (Lenkija)
SANTRAUKA
Reikšminiai žodžiai: integrinai, vežio gydymas, solidiniai tumorai, ląstelių adhezijos molekulės
Integrinai yra heterodimerinės transmembraninės molekulės, kurios priklauso ląstelių adhezijos molekulių gupei. Be adhezijos funkcijos integrinai taip pat pasižymi signalo perdavimu ląstelėms. Šis signalas yra susijęs su ląstelės augimu, dauginimusi, migracija ir apoptoze. Pastebėta, kad piktybiniai navikai turi aktyvuotus integrinus ar padidintą jų ekspresiją. Taip pat
jų sąveika su onkogeniniais signalo perdavimo keliais yra būtina vėžio migravimui-invazijai, metastazėms ir angiogenezei.
Dėl savo vaidmens naviko vystymesi integrinai tapo patrauklūs taikiniai vėžio gydyme. Etaracizumab – pirmasis integrinų,
antagonistas parodęs priešangiogenezinį poveikį, mažą toksiškumą ir ligos stabilizavimą gydant pažengusius solidinius navikus ir inkstų ląstelių karcinomą. CNTO 95 žmogaus integrinams specifinis antikūnis pirmos fazės klinikiniuose tyrimuose
pasižymėjo priešvėžiniu veikimu ir mažu toksiškumu. ATN-161 peptidas, kuris inhibuoja integriną α5β1, buvo aktyvus prieš
solidinius navikus ir stabilizavo ligą trečdaliui pacientų. E7820 – sulfonamidų junginys antros fazės klinikinuose tyrimuose
taikomas storosios žarnos vėžio gydymui. Volociximab monokloninis antikūnis skirtas solidinių tumorų gydymui šiuo metu
antroje klinikinių studijų stadijoje. Cilengitide sintetinis peptidas specifiškai jungiasi prie endotelyje esančių integrino receptorių, taip sukeldamas apoptozę ir yra plačiausiai tyrinėtas integrinų antagonistas. Integrinai yra daug žadantys vėžio gydyme,
tačiau reikia daugiau klinikinių studijų norint įsitvirtinti standartinėje klinikinėje praktikoje.
ABSTRACT
Key words: integrins, cancer therapy, solid tumors, cell adhesion molecules
Integrins are heterodimeric transmembrane molecules that belongs to group of cell adhesion factors. Apart from adhesion
integrins regulate signal transduction pathways for cell growth, proliferation, migration and apoptosis. Recently it has been
noticed that several human malignancies have up-regulated or activated integrins and their interaction with oncogenic signal
transduction pathways are crutial in cancer migration – invasion, metastasis and angiogenesis. Integrin role in tumor progression has made them attractive target. Etaracizumab first integrin antagonist showed anti-angiogenic activity, low toxicity and
disease stabillization in some patients with advanced solid tumors and renal cell cancer. CNTO 95 human integrin specific
monoclonal antibody in Phase I clinical in patients with solid tumors was well tolerated and prolonged stable disease in one
third of the patients. E7820 is a sulfonamide derivative currently undergoing Phase II clinical trials for treatment of the colon
cancer. Volociximab is monclonar antibody that is currently in Phase II clinical trials for solid tumors. Cilengitide is synthetic
peptide specifically binds to integrin receptors in endothelium and induce apoptosis it is most extensively studied integrin
antagonist hitherto. Integrins are promising targets in cancer therapy, however more clinical trials are needed to introduce
them to standard clinical practice.
Introduction
Throughout its life, a cell must constantly sense physiological changes in the microenvironment and respond by
making critical decisions regarding process of proliferation,
division, motility and death. In multicellular organisms
different cell types coordinate function to facilitate tissue
homeostasis by exchanging signals, such as growth factors
or other cytokines, and secreting, assembling, and remod-
eling an insoluble network of proteins termed the extracellular matrix (ECM) [1]. The ECM provides a structural
framework that enables cells to anchor for stationary existence, or to migrate. It also influences cell seize, shape,
and interaction with other cells and tissue formation. All
these processes are mediated by cell adhesion molecules
(CAM). Thanks to them cells are losing their ability to division after reaching a certain level of intracellular contact, as
Jerzy Lazowsk
ul. Mikolajczyka 12 m. 72, Warszawa 03984, Polska
[email protected]
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well as adhere to ECM. This is an indispensable condition
of replication of many types of cells and their proliferation.
Disturbances in CAM function may negatively interfere in
the process of cell proliferation and influence their transformation.
CAM are divided into four essential groups:
- cell adhesion molecules with immunoglobulin-like
domains which take part in the intracellular connections
communicating with other CAMs,
- integrins which are active in the intracellular communication and communication between cells and ECM,
- adherins which mediate adherence and proliferation
of the same type of cells,
- selectins which are mediators of initial interaction
between leukocytes, blood platelets and activated cells of
endothelium. [2]
The role of CAMs is not only adhesion to themselves.
They are also acting as sensors and effector factors in intracellular signal transduction which enables modification of
adherence in response to phosphorylation phenomena in
the cell.
Cell adhesion to ECM is predominantly mediated by
integrins, the most structurally and functionally diverse
family of CAMs which regulate cell-cell and cell-ECM interaction .
Closer look of integrins
Integrins are heterodimeric transmembrane molecules
consisting of two non-covalently bond α and β subunits. In
mammals, eighteen α and eight β subunits have been characterized. The ectodomains of these receptors binds specific
components of the ECM. At the same time, the cytoplasmic
domain (largely that of β subunit) is linked, via intermediary proteins, to the cyclosceleton (largely that constructed
by actin fibers); in addition, the cytoplasmic domains may
attract a variety of signal-transducing proteins that become
activated when the ectodomain binds an ECM ligand. In
the binding of both chains participate calcium and magnesium ions which are necessary to maintain correct spatial
structure and guarantee ligands binding [3].
Subunit α is responsible for the specificity of the binding. Different α subunits are binding one type of β subunit
only, and that is why integrin subgroups are defined on the
basis of common β subunit. In this way integrins β1, β2, β3
etc. have been classified. Integrins β1 and β2 binds ECM
proteins while integrin β3 are binding immunoglobulinlike opposite receptors.
Extracellular domains of integrins binds to 3 different
types of ligands:
ECM proteins (e.g. fibronectin, laminin, tenascin) - integrin bonds participate in cell adhesion to ECM,
circulating proteins originating from ECM (e.g. fiteorija ir praktika 2012 - T. 18 (Nr. 2)
bronectin, von Willebrand factor) – integrin binding results in platelet aggregation,
opposite receptors – integrins binding causes strong adherence of cells.
Activity of different integrins partially overlap. For instance integrins α4β1 and α1β2 participate in homotypical
adhesion (between cells of the same type) and cytotoxicity
of T cells. Similarly α4β1 and α3β1 can be receptors for fibronectin [4].
Extensive research over the past two decades has shown
that integrins not only “glue” cells to ECM, but also regulate important signal transduction pathways for cell growth,
proliferation, migration and apoptosis. One of the most
important features of surface integrins is their role in cell
migration. Cells adhere to substrate through their integrins.
During movement, the cell makes new attachments to the
substrate at its front and concurrently releases those at its
rear. When released from the substrate, integrin molecules
are taken back into the cell by endocytosis; they are transported through the cell to its front by endocytic cycle where
they are cycled for reuse, enabling the cell to make fresh
attachments at its leading front [5].
Integrins recognize in ligands common place of binding – tripeptide arginin-glycine-asparaginic acid called also
RGD sequence. Binding with RGD sequence stabilizes
ligand-integrin complex and synthetic peptides containing
this sequence may block integrin-ligand complex.
Integrins are most unusual in one other respect. Normally, we think that receptors are passing information from
outside the cell into the cytoplasm. Integrins surely do
this. But in addition, it is clear that signals originating in
the cytoplasm are used to control the binding affinities to
integrins for the ECM ligands. Such “inside-out” signaling enables cells to modulate their association with various types of ECM or with various points of contact with
an ECM, breaking existing contacts and forging new ones
in their place. Rapid modulation of extracellular contacts
enables cells to free themselves from one microenvironment
within a tissue and move into another, and to traverse a
sheet of ECM at least in vitro.
The significance of integrins in cellular physiology and
body homeostasis is reflected by an increasing number of
diseases states, ranging from hematologic, dermatologic,
and musculoskeletal that have been associated with altered
expression or activation of integrins.
Does integrin play role in cancer
development?
In the cancer setting interest has been fueled by recent advances in our understanding that integrins are upregulated and/or activated in several human malignancies
that are critical of almost all critical phase of tumorgenesis,
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that they interact with major oncogenic signal transduction pathways, and that they regulate important cancer
phenomena, such as migration-invasion, metastasis and
angiogenesis [6, 7].
As the main link between a cell and the EM, integrins
have an essential role in the invasion process . The cellular
integrin expression pattern is highly variable between cancer types, in individual tumors, and even in separate tumor
cells inside a single tumor. Thus, it is difficult to estimate
the involvement of an individual adhesion receptor. The
data that have accumulated with respect to integrin expression in various types of human cancer allow some conclusions to be drawn. Some integrins, especially αvβ3 seem to
promote tumor progression and metastasis. The fact that
some aggressive cells are negative for this integrin indicates
that none of the adhesion receptors are irreplaceable. It is
also obvious that some integrins have distinct functions
depending on cell type. For example, α2β1 integrin may
participate in the maintenance of differentiated cell phenotype in breast epithelial cells, and therefore it is often
down-regulated in breast cancer. However in melanoma,
prostate and gastric carcinoma, α2β1 expression is associated with tumor progression and invasion. In addition, many
experimental models support the idea that α2β1 integrin is
essential for cancer cell migration, invasion and metastasis
formation. Studies correlating integrin expression levels in
human tumors with pathological outcomes, such as patient
survival and metastasis, have identified several integrins that
might have an important role in cancer progression. Tumor
cells expression of the integrins αvβ3, αvβ5,α6β4, α4β1
and αvβ6 is correlated with disease progression in various
tumor types, therefore, these are the most studied integrins
in cancer. However, this is by no means a complete list and
other integrins certainly contribute to cancer progression,
particularly on some of the host cell types in the primary
tumors.
It is also important to remember that down-regulation
of an integrin subunit in cancer cells does not necessarily
mean that the receptor is unimportant for malignant phenotype or that it has tumor suppressor function. Maximum
cell migration speed is dependent on optimal ligand concentration, integrin expression, and ligand-integrin affinity.
Therefore, a decrease in integrin expression may actually
promote cell migration. The role of the integrins is not limited to their function as a mechanical bond in cell-matrix
contact sites, but after binding extracellular ligands, integrins are also capable of sending signals into the cell. The
cancer-related genomic instability leads to variable changes
in the expression of cellular signaling molecules and most
probably affects also integrin-linked pathways. Thus, the
function of an integrin may change during tumor progression. The integrin may be down-regulated during transfor206
mation because it supports a normal phenotype or inhibits
cell growth. However, it may also play an essential role in
invasive cancer [8].
Current therapeutic approaches
targeting integrins in cancer
treatment
The importance of integrins in several cell types that affect tumor progression has made them an appealing target
for cancer therapy [9].
The first integrin antagonist which was admitted to
clinical trials was etaracizumab (Vitaxin, MEDI-522). It
is humanized derivative of mouse antibody LM609 against
integrin α1β3, an antibody which was used in the studies
on the role of this adhesive molecule in the process of neoplasia. Etaracizumab showed in Phase I clinical trials antiangionetic activity, low toxicity and disease stabilization in
some patients with advanced solid tumors and renal cell
cancer. A Phase II clinical study showed also some efficacy
in metastatic melanoma[10].
CNTO 95, human αv integrin specific monoclonal
antibody, which targets both αvβ3 and αvβ5 integrins, also
has anti-tumor and anti-angiogenic effect on xerograft tumor models. In Phase I trial CNTO-95 was non-toxic and
showed signs of anti-tumor activity [11, 12].
Both etaracizumab and CNTO 95 are being further
evaluated in additional clinical trials.
ATN-161 is non RGD-based peptide inhibitor of integrin α5β1 that blocks breast cancer growth and metastasis
in vivo. In mouse model of colon cancer metastasis to the
liver, combination therapy with ATN-161 and fluouracil
significantly reduced tumor burden and liver metastases
compared with either treatment alone. ATN-161 was tested in patients with advanced solid tumors and was well
tolerated and prolonged stable disease in one-third of the
patients [13, 14].
E7820 is sulphonamid derivative. Its mechanism of action depends on modulation of integrin expression on the
surface of cells. It is the only integrin inhibitor used orally
and has good safety profile. Currently Phase II clinical studies are carried in which E7820 and cetuximab are evaluated
in the treatment of the colon cancer [15, 16].
Volociximab, a function-blocking monoclonal antibody against integrin α5β, inhibits angiogenesis and impedes
tumor growth. Phase I trial with patients with advanced solid malignancies showed that volociximab was well tolerated
and may have clinical efficacy. During ASCO Conference
in 2007 results of Phase II clinical trials with volocoximab
have been presented. During this study 40 patients with
recurrent, disseminated clear cell carcinoma of kidney were
receiving 10 mg/kg of volociximab every two weeks till the
progression. Stabilization of the disease was observed in
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32 (80 %) patients. Mean time to the progression was 4
months. Most often adverse effects were mild and included
fatigue, nausea, dyspnoe and joint pain. Authors concluded
that to full evaluation of volociximab effectiveness further,
randomized trial are necessary [17].
Cilengitide is synthetic peptide containing sequence
RGD which specifically binds to αvβ3 and αvβ5 integrin
receptors in endothelium and in the consequence causes
apoptosis, disturbing process of creating new blood vessels and eventually inhibition of tumor growth. Cilengitide is the most extensively studied integrin antagonist
hitherto.
In three Phase I clinical trials effectiveness of cilengitide
had been evaluated: (1) in monotherapy of metastatic solid
tumors, (2) in combination with gemcitabine in pancreas
cancer and (3) in glioblastoma. In all these trials toxicity of
cilengitide was low and side effects included nausea, anorexia, fatigue and vomiting. Hematologic toxicity has not
been observed. The best result were obtained in the third
study. Objective response was observed in 9 % of patients,
and in 50 % of them stabilization of the disease lasted for 5
months (range 3–11 months).
In 2007, during ASCO Conference, results of two Phase
II clinical studies on cilengitide effectiveness in monotherapy of (1) glioblastoma and (2) melanoma were presented.
The primary end point of the first trial was progression free
survival at 6 months. In patients treated with 500 mg i.v.
of cilengitide two times a week mean overall survival was
6,5 month and in patients receiving 2000 mg i.v. twice in
a week it was 9,9 months. The drug was well tolerated and
dose-limiting toxicity was not observed. The same dosing
schedule was used in the second trial, but effectiveness of
cilengitide in melanoma was minimal.
The favorable results obtained from earlier clinical studies provided impetus for a Phase III trial with cilengitide
that began in October 2008. The trial under the acronym
CENTRIC will enroll approximately 500 patients and
measure effect of cilengitide on survival of patients with
glioblastoma [18-20].
In 2004 Committee for Orphan Medicinal Products
enlisted cilengitide as an orphan dug in the treatment of
glioblastoma.
Conclusions
Integrin inhibitors may become an important tool in
the treatment of malignancies in the future. Hitherto trials
has proven that they are medicines with low toxicity, and
two of them, vitaxin and cilengitide have shown efficacy
in palliative treatment of melanoma and glioblastoma. Integrins are promising group in respect of targeted therapy,
however introducing them to standard clinical practice still
need intensive trials.
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Gautas 2012 m. sausio 24 d., aprobuotas 2012 m. balandžio 20 d.
Submitted January 24, 2012, accepted April 20, 2012
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