REVIEWS cro

Cell adhesion in cancer: Beyond the migration of single cells

Published, Papers in Press, January 14, 2020, DOI 10.1074/jbc.REV119.007759
X Michalina Janiszewska‡1, Marina Candido Primi§, and X Tina Izard§2
From the ‡Department of Molecular Medicine and the §Cell Adhesion Laboratory, Department of Integrative Structural and
Computational Biology, The Scripps Research Institute, Jupiter, Florida 33458
Edited by Mike Shipston

Homeostasis in healthy tissues strongly relies on cell-to-cell cell adhesion molecules or the extracellular matrix. Thus, cell
adhesion and cell-to-extracellular matrix interactions. For adhesion molecules often integrate the extracellular cues with
instance, normal epithelial cells maintain tissue structure by cell intrinsic signaling, affecting intracellular responses, cyto-
adhering to each other and to the extracellular matrix. The pro- skeletal organization, intracellular signaling, and gene expres-
teins that mediate these distinct interactions are collectively sion (3, 4).
called cell adhesion molecules and are divided into four major Based on their protein sequence and structures, cell adhesion
groups: cadherins, integrins, selectins, and immunoglobulins. molecules can be divided into four major groups: cadherins,
They not only physically anchor cells, but also critically inte- integrins, selectins, and immunoglobulins (Igs)3. This division
grate signaling between the extracellular microenvironment is strongly linked to the distinct types of cellular junctions built
and cells. These signals include biochemical cues, as adhesion by these proteins expressed on the cell surface (summarized in
proteins can both act as ligand-activated receptors and activate Fig. 1). Even though the primary role of adhesion molecules is to
mechanotransduction triggered by changes in the physical envi- maintain cell-to-cell contact and attachment to the extracellu-
ronment. Molecular mechanisms related to cell adhesion signal- lar matrix, they also function as signaling effector molecules
ing have been extensively studied, especially because mutations involved in cellular functions, such as cell growth, survival, and
and changes in expression of these proteins, particularly cad- transcriptional activity (5–7). In this review, we will focus on
herins and integrins, are frequently associated with diseases describing the distinct roles that the two major groups of adhe-
ranging from developmental intellectual disability to cancer. In sion molecules, cadherins and integrins, play in cancer biology.
fact, two major hallmarks of cancer, loss of cell-to-cell adhesion
and anchorage-independent growth, are both dependent on cell Cell adhesion molecules structure and function in
adhesion molecules. Despite many studies elucidating the rela- normal tissues
tionships between malignant transformation and metastasis Cadherins and integrins are among the most studied classes
and cellular adhesion processes, several areas still await explo- of adhesion receptors. Homotypic cell-cell adhesions are medi-
ration. Here, we highlight recently discovered roles of adhesion ated by cadherins, whereas adhesion between the cell and its
molecules in collective cancer cell migration and discuss the extracellular matrix is mediated by integrins. Because cad-
utility of three-dimensional models in studying cell-cell adhe- herins and integrins comprise a wide variety of interactions at
sion. We also describe recent therapeutic approaches targeting different levels, they are considered to be directly related ele-
adhesion molecules. ments that are part of a large adhesive network (3, 6, 8).
Cadherins are calcium-dependent transmembrane proteins
that play a fundamental role in junctional adhesions, holding
Cell adhesion molecules are mostly transmembrane receptor cells within tissues together, maintaining their intracellular
proteins widely expressed through the normal epithelium and cohesion, and preserving tissue architecture. These proteins
endothelium and by distinct immune cells. These proteins pro- are indispensable for morphogenesis, tissue remodeling, and
mote cell-to-cell and cell-to-extracellular matrix adhesion and maintenance of tissue barriers (4, 9). The structure of cadherins
are composed of three domains: an intracellular domain, a comprises several domains, typically presenting one signal
transmembrane domain, and an extracellular domain (1, 2). sequence, a protein precursor, one single transmembrane
The intracellular domain interacts with the cytoskeleton, domain, and five ectodomains. Four of the ectodomains corre-
directly or via scaffolding proteins, and is responsible for sig- spond to the protein module of the immunoglobulin-like fold
naling, whereas the extracellular domain interacts with other called an extracellular cadherin domain, which binds to cal-
cium ions to facilitate its proper folding. The fifth domain con-
This is publication number 29874 from The Scripps Research Institute. The tains four conserved cysteines and an N-terminal extracellular
authors declare that they have no conflicts of interest with the contents of
this article. The content is solely the responsibility of the authors and does domain. Typically, any protein containing one or more extra-
not necessarily represent the official views of the National Institutes of cellular cadherin domain is designated as a member of the cad-
Health. herin family. The cadherin superfamily includes a wide variety
1
Supported by National Institutes of Health grant and by start-up funds pro-
vided to The Scripps Research Institute by the State of Florida. To whom
correspondence should be addressed. E-mail: [email protected].
2 3
Supported by National Institutes of Health Grants, the Department of The abbreviations used are: Ig, immunoglobulins; Ig-CAM, immunoglobu-
Defense, and start-up funds provided to The Scripps Research Institute by lin-like cell adhesion molecule; EMT, epithelial-mesenchymal transition;
the State of Florida. CAF, cancer-associated fibroblast; FGFR, fibroblast growth factor receptor.
This is an Open Access article under the CC BY license.
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© 2020 Janiszewska et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
JBC REVIEWS: Cell adhesion in normal and malignant cells

Figure 1. Cell adhesion molecules in normal and cancer cells A, schematic representation of the structure of four major classes of cell adhesion molecules. B,
interactions between cell adhesion molecules on the cell surface create different types of cellular adhesions, including adherens junctions, gap junctions,
desmosomes, and hemidesmosomes. C, alterations in cell adhesion molecules in the transition between the normal epithelial cell state (left) and malignancy
(right). The localization of the distinct cell adhesion complex types is shown. EGF, epidermal growth factor; CRP, complement regulatory protein domains.

of proteins, and there are many isoforms distributed in a tissue- strand-swapped interfaces are preferentially formed between
specific manner (10, 11). cadherins from apposed cells, mostly in the presence of cal-
Some cadherins, termed classical cadherins, have been cium. The assembly of cadherins between apposed adherent
shown to mediate homotypic adhesive interactions. The first cells generates junctional structures that are densely packed
classical cadherins identified in vertebrates were E- and N-cad- (13, 14).
herin. Classical cadherins depend on a proteolytic removal of Integrins are the major class of receptors involved in homo-
the pro-domain to exert their adhesive capacity (10, 12). In typic and heterotypic adhesive events. These proteins transmit
addition, these proteins form an adhesive dimer interface signals via inside-out and outside-in signaling and comprise a
where a swapping of paired extracellular cadherin 1 N-terminal large and complex family of transmembrane glycoproteins.
domains generates a 2-fold symmetric interaction. These Structurally, these proteins are heterodimeric transmembrane

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 JBC REVIEWS: Cell adhesion in normal and malignant cells

receptors formed by noncovalent association of two such trans- and forces that generate movement. Integrins perform these
membrane glycoproteins. These two subunits are identified as various functions by their conformational changes that are trig-
␣ and ␤, whereby 18 integrin ␣ subunits and eight ␤ subunits gered by their binding either to the extracellular matrix or to
are so far known to heterodimerize into 24 different integrins intracellular proteins that alter the binding affinity of integrin,
(15). The subunits ␣ and ␤ are composed by one transmem- affect their clustering, and recruit cytoskeletal linker proteins
brane domain, one ectodomain, and a short cytoplasmic tail (18). These changes remodel nascent or focal adhesions and
domain. Their extracellular domains form elongated stalks and generate tension, whereas coordinated assembly and disassem-
a globular ligand-binding head region that mostly binds with bly of these adherent structures generate forces of cellular
other glycoproteins and connective tissue components, such as movement (28 –30).
collagens, laminins, and fibronectin. Integrin ␤ subunits harbor Single-cell migration and invasion are vital for many physio-
a metal ion-dependent adhesion site, which coordinates for logical processes, including immune cell trafficking. However,
example with magnesium ions. The metal ion– dependent in morphogenesis and wound healing, an alternative process of
adhesion site coordination with magnesium ions is altered due collective cell migration has also evolved (reviewed in Ref. 31).
to integrin ligand binding, causing conformational changes that In this process, assemblies of cells move together, as the cell-cell
lead to an open and active integrin conformation (5, 16 –18). junctions remain intact, allowing neighboring cells to adhere to
The vast majority of integrins connect with the actin cytoskel- each other during the movement. Adherens junctions in collec-
eton in cell-matrix adhesions via cytoskeletal linker proteins tive migration are maintained by homotypic cadherin interac-
(e.g. talin, paxillin, and vinculin). These connections between tions between the cells in a group (32). Other members of the
integrins and the actin cytoskeleton are necessary for activation adhesion molecule family, including Igs L1CAM, NCAM, and
of downstream pathways. Thus, integrins provide a link ALCAM, can also support this function (33, 34). Integrins also
between the outside environment and cellular responses play a role in collective adhesion, as they can bind intercellular
related to motility, such as immune cell trafficking, hemostasis, deposits of extracellular matrix and in this way support cell
and migration of cancer cells (18 –20). Many pathways related cohesion (35). Variability of adhesion molecules and signaling
to growth factor response depend on integrin-mediated adhe- contexts results in plasticity of cell-cell junctions and leads to
sion to the extracellular matrix or integrin-dependent intracel- distinct modes of collective migration, ranging from sheet
lular signaling, linking integrin to cell proliferation and anchor- migration to movement of cellular strands and clusters (36).
age-dependent survival (21–23). Thus, adhesion molecules are key proteins regulating all
Immunoglobulin-like cell adhesion molecules (Ig-CAMs) modes of cellular movement in tissue plasticity and
have highly glycosylated extracellular domains consisting of remodeling.
variable number of immunoglobulin-like loops (24). The extra-
cellular domain of Ig-CAM may be anchored in the membrane Loss of cell adhesion during malignant transformation
by glycophosphatidylinositol anchors or linked to a transmem- In the classic view of malignant transformation in the epithe-
brane domain. Homotypic interactions between Ig-CAMs can lium, cells lose their dependence on integrin-mediated interac-
drive cell-to-cell adhesion, whereas the cytoplasmic tail of these tions with the extracellular matrix and resulting signaling
proteins may interact with cytoskeletal proteins. The most events (Fig. 1C). During this process, adherens junctions that
well-known members of this superfamily are major histocom- are mediated by E-cadherin and that are crucial for cell-cell
patibility complex class I and II molecules and T-cell receptor adhesion are lost. This can be a result of a direct genetic muta-
complex. Other members include ICAM, VCAM, MadCAM-1, tion, which occurs in 4% of all cancers (37, 38), or a decrease in
and ALCAM, which are all important in leukocyte trafficking E-cadherin expression due to its promoter methylation or tran-
(25). scriptional repression (39 –44). Additional alterations are also
Selectins are another class of adhesion molecules related to observed in the specialized multiprotein complexes present in
immune function. Selectins mediate cell-cell adhesions by stratified epithelia named hemidesmosomes. Integrin ␣6␤4
binding to carbohydrates in a calcium-dependent manner (26). present in hemidesmosomes interacts with the keratin inter-
These transmembrane proteins are responsible for the initial mediate filament instead of actin filaments via binding to plec-
steps of leukocyte rolling, which initiates migration of the tin isoform 1a (P1a), which is a unique characteristic when
immune cell through the blood vessel wall into the surrounding compared with other members of this family. In tumor cells, the
tissue (27). lack of polarity is displayed by actin protrusions, which will
All of molecules described above play distinct roles in con- disassemble the hemidesmosomes and mediate cell migration
text-dependent cell-cell and cell-extracellular matrix adhesion. and invasion. After hemidesmosomes disassemble, ␣6␤4 integ-
However, the ability to transduce the signals from the environ- rin becomes phosphorylated and relocates to an F-actin–rich
ment and trigger intracellular responses, as well as outside- protrusion, where integrin interacts with actin filaments (45).
in signaling, provides adhesion molecules with functional All of these changes are associated with epithelial-mesenchy-
versatility. mal transition, which renders cancer cells more motile and
invasive (46).
Role of adhesion molecules in migration Further, epithelial-mesenchymal transition (EMT) is a
Whereas integrins play a key role in single-cell migration, reversible transcriptional program considered the primary ele-
which requires complete loss of adherens junctions that is ment driving tumor progression to metastasis (47). Epithelial-
mediated by E-cadherin, integrins also sense the environment mesenchymal transition allows epithelial cells to adopt a more

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JBC REVIEWS: Cell adhesion in normal and malignant cells

mesenchymal state, which enhances cellular migration. This These recent findings point to the seemingly opposing traits
process in normal physiological conditions contributes to related to malignancy-cellular adhesion loss that could lead to
embryogenesis, organ development, and wound healing, increased motility and pro-tumorigenic downstream signaling
whereas in cancer, it supports several malignant traits, includ- mediated by adhesion molecules. Thus, altering the expression
ing metastatic spread and drug resistance (48). In tumors, the of certain adhesion molecules may allow cancer cells to increase
EMT phenotype was also reported to be associated with a more their malignant potential in different ways.
inflammatory tumor microenvironment and was thus pro-
posed as a potential biomarker for immune checkpoint block- Cell adhesion in invasiveness by collective migration
ade agents (49, 50). However, the impact of epithelial-mesen- As described above, loss of cell adhesion has been classically
chymal transition in the efficiency of this blockade is still viewed as a pro-tumorigenic feature. However, in many epithe-
unknown. lial tumor types, normal cell adhesion through cell junctions is
One of the hallmarks of epithelial-mesenchymal transition is retained despite the more mesenchymal phenotype of cells
the “cadherin switching” characterized by loss of E-cadherin within a tumor. This enables cancer cells to adopt a collective
expression and increased expression of N-cadherin, as well as migration mode (58). Collective migration is defined as two or
changes in the integrin repertoire (51). This promotes a shift more cells moving together across a two-dimensional layer of
from tight cell-to-cell and cell-basement membrane connec- extracellular matrix while retaining their cell-cell junctions or
tions, mediated by E-cadherin and ␣6␤4 integrins, to N-cad- when they move into a three-dimensional interstitial tissue
herin-dependent adhesions, mediated by ␤1 and ␤3 integrins. scaffold. This process is key to normal morphogenesis and epi-
Thus, EMT allows cells to adhere readily to collagen, a compo- thelial homeostasis as an important strategy for local tissue
nent of the extracellular matrix, rather than the basement infiltration (59).
membrane. N-cadherin also activates the Rho-family GTPase The invasion by collective migrating carcinomas is charac-
signaling pathway, enhances fibroblast growth factor signaling, terized by a fine balance between cell-cell and cell-extracellular
and modulates the Wnt signaling pathway (52). All of these matrix adhesions (60). Three hallmarks define collective cell
pathways contribute to the aggressive tumor phenotype with migration: cells remain physically and functionally connected;
the capacity to escape from the primary tumor location to sec- cell-cell junctions are maintained; and, in most cases, the move-
ondary sites (52). Moreover, EMT induced by silencing of ment of cell groups modifies the tissue along the migration path
E-cadherin has also been shown to protect cells from anoikis, (31). Cell-cell junctions play a crucial role in this process by
cell death triggered by disrupted anchorage to basement mem- controlling the collective movement of proteins, in particular
brane (53). However, E-cadherin was also recently shown to act cadherins, the immunoglobulin superfamily members, and
as a survival factor in metastatic invasion of breast cancer by integrin. This process critically depends on the coupling of the
limiting reactive oxygen species-mediated apoptosis (54). Thus, actin cytoskeleton to multiple cells, transmitting forces, and
context-dependent adhesion molecule switching not only con- guiding the signaling that drives the migration of the group of
tributes to cancer cell motility, but also promotes their prolif- cells (reviewed in Refs. 42 and 43).
eration and survival ability in the bloodstream, thereby increas- Integrin can control collective migration in several ways, one
ing the probability of distant metastases forming. of them involving focal adhesion kinase and the tyrosine-pro-
The role of adhesion molecule switching during the epithe- tein kinase Src capacity of up-regulating integrin expression,
lial-mesenchymal transition and malignancy has been exten- which contributes to the processes of integrin-mediated cell
sively studied by overexpression of the EMT-driving transcrip- spreading and migration. Their inhibition effects integrin-me-
tion factors in cell line models (55). Down-regulation of diated signaling, thereby generating a suppression of E-
E-cadherin, ␣6␤4 integrins, and epithelial cell adhesion mole- cadherin– dependent collective cell movement. Further, it is
cules during the transition is orchestrated by twist-related pro- known that focal adhesion kinase in complex with the Src pres-
tein 1, zinc finger E-box– binding homeobox proteins, and the ents a central role in cancer through its ability to promote pro-
transcriptional repressors SNAIL and SLUG (44). The same liferation and resistance in tumor cells, thereby expanding the
factors promote overexpression of N-cadherin as well as ␤1 and influence of integrin signaling when involved in the inhibition
␤3 integrins. However, recent studies have shown that com- of this complex (62, 63).
plete state transition is rarely observed, and in more physiolog- Evidence of collective migration has also been identified in
ical conditions, cancer cells express a combination of epithelial vivo, as clusters of circulating tumor cells have been found in
and mesenchymal markers, thereby creating a heterogeneous the bloodstream of cancer patients (64 –67). In vivo experi-
continuum rather than two binary states (47, 56). In breast can- ments have shown that clusters of circulating tumor cells are
cer models, among these hybrid epithelial-mesenchymal cells, derived from oligoclonal tumors and are not just a mere aggre-
intermediate levels of integrin ␤4 expression mark a population gation of cells in circulation (67). Clusters of circulating tumor
of cells with higher tumor-initiating capacity than integrin 4high cells are migrating out of the primary tumor as a collective and
and integrin ␤4low populations (57). Integrin ␤4 mRNA was are thus more efficient in establishing metastases than individ-
also associated with relapse-free survival in triple-negative ual cancer cells. Abundance of circulating tumor cell clusters is
breast cancer (57). It is not clear which molecular mechanisms clinically relevant, as it correlates with worse patient outcomes
mediated through integrin ␤4 are responsible for the tumor- in different tumor types (68 –70). Characterization of circulat-
initiating properties and maintenance of the intermediate epi- ing tumor cell clusters revealed that the cell adherens junction
thelial-mesenchymal state. protein plakoglobin is crucial for cluster formation, and its

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 JBC REVIEWS: Cell adhesion in normal and malignant cells

Figure 2. Cancer cell clusters, spheres, and organoids. Shown are aspects of cancer cell biology where cell adhesion is crucial yet not well-understood.

knockdown resulted in reduced metastatic spread (67). migration process in standard two-dimensional cultures has
Whereas circulating tumor cell clusters express mesenchymal proven to be challenging, and novel approaches that recapitu-
markers, the presence of cell junctions points again to an inter- late the physical environment of cancer cells are now advancing
mediate epithelial-mesenchymal state, where aspects of epithe- this field. Three-dimensional cell culture conditions that pro-
lial cell adhesion are maintained (71). mote formation of multicellular spheroids, spherical aggregates
Collective migration requires remodeling of the extracellular of cancer cells that produce their own extracellular matrix but
matrix, to facilitate the movement of a group of cells. This do not adhere to the culture dish surface, have been developed
remodeling may also be driven by cancer cells at the leading for many tumor types. Cancer cells grown as spheroids can
front of the invasive group. Recent studies have shown that switch between single-cell epithelial-mesenchymal transition–
cancer-associated fibroblasts (CAFs) can remodel the matrix driven migration and collective migration in response to extra-
and create tracks, which can then be used by migrating cancer cellular matrix porosity and confinement (74). Switching
cells (72). Moreover, by generating heterotypic junctions toward the collective migration mode depends on pericellular
between N-cadherin on the CAF membranes and E-cadherin proteolysis, whereby secretion of matrix metalloproteinases
on the cancer cell membrane, CAFs can generate intercellular enables proteolysis and remodeling of the extracellular matrix
physical force and drive collective invasion of cancer cells (73). and generates space for multicellular assembly movement.
A better understanding of the mechanisms behind the collec- However, the exact mechanisms of remodeling by cellular clus-
tive migration will be of significant clinical relevance, as this ters and their adhesion to remodel extracellular matrix, which
process is often associated with increased resistance to chemo- is required for motility, remain largely unknown (31, 76).
therapy, radiation, and targeted approaches. Recent advances in organotypic cultures allow for three-di-
mensional reconstruction of spheroids and organoids from
Cell-cell interactions and collective migration in three-
patient samples (Fig. 2). Spheroid cultures allow for in vitro
dimensional cultures
maintenance of intratumor heterogeneity that exists in patient
In vitro studies have shown that mesenchymal cells in pri- samples but is mainly lost in standard two-dimensional cul-
mary tumors adopt collective invasion traits as a result of con- tures. Organoids are multicellular assemblies that contain not
finement by the increase of the extracellular matrix density only tumor cells, but also distinct populations of tumor-associ-
(74). Thus, it is possible that clusters of circulating tumor cells ated stroma cells, which contribute to the generation of the
are generated in an increasingly dense extracellular matrix as a extracellular matrix and remodeling (reviewed in Ref. 77).
result of “cell jamming.” This hypothesis could help explain Interestingly, both of these in vitro three-dimensional tumor
why breast tissue density is associated with an increased risk of models are significantly better at reflecting drug responses of
invasive and metastatic cancer (75). It also underlines the tight the patients from which they were derived. This would point to
connection between the microenvironment and the control of the significance of cell-to-cell contact, adhesion, and extracel-
cell adhesion. To address the clinically significant switch lular matrix interactions in therapy responses. Further studies
between single-cell and collective migration, more studies of the properties of organoid cultures are needed to dissect the
focusing on the role of the tumor microenvironment and its molecular mechanisms of cell clustering and interactions.
physical properties are needed. However, collective migration Whereas most of the current drug discovery efforts focus on
occurs when two or more cells move together across a two- cytotoxic effects, we expect that as the three-dimensional mod-
dimensional layer of extracellular matrix while retaining their els become more widely adopted in high-throughput screening
cell-cell junctions or when they move into a three-dimensional platforms, new compounds that could affect cellular adhesion
interstitial tissue scaffold (59). Modeling of the collective will also emerge.

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Integrins, three-dimensional cultures, and cancer mitogen-activated protein kinase pathway and increased motil-
stemlike cells ity and invasion of cancer cells (86). These interactions occur
Organoids and tumor spheroids provide a more faithful independently of the adhesive properties of cadherin and were
model of human tumors, as they retain a higher frequency of shown to drive stemlike properties and epithelial-mesenchy-
cancer stemlike cells compared with traditional cultures. mal transition (89). Because the fibroblast growth factor recep-
Specifically, the first protocols for cancer stemlike cell cul- tor is frequently amplified in genomes of distinct cancer sub-
ture were derived from adult stem cell cultures. These rela- types, targeting this mechanism could be of high clinical
tively rare populations of cancer cells can give rise to relevance.
diversely differentiated subpopulations and are more resist- Another receptor tyrosine kinase also frequently ampli-
ant to standard therapies. fied in cancer is the epidermal growth factor receptor, which
The first protocols for cancer stemlike cell culture were is a crucial factor of breast cancer metastasis (90, 91). Inter-
derived from adult stem cell cultures. Just like normal stem estingly, downstream pathways of the epidermal growth fac-
cells, cancer stemlike cells rely on asymmetric cell division to tor receptor can also be affected by adhesion-independent
retain the pool of undifferentiated cancer stemlike cells, a prop- interactions with the adhesion molecule desmoglein 1 (92).
erty often controlled by contact of cancer stemlike cells with the Because desmoglein 1 is a desomosome protein, which is
stem cell niche. These interactions, both in normal and cancer usually down-regulated in malignant progression, restora-
tissues, are driven by integrins. Depending on the tumor type tion of its expression levels leads to attenuation of epidermal
and genetic background, integrins ␣6␤1, ␣6␤4, and ␣V␤3 have growth factor receptor signaling. This is due to the seques-
all been implicated in stem cell self-renewal, by supporting the tration of the receptor within the membrane, preventing
interactions between cancer stem cells and their niches (78, 79). receptor internalization and activation of Erk1/2, ultimately
leading to a decrease in the formation of cellular protrusions,
Integrins were also shown to provide the anchorage-dependent
such as invapodia, that are needed for invasion. Interactions
context that allows for asymmetric cell division of different pro-
between oncogenic receptor tyrosine kinases could thus be
genitor and stem cells (80 –82) and could play similar functions
attractive targets for therapeutics.
in cancer stem cells.
By activation of focal adhesion kinase, integrin complexes Role of cell adhesion molecules in the tumor
affect the Wnt and hedgehog signaling pathways, which are key microenvironment
to self-renewal and expansion of the stem cell pool and are
Expression of distinct adhesion molecules in malignancy is
considered essential regulators of oncogenesis (83). It is thus
not limited to cancer cells, and it can be significantly altered in
plausible that adhesion molecules expressed in cancer cells in
noncancerous cells of the tumor microenvironment. Cancer
three-dimensional organoid cultures provide signaling that
cell secretion of pro-angiogenic factors results in increased
mimics the supportive environment of the stem cell niches.
blood vessel generation (93). However, the endothelial cells that
This is another unexplored area where studies of cellular adhe-
line these new vessels have lower than normal expression of
sion could lead to the identification of novel therapeutic
endothelial adhesion molecules, such as intercellular adhesion
approaches.
molecules 1 and 2, vascular cell adhesion molecule 1, E-selectin,
and CD34 (94). This endothelial anergy, characterized as unre-
Role of growth factors in adhesion molecule signaling
sponsiveness to inflammatory signaling, results in decreased
Cell-to-cell contact maintenance is not the only biological adhesion of immune cells to the wall of the vessel, leading to
function of adherent molecules related to cancer progression or reduced effector T-cell infiltration into the tumor, which is a
inhibition. Ample evidence shows that these molecules can also key mechanism of immune evasion of solid malignancies (95).
activate signaling pathways independently of adhesion (84). Adhesion molecules are also key in leukocyte-cancer cell
One such function, relevant to cancer progression, is the ability interactions. For example, dendritic cells responsible for phag-
of cell adhesion molecules to modulate growth factor receptor ocytosis and cancer-derived antigen presentation interact with
signaling, which is of great relevance because growth factor dying cancer cells via integrins, such as integrin ␣V␤4 (96, 97).
stimulation is one of the most important hallmarks of cancer On the other hand, dendritic cells can also express ␤2 integrin,
(recently reviewed in Ref. 60). For example, the fibroblast which promotes anti-inflammatory interactions. Integrin ␣E,
growth factor receptor (FGFR) tyrosine kinase can be bound by which is expressed by dendritic cells, but also by myeloid-de-
several adhesion molecules, including N-cadherin, NCAM, and rived suppressor cells and regulatory T cells, promotes pro- or
L1CAM (85). N-cadherin can trigger cis-dimerization of FGFR, anti-tumorigenic action of immune cells, depending on its cel-
which leads to autophosphorylation of the receptor and recruit- lular context (94). The exact role of distinct classes of adhesion
ment and phosphorylation of downstream factors (86). This molecules expressed by dendritic cells in the anti-tumor
growth-promoting signaling is independent of the ligand. The immune response remains to be determined.
extracellular domain of N-cadherin can also interact with FGFR
and inhibit its internalization, which leads to increased signal- Cadherins and integrins as targets for cancer therapy
ing in a ligand-independent fashion (87). Additionally, N-cad- Cadherin as well as integrin expression and activation
herin was also shown to prevent FGFR ubiqitination and directly influence human malignancies. Due to their broad im-
degradation (88). Both FGFR and N-cadherin are often overex- pact in malignant transformations, they are considered poten-
pressed in metastatic cells, which results in up-regulation of the tial targets for cancer therapy (94). Cadherin-mediated cell-cell

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 JBC REVIEWS: Cell adhesion in normal and malignant cells

adhesion disruption is frequently observed in solid and hema- (Fig. 3A) that inhibits the growth of drug-sensitive and -re-
tological tumors. By analyzing CD34⫹ cell populations from sistant cells in the micromolar range, reduces cell migration
patients with myelodysplastic syndrome, it was shown that the and invasive abilities, and presents an increased potency
promoter of E-cadherin often hypermethylated, which results compared with sunitinib (107).
in decreased protein expression (98). Further, comparison of From a genome-wide study of taxol resistance, the miR-29c
bone marrow and blood revealed that in normal control sam- miRNA was identified, which is directly related to the resis-
ples, the E-cadherin promoter was essentially unmethylated, tance observed in therapy against nasopharyngeal carci-
and 78% of the leukemia samples presented abnormal hy- noma. Regulation of taxol resistance by miR-29c was dem-
permethylation of this region, thus reinforcing the E-cad- onstrated to occur due the inhibition of integrin ␤1. When
herin gene as a common target for hypermethylation in silencing miR-29c, a marked increase in growth of taxol-
hematologic malignancies (99). resistant nasopharyngeal carcinoma tumor occurred, whereas
Leukemic stem cell self-renewal is largely dependent on the knockdown of integrin ␤1 reversed the tumor growth.
N-cadherin, which causes future evasion of chemotherapy These results indicate that miR-29c has the potential to be
effects. The overexpression of N-cadherin in hematopoietic used in taxol-resistant nasopharyngeal carcinoma therapy by
stem and progenitor cells was shown to promote and pre- inhibiting integrin ␤1 (108) and support the interest in
serve hematopoietic stem and progenitor cells during serial designing compounds targeting integrin for the treatment of
bone marrow transplantations. Further, inhibition of N- drug-resistant tumors.
cadherin resulted in a significant reduction in long-term Further, siRNA is a novel emerging therapy approach for
engraftment. These findings suggest that N-cadherin– treating various diseases, such as cancer. In this approach,
mediated cell adhesion is functionally essential for the regu- the specific delivery to the desired target cells is necessary to
lation of hematopoietic stem and progenitor cell activity in achieve high therapeutic efficacy. Drug delivery systems
the bone marrow and thus an interesting target for the treat- such as dendrimers have been used as promising strategies to
ment of leukemia (100). siRNA delivery. One example of this approach was the
Integrins are considered prime promising anti-cancer design of an amphiphilic dendrimer (Fig. 3B) composed with
drug targets, and their antagonists have been shown to a dual-targeting peptide bearing an RGDK lipopeptide (Fig.
achieve success by impeding integrin trafficking that in- 3C) warhead designed to interact with integrin. This tar-
volves invasion and migration of cells in tumors, which are geted system enhanced siRNA delivery, increasing gene
crucial in promoting cancer metastasis (4). Some ␣V integrin silencing, and anticancer activity, reducing proliferation of
antibodies have been evaluated in late-stage clinical trials, cells (106).
such as abituzumab (Merck KGaA, Darmstadt, Germany) Integrin has also been studied as a cancer target by employing
and intetumumab (Centocor, Malvern, PA). Both bind the a drug-repurposing approach. It is known that integrin ␤3
integrin ␣V subunit and inhibit all five ␣V integrins. They could potentially overcome chemoresistance due to its abun-
were both shown to inhibit ligand binding and tumor growth dant expression in drug-resistant cells that have a mesenchymal
in xenograft models. Abituzumab showed a favorable safety phenotype. Thus, an in silico screening approach was used to
profile for progressive castration-resistant prostate cancer search for drugs that mimic the changes of the transcriptome
patients with bone metastases after chemotherapy. Intetu- level caused by the knockdown of integrin ␤3. By this approach,
mumab showed the potential to be efficacious as a single atorvastatin (Fig. 3D) was identified as a novel candidate for
agent for the treatment of metastatic melanoma and dis- drug repurposing, which represents an alternative path to drug
played a manageable safety profile. The results presented discovery for undruggable integrins. It was shown that atorvas-
support further larger clinical studies (101–104). tatin sensitized cancer cells to conventional chemotherapeutic
Integrin ␤2 inhibitors function by inhibiting cell adhesion drugs, such as doxorubicin (109).
and trapping of white blood cells. Antibodies and small mole- The examples discussed above represent a minor fraction of
cules have been generated, but in most cases, issues were the broad diversity of approaches that have been studied in past
encountered during the trials (105). Here, the shortage of ani- years involving cadherins and integrins as drug targets for can-
mal models, including knockout mouse models, is one of the big cer. They clearly show the promising nature of these strategies
difficulties because proper in vivo models are required to vali- and the plurality of paths that can be applied to achieve their
date the target. Further roadblocks are encountered due to the goals.
low therapeutic effect, the lack of selectivity, and the presence
of side effects, in particular hepatotoxicity. In addition to the Outlook
compounds that have already reached clinical trials, there are a Cell adhesion molecules could constitute an attractive
wide variety of recent studies on integrin inhibition as a target therapeutic target group, as their extracellular domains
for cancer therapy strategy (106). could be easily accessed by antibodies or small-molecule
Another study using the integrin-targeted approach was inhibitors. Multiple clinical trials have been initiated based
undertaken for drug-resistant ovarian carcinoma. Conju- on successful reduction of tumor growth by integrin target-
gates presenting a selective binder for the extracellular por- ing, especially ␣V and ␤1 (101–105). Thus far, most of the
tion of integrin ␣V␤3 covalently linked to sunitinib, a tyro- clinical trials have not significantly affected the disease-free
sine kinase inhibitor, were screened for their anti-tumor or overall survival in patients (67). This may be due to the
potential. This strategy resulted in one active compound redundancy in signaling mediated by integrins, but also due

J. Biol. Chem. (2020) 295(8) 2495–2505 2501

JBC REVIEWS: Cell adhesion in normal and malignant cells

Figure 3. Different drug discovery approaches to targeting integrin for cancer therapy. A, conjugate presenting a selective binder for the extracellular
region of integrin aVb3 (black) covalently linked to sunitinib (blue) (79). B, amphiphilic dendrimer composed with a dual-targeting peptide bearing an
Arg-Gly-Asp-Lys (RGDK) lipopeptide (red) (C) (81). D, atorvastatin identified as a novel candidate for drug repurposing for undruggable integrins (82).

to adverse effects caused by disruption of integrin-depen- microenvironment are also warranted to open new avenues
dent functions in normal tissues. New studies targeting cell for more effective cancer treatment.
adhesion in combination with other drugs are under way. A
bispecific antibody targeting ␤2 integrin LFA-1 and Id was
Acknowledgment—We thank Dr. Erumbi Rangarajan (The Scripps
recently developed (61). In preclinical trials for B cell lym-
Research Institute) for insightful discussions.
phoma, this antibody targeted cancer cells exclusively,
despite expression of ␤2 integrin on several normal cell
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