A cell-cell and cell-extracellular matrix (ECM) contacts

A growing body
of evidence indicates that cell-cell and cell-extracellular matrix (ECM) contacts can modulate
drug resistance, and this phenomenon is called cell adhesion-mediated drug
resistance (CAM?DR) 91, 92. Most mechanisms of CAM?DR
are not fully understood, possibly due to multifactorial processes involving different
molecular players, such as cell adhesion molecules and ECM components.
The literature indicates that multidrug-resistant phenotypes of
cancer cells are associated with cell adhesion molecules that play a key role
in cell adhesion processes 92.
An increasing number of studies demonstrate that different types of CAMs may be
involved in the resistance to chemotherapy treatment 91, 93-98. This section discusses the
literature focusing on CAMs as attractive therapeutic targets to overcome
chemoresistance in cancer therapy. The broad
spectrum of CAMs are classified into different families, although most belong
to four principal classes: Ig (immunoglobulin) superfamily (IgSF CAMs),
integrins, cadherins and selectins. Some unclassified CAMs, including CD44 and
EpCAM, are considered as separate to the above four classifications 99-101. Over the past decade, a
number of studies have demonstrated that many CAMs are overexpressed in
chemotherapy-resistant cancer cells, whereas some CAMs, such as integrin ?2?1,
CD31 and E-cadherin, underexpressed in cancer cells 93, 102. The loss of E-cadherin
expression is related to chemoresistance  in response to Paclitaxel and DocetaxelTD1 , and epithelial-to-mesenchymal
transition 103, 104TD2 .
studies have demonstrated that cell-adhesion mediated drug resistance (CAM-DR) is
based on a number of mechanisms, such as decreasing of anticancer drug-induced
DNA damage and activation of DNA repair by the Fanconi anemiaTD3  (FA)/BRCA pathway 96, 105-109; increasing resistance to
detachment-induced cell death (anoikis
resistance), and inhibition of Fas-mediated apoptosis 110-113. Although CAM-DR is not main TD4 form of cancer drug
resistance 114,
recent studies have revealed a plethora of tumors that have altered expression
of CAMs associated with aggressive tumor growth, metastasis and resistance to chemotherapy.
Therefore targeting CAMs introduces special interest TD5 for scientists and
pharmacological companies as well as for the development of anti-CAM-DR
strategy to sensitize cancer cells 92, 115.Most research targeting
CAM-DR TD6 has focused largely
on integrins 116-118 (see Table 2).
Considerable efforts have been directed at examining the inhibitory action of
integrin agonists, such as antibodies, peptides and small molecules 116, 119, 120. The synthetic
Arg-Gly-Asp-motif peptide integrin a5a3 inhibitor EMD-121974 (Cilengitide),
was a very attractive drug for anti-CAM-DR strategyTD7 . Cilengitide was tested
in several clinical trials for different types of tumors, including glioma,
NSCLC and squamous cell carcinoma 121-125. Despite positive results
from preclinical studies and second phase clinical trials, the addition of
cilengitide to temozolomide chemoradiotherapy did not improve patient’s overall
survival with newly diagnosed glioblastoma in an EORTC phase III randomized,
controlled, multicenter clinical trial 122. ExCentric, a multicentre
open-label phase II trial, showed that cilengitide combined with metronomic
temozolomide and procarbazine in MGMT-promoter unmethylated glioblastoma did
not improve survival compared with historical data 125.
Results of the randomized phase I/II ADVANTAGE trial (phase II part)
demonstrated that cilengitide with cetuximab and platinum-based chemotherapy in
recurrent/metastatic squamous cell carcinoma of the head and neck did not
result in any positive outcome 124. Cilengitide combined
with cetuximab and platinum-based chemotherapy was tested in an open-label
randomized controlled phase II study (CERTO) as first-line treatment for
patients with advanced non-small-cell lung cancer (NSCLC) 123. The study showed that
patients with advanced NSCLC had improved progression-free survival rate compared
with control.Different preclinical
in vitro and in vivo studies showed that targeting a4
integrin by antibodies sensitizes multiple myeloma to chemotherapy using melphalan
or bortezomib 126, 127 (Table 2), and a4 integrin small molecule inhibitor
TBC3486 increases acute lymphoblastic leukemia
sensitivity to vincristine treatment 128, 129.
There is only one known phase I/II clinical trial (NCT00675428) in patients
with refractory multiple myeloma treated by Natalizumab, a recombinant
humanized IgG4 monoclonal antibody, which binds integrin-a4. However, this clinical
trial was terminated due to low enrollment.It
was shown that the HMG-CoA reductase inhibitor simvastatin can selectively
inhibit integrins and shows antimyeloma activity and up-regulates HMG-CoA
reductase in chemotherapy-resistant cancer cells 130-132. Schmidmaier and co-authors showed that simvastatin at very low
concentrations overcomes CAM-DR in multiple myeloma by geranylgeranylation of
Rho proteins and activation of Rho kinase 133. Also,
simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells
by decreased expression of VCAM-1 and ?1 integrin 134. Simvastatin as an inhibitor of CAM-DR in patients with
refractory multiple myeloma was tested in phase 2 clinical trials by
Ludwig-Maximilians – University of Munich. This clinical trial showed reduction
of drug resistance by inhibition of HMG-CoA-reductase.Although
most studies in this area have focused on integrins, other CAMs have potential
for anti-CAM-DR strategy. Thus, recent data showed that down-regulation of
endothelial adhesion receptor CD31/PECAM-1 was associated with resistance
against oxidative stress and DNA damage in angiosarcoma cells due to YAP
signaling, and inhibition of YAP by Pazopanib re-sensitized cancer cells to doxorubicin
135. Pazopanib
may find use as a CAM-DR inhibitor as it inhibits VEGF-induced up-regulation of
adhesion molecules on tumor cells 136. Pazopanib
maintenance therapy provided a statistically significant and clinically
meaningful PFSTD8  benefit in
patients with advanced epithelial ovarian, fallopian tube, or primary
peritoneal cancers in phase III trials 137. E-cadherin TD9 is considered as a key
player in the process of acquiring chemoresistance 94, 103, 104, 138. Recently, Notch
signaling was identified to play a significant role in E-cadherin  associated cancer chemoresistance 103.
The results of these preclinical studies suggest inhibitors of Notch signaling
as potential anti CAM-DR drugs. The ?-secretase inhibitor
MK-0752 combined with docetaxel improved health of patients with advanced
breast cancer in Phase 2 clinical trial 139. Furthermore, there
is increasing evidence that selectins play an important role in the progression
of different types of cancer and CAM-DR 140-143. It was reported that
small molecule glycomimetic antagonist to selectins have the ability to inhibit
selectins and to sensitize cancer cells. Recently, the addition of E-selectin
inhibitor GMI-1271 to standard agents based chemotherapy induction in untreated
elderly patients with acute myeloid leukemia demonstrated a high remission rate
with acceptable side effect profile and low induction mortality 144.
CD44 a
transmembrane receptor for hyaluronan is a functional component of cell
adhesion-mediated drug resistance 145, 146. Recently, Zheng  et all reported that small molecule aurora kinase inhibitor
attenuates breast tumor-initiating cells and overcomes epirubicin  resistance by inhibition of CD44 147.
These data strongly
support that translation of CAM-DR signaling pathway regulators to clinic in
combination with standard therapy can be considered as a rational strategy to
overcome resistance.In
comparison with the significant advances in other strategies for overcoming
chemoresistance progress made with respect to anti CAM-DR has been relatively
slow. Main clinical trial failure became cilengitide in Newly Diagnosed
Glioblastoma in phase III clinical trial. Despite the challenges in this area
and gaps in our knowledge our understanding is that a creation of effective
strategies for overcoming chemoresistance will require a better understanding through cell adhesion drug resistance interaction
with other types of chemoresistance. Table 2 summarizes CAM signaling
pathways involved in chemoresistance.   

 TD1cancer types??

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 TD2what does this mean?



 TD3this needs better explanation




 TD5explain better

 TD6you need to double check these data
with the references and Table 2 as mistakes are being made.





 TD8define abbrevs


 TD9I stopped here as I am tired


to you to do a second dratft based upon my changes.