Cancer–stroma interactions as a target for cancer treatment.
During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of tumor. The success of immune checkpoint therapy generates a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual component...
Gespeichert in:
| Datum: | 2018 |
|---|---|
| Hauptverfasser: | , , |
| Format: | Artikel |
| Sprache: | English |
| Veröffentlicht: |
2018
|
| Schriftenreihe: | Інститут молекулярної біології і генетики НАН України |
| Schlagworte: | |
| Online Zugang: | http://dspace.nbuv.gov.ua/handle/123456789/154273 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Zitieren: | Cancer–stroma interactions as a target for cancer treatment. / I.V. Alekseenko, V.V. Pleshkan, E.D. Sverdlov // Вiopolymers and Cell. — 2018. — Т. 34, № 4. — С. 271-283. — Бібліогр.: 69 назв. — англ. |
Institution
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
irk-123456789-154273 |
|---|---|
| record_format |
dspace |
| spelling |
irk-123456789-1542732019-07-07T12:40:52Z Cancer–stroma interactions as a target for cancer treatment. Alekseenko, I.V. Pleshkan, V.V. Sverdlov, E.D. Reviews During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of tumor. The success of immune checkpoint therapy generates a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but rather to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. In this minireview we consider cancer associated fibroblasts (CAF) and their interactions with cancer cells as a promising direction for cancer therapy. В ході еволюції пухлини ракові клітини використовують взаємодії пухлина-строма для реорганізації мікрооточення для досягнення максимальної стійкості пухлини. Успіх терапії з використанням імунних контрольних точок запропонував нову парадигму лікування раку: для перемоги раку, слід відмовитися від спроб його лікування, націлюючись лише на ракові, або тільки на стромальні клітини, або на компоненти складних внутрішньоклітинних взаємодій. Замість цього потрібно докладати зусиль для руйнування пухлини в цілому, розірвавши взаємодії між її частинами, зокрема, шляхом впливу на прямі контакти між власне раковими і стромальних клітинами пухлини. У цьому міні-огляді ми розглянемо можливість використання пухлина-асоційованих фібробластів (ОАФ) і їхню взаємодію з раковими клітинами як перспективний напрям терапії раку. В ходе эволюции опухоли раковые клетки используют взаимодействия опухоль-строма для реорганизации микроокружения с целью достижения максимальной устойчивости опухоли. Успех терапии с использованием иммунных контрольных точек породил новую парадигму лечения рака: для того, чтобы победить рак, следует отказаться от попыток его лечения, нацеливаясь только на раковые, или только на стромальные клетки, или на компоненты сложных внутриклеточных взаимодействий. Вместо этого нужно предпринимать усилия для разрушения опухоли в целом, разорвав взаимодействия между ее частями, в частности, путем воздействия на прямые контакты между собственно раковыми и стромальными клетками опухоли. В этом мини-обзоре мы рассмотрим возможность использования опухоль-ассоциированных фибробластов (ОАФ) и их взаимодействий с раковыми клетками в качестве перспективного направления терапии рака. 2018 Article Cancer–stroma interactions as a target for cancer treatment. / I.V. Alekseenko, V.V. Pleshkan, E.D. Sverdlov // Вiopolymers and Cell. — 2018. — Т. 34, № 4. — С. 271-283. — Бібліогр.: 69 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000980 http://dspace.nbuv.gov.ua/handle/123456789/154273 571.27 en Інститут молекулярної біології і генетики НАН України Вiopolymers and Cell |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| topic |
Reviews Reviews |
| spellingShingle |
Reviews Reviews Alekseenko, I.V. Pleshkan, V.V. Sverdlov, E.D. Cancer–stroma interactions as a target for cancer treatment. Інститут молекулярної біології і генетики НАН України |
| description |
During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the microenvironment for maximum robustness of tumor. The success of immune checkpoint therapy generates a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but rather to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. In this minireview we consider cancer associated fibroblasts (CAF) and their interactions with cancer cells as a promising direction for cancer therapy. |
| format |
Article |
| author |
Alekseenko, I.V. Pleshkan, V.V. Sverdlov, E.D. |
| author_facet |
Alekseenko, I.V. Pleshkan, V.V. Sverdlov, E.D. |
| author_sort |
Alekseenko, I.V. |
| title |
Cancer–stroma interactions as a target for cancer treatment. |
| title_short |
Cancer–stroma interactions as a target for cancer treatment. |
| title_full |
Cancer–stroma interactions as a target for cancer treatment. |
| title_fullStr |
Cancer–stroma interactions as a target for cancer treatment. |
| title_full_unstemmed |
Cancer–stroma interactions as a target for cancer treatment. |
| title_sort |
cancer–stroma interactions as a target for cancer treatment. |
| publishDate |
2018 |
| topic_facet |
Reviews |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/154273 |
| citation_txt |
Cancer–stroma interactions as a target for cancer treatment. / I.V. Alekseenko, V.V. Pleshkan, E.D. Sverdlov // Вiopolymers and Cell. — 2018. — Т. 34, № 4. — С. 271-283. — Бібліогр.: 69 назв. — англ. |
| series |
Інститут молекулярної біології і генетики НАН України |
| work_keys_str_mv |
AT alekseenkoiv cancerstromainteractionsasatargetforcancertreatment AT pleshkanvv cancerstromainteractionsasatargetforcancertreatment AT sverdloved cancerstromainteractionsasatargetforcancertreatment |
| first_indexed |
2025-07-14T05:55:41Z |
| last_indexed |
2025-07-14T05:55:41Z |
| _version_ |
1837600647961116672 |
| fulltext |
271
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
© 2018 I. V. Alekseenko et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Bio-
polymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited
UDC 571.27
Cancer–stroma interactions as a target for cancer treatment
I. V. Alekseenko1,2, V. V. Pleshkan1,2, E. D. Sverdlov1,2
1 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS
16/10, Miklukho-Maklaya, Moscow, Russian Federation, 117997
2 Institute of Molecular Genetics, Russian Academy of Sciences,
2, Kurchatov Sq. Moscow Russian Federation, 123182
irina.alekseenko@mail.ru
During tumor evolution, cancer cells use the tumor-stroma crosstalk to reorganize the mi-
croenvironment for maximum robustness of tumor. The success of immune checkpoint
therapy generates a new cancer therapy paradigm: an effective cancer treatment should not
aim to influence the individual components of super complex intracellular interactomes
(molecular targeting), but rather to disrupt the intercellular interactions between cancer and
stromal cells, thus breaking the tumor as a whole. In this minireview we consider cancer
associated fibroblasts (CAF) and their interactions with cancer cells as a promising direction
for cancer therapy.
K e y w o r d s: cancer, hallmark, therapy, immunotherapy, stroma, crosstalk
Abbreviations: CAF — cancer associated fibroblast; ECM — extracellular matrix; TCR —
T cell receptor; TIL — tumor-infiltrating lymphocyte; TME –tumor microenvironment.
Introduction. Not only Cancer cells
but their microenvironment is critical
for tumor progression
In 2000, Hanahan et al. commented that the
medical implications of the concept of com-
mon hallmarks of cancer are as follows: “We
envision development of anticancer drugs tar-
geted to each of the hallmark capabilities of
cancer; some, used in appropriate combina-
tions … will be able to prevent incipient can-
cers from developing, while others will cure
preexisting cancers, elusive goals at pre-
sent.” [1]. The hallmarks were principally de-
duced for cancer cells, [2, 3], although almost
all of them, except replicative immortality,
which is questionable, implicated the participa-
tion of the tumor microenvironment cells [2].
Therefore, the concept in this approach implies
that the therapies act against cancer cells. As
early as 2006, Orimo and Weinberg noted the
importance of stroma for tumor progression
[4]. From approximately 2010, the number of
publications describing stroma’s contribution
ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2018. Vol. 34. N 4. P 271–283
doi: http://dx.doi.org/10.7124/bc.000980
mailto:irina.alekseenko@mail.ru
272
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
to cancer development has quickly increased
[2, 5, 6], although “abetting microenviron-
ment” has been included in the list of the main
hallmarks only in 2017 [7].
This inclusion makes sense. The current
view of the tumor stroma is not just a physical
support of mutated epithelial cells. All tumors
engage in a broad repertoire of normal cells in
their evolution and adopt them for their needs.
The recruited normal cells facilitate the acqui-
sition of characteristic traits and form what is
called the tumor microenvironment (TME).
TME is an ecological niche, which plays the
most important role in both the development
of a primary tumor and its metastasi-
zing [2, 8–13].
Neither cancer cells, nor stromal cells alone,
but their interactions lead to the evolution of
a tumor as an organ-like entity. These interac-
tions include: (i) direct binary contacts be-
tween ligands and receptors exposed on the
surfaces of cancer and stroma cells, and (ii)
paracrine communications between cancer
(usually epithelial) cells and various cells of
TME [14, 15] (Fig. 1). Some authors use the
term “symbiotic” [16, 17] for tumor–stroma
interaction: “The relationship between tumor
and stroma is symbiotic. Stromal cells are cor-
rupted by malignant epithelium, creating a
permissive microenvironment, which drives
cancer progression” [18] (see also [16, 17]).
It is now clear that to defeat cancer, we
should move from the indecipherable complex-
ity of intracellular interactomes to disrupting
the system as a whole by destroying interac-
tions of its parts.
This simple “home-grown intuition” [19]
determines a new paradigm for cancer therapy:
the search and destruction of the intercellular
crosstalk that lies at the root of the success of
the malignant tumors’ murderous mission.
A stromal component of tumors — an
indispensable part of cancer evolution
The American National Cancer Institute de-
fines TME as “normal cells, molecules and
blood vessels that surround and feed a tumor.
A tumor can change its microenvironment; the
microenvironment can affect how a tumor
grows and spreads.” In solid tumors, the can-
cer microenvironment consists of two main
components, cellular and non-cellular, whose
ratios and composition vary depending on the
location and stage of the tumor.
The non-cellular components mainly in-
clude the extracellular matrix (ECM) com-
posed of proteins, glycoproteins, and proteo-
glycans, which serves as a scaffold for sup-
porting tissue architecture [2, 8, 20].
The cellular components include fibroblasts,
such as cancer associated fibroblasts (CAFs),
Fig. 1. Direct and paracrine interactions in tumor. Di-
rect binary contacts between antigen-presenting cell and
T-cell are displayed in example of MHC-antigene-Tcell
receptor (TCR) and checkpoint molecules (CTLA-4 and
CD80/86) interactions. Paracrine signaling is presented
by soluble factors (various circles) and their receptors.
273
Cancer–stroma interactions as a target for cancer treatment
mesenchymal stem cells, adipocytes, pericytes,
endothelial cells, networks of lymphatic ves-
sels, and tumor-infiltrating cells of the immune
system [18, 21–24]. From the therapeutic point
of view, immune cell interactions with cancer
cells might be the most successful targets for
cancer treatment, and they could serve as a
paradigm for more general approach.
Immune checkpoint therapy —
a new paradigm for tumor therapy
T-cells of the immune system have proteins
on their surface called checkpoints that turn
on an immune response and other proteins that
turn it off. Checkpoint proteins activate
T-cells, for example, when an infection or
cancer cells is present. However, if T-cells are
active for too long, or react to things they
shouldn’t, then other checkpoints switch off
the T-cells. Some cancer cells make high lev-
els of checkpoint proteins that switch off
T-cells, so that they can no longer recognize
and kill cancer cells.
The simple principle of how the T-cells can
avoid immunosuppression and resume tumor
annihilation is illustrated in Fig. 2. Monoclonal
antibodies against CTLA-4 or PD-1, or their
ligands, disrupt the interaction of these mo le-
cules with T-cells allowing them to destroy
tumors. This concept was proven by a revolu-
tionary therapeutic success of targeting the
binary interactions between the stromal im-
mune cells and antigen-presenting cells, stro-
mal immune cells and cancer cells, stromal
immune cells (CD8+ cytotoxic lymphocytes)
and CAFs. This kind of therapy was named
the immune checkpoint therapy.
The most impressive effect of the CTLA-4
blockade is its ability to induce a long-term
tumor regression that lasted up to 13 years in
clinical trials with some melanoma patients.
However, success rate in the case of mela-
noma was only about 8 % (see the latest data
in [25]). Moreover, drug-activated T-cells
affect healthy tissues. Clinical trials revealed
severe side effects in about 15 % of patients,
including several fatal outcomes. The reader
can find the toxicity data in [26]. Still, the
inhibition of CTLA-4 checkpoint made a
revolutionary shift in the perception of cancer
as an incurable disease. The success of im-
munotherapy stimulated the search for other
inhibiting checkpoints for cancer treat-
ment [27, 28].
Fig. 2. Suppression of T-cell and its activation by
checkpoint inhibitors. On the upper side the T-cell is
suppressed by expressed on CAF surface ligands PD-L1/
PD-2 and CD80/86 binding to PD-1 and CTLA-4 recep-
tors of the T-cell, respectively. Lower is demonstrated
restoration of T-cell activity when blocking antibodies
(black ancipital fork) to various receptors/ligands are
present. This disrupts the cell-cell interaction.
274
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
CTLA-4 and PD-1 regulate different inhi-
biting pathways and have the non-overlapping
action mechanisms, suggesting that a com-
bined therapy might be more efficient. Indeed,
this was experimentally demonstrated in pre-
clinical trials with mouse models. The pre-
liminary clinical trials with anti -CTLA-4
combined with anti-PD-1 or anti-PD-L1 anti-
bodies in other types of tumors produced
promising results that declare the new com-
bination immunotherapy an efficient strategy
for cancer patients [27, 29]. However, the
combined procedure has a somewhat higher
toxicity.
Although these methods have greatly in-
creased the lifespan of many patients with
malignant neoplasms, many patients with com-
mon cancer types do not respond to this treat-
ment. Further, inhibition of immune check-
points causes multiple side effects, mostly
autoimmune inflammatory reactions also
known as immune-related adverse events
(IRAEs) [26, 30–32].
Lessons of checkpoint therapy. Inter-
cellular (possibly, synapse-like) con-
tacts vs intracellular interactomes
Cell-surface proteins represent attractive tar-
gets for therapy due to their accessibility and
involvement in essential signaling pathways,
often dysregulated in cancer [33]. A receptor-
ligand interaction is in itself a single key
event — the binding of a signaling molecule
(ligand) to its receiving molecule (receptor).
Thus, they are involved in relatively simple
binary interactions.
This is the basis of well-recognized drug-
gable properties of receptors and their cognate
ligands, which make them especially useful
clinical targets [34]. Furthermore, interacting
cells in intercellular contacts are brought to-
gether to a distance comparable to the length
of the receptor-ligand complexes, typically
15-40 nm [35]. Therefore, inhibition of the two
targets might also result in the inhibition of
paracrine crosstalk.
These considerations lead to a concept of
therapeutically promising area of direct inter-
cellular interactions as an antithesis of molec-
ular-targeted therapy whose targets are the
components of complex intracellular interac-
tomes. Immune checkpoint therapy is a strik-
ing example of the success of the above-men-
tioned concept [36]. However, its complexity
is manifested here by its rather high toxicity
and the enormous variability of patients’ re-
sponses ranging from none to complete remis-
sion, which presents a challenging problem
[26, 30, 37, 38].
Worse still, the available long-term follow-
up data on melanoma shows that a substantial
number of patients that were earlier responding
to the therapy with inhibitors of immune
checkpoints become resistant [38, 39]. We do
not understand why T-cell checkpoints are
ineffective in the majority of cancer pa-
tients. This could be because their immune
system does not recognize antigens of cancer
cells or due to different mechanisms of im-
mune inhibition [40].
A multitude of new agents targeting other
immune and non-immune processes and tumor
components is under investigation [39]. These
include inhibitors of immune checkpoints, co-
stimulating agonists, oncolytic viruses, vac-
cines, and adoptive cell therapy, as well as
combinations with traditional methods of treat-
ment [41].
275
Cancer–stroma interactions as a target for cancer treatment
Other TME components as potential
participants of cancer stroma
interaction
Keeping in mind a successful approach of
destroying the direct interactions between im-
mune and cancer cells, we hypothesize that a
similar strategy might be fruitful if such pro-
tumor binary contacts existed between the
cancer cells and other components of stroma.
It is widely accepted that paracrine crosstalk
between tumor stroma cells causes a transfor-
mation of stromal fibroblasts to CAFs. The
binary contacts between cancer cells and oth-
er components of stroma might be a target for
therapeutic action. We will give a very concise
outline of the potentially promising explor-
atory approaches wherein tumor-stroma and
stroma-stroma interactions can be detected. To
this end, we will consider an example of CAFs
which are better studied than the other stromal
constituents.
A brief overview of cancer-associated
fibroblasts, barely explored architects
of cancer pathogenesis
CAFs are some of the most prevalent stromal
cells in a number of carcinomas, including
breast, prostate, pancreas, esophagus, and in-
testine cancer [22]. In other carcinomas, in-
cluding ovarian carcinoma, melanomas, and
kidney tumors, CAFs are less frequent, but still
occur [8]. CAFs as targets for enhancing can-
cer therapy efficiency attracted great attention.
Some authors even call them “The Architects
of Stroma Remodeling” [42] or “Architects of
Cancer Pathogenesis” [43]. CAFs have been
reported to variously affect the tumor pro-
gression, involving ECM degradation, re-
lease of numerous soluble factors, regulation
of tumor metabolism, and promotion of
cancer cell proliferation, migration, and
metastasis. The most recent findings are found
in the relevant reviews [22–24, 42, 44, 45].
The normal fibroblasts can have a variety
of suppressive functions against the initiation
of cancer and metastatic cells through direct
contacts with cells and paracrine signaling
with soluble factors. The tumor-induced
transformation of the normal fibroblasts into
CAFs causes a number of pro-tumorigenic
signals, followed by a distortion of the normal
tissue structure, thus supporting the growth of
cancer cells [46]. CAFs are a heterogeneous
‘family’ or ‘group’ of cells that exhibit mes-
enchymal-like features.
Conversion of the normal fibroblasts to
CAFs is considered a three-step process. First,
distant normal cells are recruited by malignant
or pre-malignant cells through paracrine and
endocrine signals. Second, the recruited cells
are transformed into CAFs. Finally, the third
step is the maintenance, expansion and evo-
lution of CAF populations in the cancer mi-
croenvironment, enabled by the persistent sig-
nals produced by malignant cells [47, 48]. In
return, CAF population emanates paracrine
signals that affect cancer progression.
Bidirectional crosstalk between cancer cells
and fibroblasts is presumed to be the leading
cause of malignant cancer phenotype forma-
tion [49, 50].
One of the most significant features of CAFs
is that their phenotype, which promotes tumor
progression, is stably maintained in vitro and
ex vivo even without a steady contact with
neighboring cancer cells [20, 45, 51]. Recent
studies reported that many types of cells could
be recruited as predecessors of CAFs: resident
276
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
tissue fibroblasts, peritumoral adipocytes, bone
marrow mesenchymal stem cells, hematopoi-
etic stem cells, and many others [44, 45]. After
recruiting from various sources, a subset of
these precursors acquires the CAFs phenotype
through complex activation processes that are
still poorly understood. Most researches agree
that irrespective of the precursor, CAFs express
similar sets of mar kers, such as α-smooth mus-
cle actin (α-SMA), fibroblast activation protein
(FAP), and the α and β platelet-derived growth
factor receptor (PDGFR) [44]. Unlike in epi-
thelial cancer cells, the genetic changes such
as oncogene/tumor suppressor mutations are
rare in CAFs. In contrast, epigenetic chang-
es, such as DNA methylation, histone modifi-
cations and nucleosome structure, changes in
the expression of non-coding RNAs and ab-
normal activation of several signaling path-
ways, are often observed when the CAF
phenotype is acquired. These changes affect
the expression of many genes encoding growth
factors, cytokines, and other products which
intensifies proliferation, stimulates secretion of
ECM proteins and various growth factors, and
causes remodeling of cytoskeleton [2, 8, 22,
44, 45, 52].
Therefore, the stroma currently attracts a
significant attention of researchers developing
the new approaches to cancer treatment [5, 21,
51, 53].
Cancer associated fibroblasts can
inhibit antitumor immune response
through direct contact with immune
cells
Because of their preponderance in the tumor
microenvironment, CAFs were recently stud-
ied as regulators of immune cell recruitment
and function. As the result, CAFs were shown
to play pro-inflammatory and immunosup-
pressive roles through secretion of TGF and
other cytokines, thus affecting both the in-
nate and adaptive immune response [45, 54].
In this review, we will consider direct contact
of CAFs with cells of the immune system,
which, in our opinion, are important for
strengthening and guiding the action of para-
crine factors.
CAFs can establish direct contacts with
immune cells and affect the efficiency of
checkpoint immunotherapy by means of the
expression of co-inhibitory receptor ligands
[55–58]). By now, such a possibility was ex-
perimentally demonstrated for PD-L1 and/or
PD-L2 expression. Nazareth and colleagues
[57] found a constitutively high expression of
functional PD-L1 and 2 in the fibroblasts cul-
tured from human non-small cell lung cancers.
It was also shown that CAFs of large intestine
cancer express PD-L1 and PD-L2 and nega-
tively regulate the proliferative response of
CD4+ Th-cells. Similar observations were re-
ported for CAFs from melanoma cells (see
review [45]). However, most of these findings
were made in in vitro experiments using iso-
lated CAFs, and, therefore, require further
studies to confirm the physiological signifi-
cance of PD-L1/L2 expression by CAFs for
their immunosuppressive role in vivo [45].
Recent research [55], presents further evi-
dence of the immuno-inhibiting function of
CAFs resulting from their direct interactions
with immune cells. The authors show that
CAFs can function as antigen presenting cells,
able to absorb, process, and present on their
surface tumor specific antigens combined with
MHC-I proteins. With the help of PD-L2 and
277
Cancer–stroma interactions as a target for cancer treatment
FASL, this triggers an antigen-specific nega-
tive regulation of tumor-specific CD8+T cells,
which leads to their dysfunction and apoptosis.
Neutralization of PD-L2 or FASL reactivates
the cytotoxic capacity of T cells in vitro and
in vivo.
Thus, CAFs might support T-cell suppres-
sion within the tumor microenvironment by a
mechanism dependent on immune checkpoint
activation. [55], making it another mechanism
of T-cell depletion and dysfunction within
tumors [55].
CAFs can directly interact with can-
cer cells and enhance their invasion
and metastasis
CAFs are often found in the vicinity of, or in
direct contact with, neoplastic cells [8, 22, 23,
53]. However, only a few reports provide an
experimental evidence for the CAF-cancer
cell direct interaction and study its func-
tional consequences. The most obvious and
important consequence of such direct interac-
tions is the involvement of CAFs in promot-
ing cancer cell epithelial-mesenchymal tran-
sition, invasion and metastasis [42, 59–64].
This should be expected as collective cell mi-
gration is ubiquitous in multicellular organ-
isms. In addition, it is recognized that the
physical interaction between cells in conjunc-
tion with chemical signals plays a fundamen-
tal role in this process [65].
Gaggioli et al. [59] demonstrated that CAFs
led the invasion of squamous cell carcinoma
cells (SCCs) by generating tracks in the extra-
cellular matrix in a co-culture system. During
joint invasion, the leading cells were CAFs,
and associated SCC cells followed. Thus, SCC
cell invasion needs either close proximity, or
direct contact, to CAFs. Similar evidence is
presented in the review [63].
To investigate the differential contribution
of direct cell–cell contacts and paracrine sig-
naling factors to NSCLC metastasis, Choe et
al. [61] performed two types of co-cultures:
direct co-cultures of the NSCLC cell line with
primary cultures of CAFs from patients with
resected NSCLC and indirect cocultures across
a separable membrane. CAFs more potently
induced EMT in case of direct co-culture,
providing evidence that the physical contacts
between NSCLC cells and CAFs might control
the metastatic potential of NSCLC. This prob-
ably does not exclude the participation of para-
crine crosstalk that could be strengthened by
the physical cell-to-cell interaction, similar to
the immune synapses.
In a more recent review [42], it is indicated
that CAFs adjacent to cancer regions were able
to increase the invasiveness of cancer cells
through both cell-cell interactions and various
pro-invasive molecules, such as cytokines,
chemokines and inflammatory mediators. It is
also known [42] that CAFs can travel togeth-
er in blood with circulating murine metastatic
lung carcinoma cancer cells probably support-
ing the cancer cell viability and growth advan-
tage at the metastatic site. The authors hypoth-
esized that in invasive tumors, the cancer and
stromal cells were in direct contact and estab-
lished a complex crosstalk that evolved during
tumor development.
In a very important study [64], the authors
demonstrated that CAFs caused a collective
invasion by means of a heterophilic adhesion
involving N-cadherin at the CAF membrane
and E-cadherin at the cancer cell membrane.
Impairment of the E-cadherin/N-cadherin ad-
278
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
hesion abrogates the ability of CAFs to guide
collective cell migration and blocks cancer cell
invasion. In parallel, the organizers of intercel-
lular junctions, nectins and afadin, are recruit-
ed to the cancer cell/CAF interface. These
findings show that a mechanically active het-
erophilic adhesion between CAFs and cancer
cells enables cooperative tumor inva-
sion. Contacts between cancer cells and CAFs
may also be implemented through the interac-
tion of Eph-receptor and reciprocal ephrin li-
gands [66]. One can assume that these direct
contacts form synapse-like structures, strength-
ening the paracrine cross-talk.
CAFs promote tumor invasion and metas-
tasis. We show that CAFs exert a physical
force on cancer cells that enables their col-
lective invasion. Force transmission is medi-
ated by a heterophilic adhesion involving
N-cadherin at the CAF membrane and
E-cadherin at the cancer cell membrane.
This adhesion is mechanically active. When
subjected to force, it triggers β-catenin re-
cruitment and adhesion reinforcement depen-
dent on α-catenin/vinculin interaction.
Impairment of E-cadherin/N-cadherin adhe-
sion abrogates the ability of CAFs to guide
collective cell migration and blocks cancer
cell invasion. N-cadherin also mediates re-
polarization of the CAFs away from the can-
cer cells. In parallel, nectins and afadin are
recruited to the cancer cell/CAF interface and
CAF repolarization is afadin dependent.
Heterotypic junctions between CAFs and can-
cer cells are observed in patient-derived ma-
terial. Together, our findings show that a me-
chanically active heterophilic adhesion be-
tween CAFs and cancer cells enables coop-
erative tumour invasion [64].
Attempts of targeting the interaction
between CAFs and carcinoma cells
The sinister role of direct interactions of CAFs
with cancer cells in the process of metastasis
makes it especially important to destroy these
contacts for therapeutic purposes. With such a
goal, Yamaguchi et al. [63] tried to identify
inhibitors of direct interaction between
CAFs and cancer cells, and found that the Src
inhibitor dasatinib effectively blocked the
physical association between CAFs and scir-
rhous gastric carcinoma (SGC) cells with a
very low cytotoxic effect. Dasatinib was also
effective against peritoneal dissemination of
SGC in mouse model experiments. Importantly,
histological analysis revealed that metastasiz-
ing tumors were less associated with stromal
fibroblasts in mice treated with dasatinib com-
pared to controls. These results demonstrate
that direct interaction between CAFs and
SGC cells can be a target for anti-metasta-
sis therapy [63]. Nevertheless, the authors
advise caution, referencing the studies which
showed that the depletion of CAFs in mouse
models accelerated progression of pancreatic
cancer. Although these results are contradic-
tory, they accentuate the need for thorough
safety testing of the inhibitors of CAF-cancer
interactions in anticancer therapy. On the oth-
er hand, if the therapeutic target were the CAF-
cancer contacts and not CAFs themselves, the
strategy might be safe because CAFs would
not be depleted.
The use of CAF as a trans-shipment
point for the delivery of genetic thera-
peutic constructs to cancer cells
Another feature of CAFs, important from the
viewpoint of new therapeutic targets, is worth
279
Cancer–stroma interactions as a target for cancer treatment
noting: fibroblasts are more genetically stable
than “true” cancer cells [21, 67]. They divide
slowly and, accordingly, slowly mutate. Due
to this, stromal therapeutic targets might be
more stable compared to cancer cells with a
permanently changing genetic structure.
Several strategies have now emerged to
utilize therapeutic gene delivery to intention-
ally alter the CAFs. It has been shown that
plasmid DNA can be delivered to, and ex-
pressed in, CAFs using lipid-based nanopar-
ticles as carriers [68, 69]. The delivery of a
gene that produced a soluble TNFa-related
apoptosis inducing ligand (sTRAIL) to CAFs
caused apoptosis in the tumor parenchyma,
and ultimately tumor regression [69]. Similarly,
several studies have shown that delivery to
CAFs of genes encoding fusion proteins de-
signed to be secreted and bound to soluble
factors such as chemokines and cytokines in
the tumor microenvironment can cause reduc-
tion of metastasis and ultimately improve sur-
vival in animal models.
Collectively, these results offer a proof of
concept for the use of gene therapeutic con-
structs to modify CAFs for further transfer of
therapeutics to cancer cells or their environ-
ment could be an effective strategy to treat
cancers.
Conclusion
This review illustrates that cancer is no longer
regarded just as a set of mutant and dysregu-
lated epithelial cancer cells with their “driver”
mutations. Instead, cancer and TME (stroma)
cells jointly form an evolving, integrated,
cooperative, and dynamic organ-like system.
So, it becomes clear that in order to defeat
cancer, we should abandon the attempts to
treat by targeting the components of complex
intracellular interactoms, and instead try to
disrupt the system, as a whole, by destroying
the interaction of its constituent parts. Further
analysis of interactions and the development
of systems for the delivery and expression of
genes in CAF may lead to the emergence of
a new approach that will significantly improve
cancer therapy, especially in combination with
checkpoint immunotherapy and more tradi-
tional methods such as chemo- and radio-
therapy
Funding
The work was supported by the Russian Science
Foundation (project 14-50-00131) and by RFBR
according to research projects № 17-00-00194
(17-00-00190), № 16-04-01842 а, № 16-34-60185
(mol_а_dk).
REFERENCES
1. Hanahan D, Weinberg RA. The hallmarks of cancer.
Cell. 2000;100(1):57–70.
2. Hanahan D, Coussens LM. Accessories to the crime:
functions of cells recruited to the tumor microenvi-
ronment. Cancer Cell. 2012;21(3):309–22.
3. Hanahan D, Weinberg RA. Hallmarks of cancer: the
next generation. Cell. 2011;144(5):646–74.
4. Orimo A, Weinberg RA. Stromal fibroblasts in can-
cer: a novel tumor-promoting cell type. Cell Cycle.
2006;5(15):1597–601.
5. Gonda TA, Varro A, Wang TC, Tycko B. Molecular
biology of cancer-associated fibroblasts: can these
cells be targeted in anti-cancer therapy? Semin Cell
Dev Biol. 2010;21(1):2–10.
6. De Palma M, Hanahan D. The biology of personal-
ized cancer medicine: facing individual complexities
underlying hallmark capabilities. Mol Oncol.
2012;6(2):111–27.
7. Fouad YA, Aanei C. Revisiting the hallmarks of
cancer. Am J Cancer Res. 2017;7(5):1016–1036.
280
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
8. Gascard P, Tlsty TD. Carcinoma-associated fibro-
blasts: orchestrating the composition of malignancy.
Genes Dev. 2016;30(9):1002–19.
9. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G,
Sun Y. New horizons in tumor microenvironment
biology: challenges and opportunities. BMC Med.
2015;13:45.
10. Gandellini P, Andriani F, Merlino G, D’Aiuto F,
Roz L, Callari M. Complexity in the tumour micro-
environment: Cancer associated fibroblast gene
expression patterns identify both common and
unique features of tumour-stroma crosstalk across
cancer types. Semin Cancer Biol. 2015;35:96–106.
11. Stadler M, Walter S, Walzl A, Kramer N, Unger C,
Scherzer M, Unterleuthner D, Hengstschläger M,
Krupitza G, Dolznig H. Increased complexity in
carcinomas: Analyzing and modeling the interaction
of human cancer cells with their microenvironment.
Semin Cancer Biol. 2015;35:107–24.
12. Zi F, He J, He D, Li Y, Yang L, Cai Z. Fibroblast
activation protein α in tumor microenvironment:
recent progression and implications (review). Mol
Med Rep. 2015;11(5):3203–11.
13. Raffaghello L, Dazzi F. Classification and biology
of tumour associated stromal cells. Immunol Lett.
2015;168(2):175–82.
14. Perrimon N, Pitsouli C, Shilo BZ. Signaling mech-
anisms controlling cell fate and embryonic patter-
ning. Cold Spring Harb Perspect Biol. 2012;4(8):
a005975.
15. Bizzarri M, Cucina A. Tumor and the microenviron-
ment: a chance to reframe the paradigm of carcino-
genesis? Biomed Res Int. 2014;2014:934038.
16. Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W.
CXCL12/CXCR4: a symbiotic bridge linking can-
cer cells and their stromal neighbors in oncogenic
communication networks. Oncogene. 2016;35(7):
816–26.
17. Sluka P, Davis ID. Cell mates: paracrine and stromal
targets for prostate cancer therapy. Nat Rev Urol.
2013;10(8):441–51.
18. Bhome R, Bullock MD, Al Saihati HA, Goh RW,
Primrose JN, Sayan AE, Mirnezami AH. A top-down
view of the tumor microenvironment: structure, cells
and signaling. Front Cell Dev Biol. 2015;3:33.
19. Weinberg RA. Coming full circle-from endless com-
plexity to simplicity and back again. Cell.
2014;157(1):267–71.
20. Reina-Campos M, Moscat J, Diaz-Meco M. Me-
tabolism shapes the tumor microenvironment. Curr
Opin Cell Biol. 2017;48:47–53.
21. Bhome R, Al Saihati HA, Goh RW, Bullock MD,
Primrose JN, Thomas GJ, Sayan AE, Mirnezami AH.
Translational aspects in targeting the stromal tumour
microenvironment: from bench to bedside. New
Horiz Transl Med. 2016;3(1):9–21.
22. Kalluri R. The biology and function of fibroblasts
in cancer. Nat Rev Cancer. 2016;16(9):582–98.
23. LeBleu VS, Kalluri R. A peek into cancer-associated
fibroblasts: origins, functions and translational im-
pact. Dis Model Mech. 2018;11(4). pii: dmm029447.
24. Valkenburg KC, de Groot AE, Pienta KJ. Targeting
the tumour stroma to improve cancer therapy. Nat
Rev Clin Oncol. 2018;15(6):366–381.
25. Munhoz RR, Postow MA. Clinical development of
pd-1 in advanced melanoma. Cancer J. 2018/
Feb;24(1):7–14.
26. Postow M, Wolchok J. Patient selection criteria and
toxicities associated with checkpoint inhibitor im-
munotherapy. UptoDate. 2018.
27. Sharma P, Allison JP. The future of immune check-
point therapy. Science. 2015;348(6230):56–61.
28. Sharpe AH. Introduction to checkpoint inhibitors
and cancer immunotherapy. Immunol Rev.
2017;276(1):5–8.
29. Wilson RAM, Evans TRJ, Fraser AR, Nibbs RJB. Im-
mune checkpoint inhibitors: new strategies to check-
mate cancer. Clin Exp Immunol. 2018;191(2):133–148.
30. Calabrese L, Velcheti V. Checkpoint immunothera-
py: good for cancer therapy, bad for rheumatic
diseases. Ann Rheum Dis. 2017;76(1):1–3.
31. Abdin SM, Zaher DM, Arafa EA, Omar HA. Tackling
cancer resistance by immunotherapy: updated clin-
ical impact and safety of PD-1/PD-L1 inhibitors.
Cancers (Basel). 2018;10(2). pii: E32.
32. Postow MA, Hellmann MD. Adverse events associ-
ated with immune checkpoint blockade. N Engl J
Med. 2018;378(12):1165.
32. Postow MA, Sidlow R, Hellmann MD. Immune-
Related Adverse Events Associated with Immune
281
Cancer–stroma interactions as a target for cancer treatment
Checkpoint Blockade. N Engl J Med. 2018;
378(2):158–168.
33. Kuhlmann L, Cummins E, Samudio I, Kislinger T.
Cell-surface proteomics for the identification of
novel therapeutic targets in cancer. Expert Rev Pro-
teomics. 2018;15(3):259–275.
34. Kim JW, Cochran JR. Targeting ligand-receptor
interactions for development of cancer therapeutics.
Curr Opin Chem Biol. 2017;38:62–69.
35. Weikl T, Asfaw M, Krobath H, Rozycki B, Lipow-
sky R. Adhesion of membranes via receptor–ligand
complexes: Domain formation, binding cooperati-
vity, and active processes. Soft Matter.2009; 5(17):
3213–24.
36. Cogdill AP, Andrews MC, Wargo JA. Hallmarks of
response to immune checkpoint blockade. Br J
Cancer. 2017;117(1):1–7.
37. Alexander W. The checkpoint immunotherapy revo-
lution: what started as a trickle has become a flood,
despite some daunting adverse effects; new drugs,
indications, and combinations continue to emerge.
P T. 2016;41(3):185–91.
38. Madden DL. From a patient advocate’s perspective:
does cancer immunotherapy represent a paradigm
Shift? Curr Oncol Rep. 2018; 20(1): 8.
39. Dempke WCM, Fenchel K, Uciechowski P, Dale SP.
Second- and third-generation drugs for immuno-
oncology treatment-The more the better? Eur J
Cancer. 2017;74:55–72.
40. Fearon DT. The carcinoma-associated fibroblast
expressing fibroblast activation protein and escape
from immune surveillance. Cancer Immunol Res.
2014;2(3):187–93.
41. Day D, Monjazeb AM, Sharon E, Ivy SP, Rubin EH,
Rosner GL, Butler MO. From famine to feast: devel-
oping early-phase combination immunotherapy trials
wisely. Clin Cancer Res. 2017;23(17):4980–4991.
42. Santi A, Kugeratski FG, Zanivan S. Cancer associ-
ated fibroblasts: the architects of stroma remodeling.
Proteomics. 2018;18(5-6):e1700167.
43. Marsh T, Pietras K, McAllister SS. Fibroblasts as
architects of cancer pathogenesis. Biochim Biophys
Acta. 2013;1832(7):1070–8.
44. Liao Z, Tan ZW, Zhu P, Tan NS. Cancer-associated
fibroblasts in tumor microenvironment - accom-
plices in tumor malignancy. Cell Immunol. 2018.
pii: S0008-8749(17)30222–8.
45. Ziani L, Chouaib S, Thiery J. Alteration of the an-
titumor immune response by cancer-associated fi-
broblasts. Front Immunol. 2018;9:414.
46. Alkasalias T, Moyano-Galceran L, Arsenian-Hen-
riksson M, Lehti K. Fibroblasts in the tumor micro-
environment: shield or spear? Int J Mol Sci.
2018;19(5). pii: E1532.
47. De Wever O, Van Bockstal M, Mareel M, Hendrix A,
Bracke M. Carcinoma-associated fibroblasts provide
operational flexibility in metastasis. Semin Cancer
Biol. 2014;25:33–46.
48. Heneberg P. Paracrine tumor signaling induces
transdifferentiation of surrounding fibroblasts. Crit
Rev Oncol Hematol. 2016;97:303–11.
49. Augsten M. Cancer-associated fibroblasts as an-
other polarized cell type of the tumor microenviron-
ment. Front Oncol. 2014;4:62.
50. Tao L, Huang G, Song H, Chen Y, Chen L. Cancer
associated fibroblasts: An essential role in the tumor
microenvironment. Oncol Lett. 2017;14(3):2611–
2620.
51. Lamprecht S, Sigal-Batikoff I, Shany S, Abu-Fre-
ha N, Ling E, Delinasios GJ, Moyal-Atias K, Deli-
nasios JG, Fich A. Teaming up for trouble: cancer
cells, transforming growth factor-β1 signaling and
the epigenetic corruption of stromal naïve fibro-
blasts. cancers (Basel). 2018;10(3). pii: E61.
52. Du H, Che G. Genetic alterations and epigenetic
alterations of cancer-associated fibroblasts. Oncol
Lett. 2017;13(1):3–12.
53. Belli C, Trapani D, Viale G, D’Amico P, Duso BA,
Della Vigna P, Orsi F, Curigliano G. Targeting the
microenvironment in solid tumors. Cancer Treat
Rev. 2018;65:22–32.
54. Harper J, Sainson RC. Regulation of the anti-tumour
immune response by cancer-associated fibroblasts.
Semin Cancer Biol. 2014;25:69–77.
55. Lakins MA, Ghorani E, Munir H, Martins CP,
Shields JD. Cancer-associated fibroblasts induce
antigen-specific deletion of CD8 (+) T Cells to
protect tumour cells. Nat Commun. 2018;9(1):948.
56. Rozali EN, Hato SV, Robinson BW, Lake RA, Les-
terhuis WJ. Programmed death ligand 2 in cancer-
282
I. V. Alekseenko, V. V. Pleshkan, E. D. Sverdlov
induced immune suppression. Clin Dev Immunol.
2012;2012:656340.
57. Nazareth MR, Broderick L, Simpson-Abelson MR,
Kelleher RJ Jr, Yokota SJ, Bankert RB. Character-
ization of human lung tumor-associated fibroblasts
and their ability to modulate the activation of tu-
mor-associated T cells. J Immunol. 2007;178(9):
5552–62.
58. Jacobs J, Smits E, Lardon F, Pauwels P, Deschool-
meester V. Immune checkpoint modulation in
colorectal cancer: what’s new and what to expect.
J Immunol Res. 2015;2015:158038.
59. Gaggioli C, Hooper S, Hidalgo-Carcedo C,
Grosse R, Marshall JF, Harrington K, Sahai E.
Fibroblast-led collective invasion of carcinoma
cells with differing roles for RhoGTPases in lead-
ing and following cells. Nat Cell Biol. 2007;
9(12):1392–400.
60. Semba S, Kodama Y, Ohnuma K, Mizuuchi E, Ma-
suda R, Yashiro M, Hirakawa K, Yokozaki H. Direct
cancer-stromal interaction increases fibroblast pro-
liferation and enhances invasive properties of scir-
rhous-type gastric carcinoma cells. Br J Cancer.
2009;101(8):1365–73.
61. Choe C, Shin YS, Kim SH, Jeon MJ, Choi SJ, Lee J,
Kim J. Tumor-stromal interactions with direct cell
contacts enhance motility of non-small cell lung
cancer cells through the hedgehog signaling path-
way. Anticancer Res. 2013;33(9):3715–23.
62. He XJ, Tao HQ, Hu ZM, Ma YY, Xu J, Wang HJ,
Xia YJ, Li L, Fei BY, Li YQ, Chen JZ. Expression of
galectin-1 in carcinoma-associated fibroblasts pro-
motes gastric cancer cell invasion through upregulation
of integrin β1. Cancer Sci. 2014;105(11):1402–10.
63. Yamaguchi H, Sakai R. Direct interaction between
carcinoma cells and cancer associated fibroblasts
for the regulation of cancer invasion. Cancers (Ba-
sel). 2015;7(4):2054–62.
64. Labernadie A, Kato T, Brugués A, Serra-Picamal X,
Derzsi S, Arwert E, Weston A, González-Tarragó V,
Elosegui-Artola A, Albertazzi L, Alcaraz J, Roca-
Cusachs P, Sahai E, Trepat X. A mechanically active
heterotypic E-cadherin/N-cadherin adhesion enables
fibroblasts to drive cancer cell invasion. Nat Cell
Biol. 2017;19(3):224–237.
65. Theveneau E, Linker C. Leaders in collective migra-
tion: are front cells really endowed with a particular
set of skills? F1000Res. 2017;6:1899.
66. Wang B. Cancer cells exploit the Eph-ephrin system
to promote invasion and metastasis: tales of unwit-
ting partners. Sci Signal. 2011;4(175):pe28.
67. Castells M, Thibault B, Delord JP, Couderc B. Im-
plication of tumor microenvironment in chemore-
sistance: tumor-associated stromal cells protect tu-
mor cells from cell death. Int J Mol Sci.
2012;13(8):9545–71.
68. Harrison EB, Azam SH, Pecot CV. Targeting Acces-
sories to the crime: nanoparticle nucleic acid deliv-
ery to the tumor microenvironment. Front Pharma-
col. 2018;9:307.
69. Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L,
Yin W, Hu S, Kim WY, Huang L. Targeting tumor-
associated fibroblasts for therapeutic delivery in
desmoplastic tumors. Cancer Res. 2017;77(3):
719–731.
Взаємодії пухлина-строма як мішень
для протипухлинної терапії
І. В. Алексеєнко, В. В. Плешкан,
Є. Д. Свердлов
В ході еволюції пухлини ракові клітини використову-
ють взаємодії пухлина-строма для реорганізації мікро-
оточення для досягнення максимальної стійкості пух-
лини. Успіх терапії з використанням імунних контр-
ольних точок запропонував нову парадигму лікування
раку: для перемоги раку, слід відмовитися від спроб
його лікування, націлюючись лише на ракові, або
тільки на стромальні клітини, або на компоненти
складних внутрішньоклітинних взаємодій. Замість
цього потрібно докладати зусиль для руйнування пух-
лини в цілому, розірвавши взаємодії між її частинами,
зокрема, шляхом впливу на прямі контакти між власне
раковими і стромальних клітинами пухлини. У цьому
міні-огляді ми розглянемо можливість використання
пухлина-асоційованих фібробластів (ОАФ) і їхню вза-
ємодію з раковими клітинами як перспективний на-
прям терапії раку.
К л юч ов і с л ов а: рак, маркер, терапія, імунотера-
пія, строма, взаємодії
283
Cancer–stroma interactions as a target for cancer treatment
Взаимодействия опухоль-строма как мишень
для противоопухолевой терапии
И. В. Алексеенко, В. В. Плешкан, Е. Д. Свердлов
В ходе эволюции опухоли раковые клетки используют
взаимодействия опухоль-строма для реорганизации
микроокружения с целью достижения максимальной
устойчивости опухоли. Успех терапии с использованием
иммунных контрольных точек породил новую
парадигму лечения рака. Для того, чтобы победить рак,
следует отказаться от попыток его лечения, нацелива-
ясь только на раковые, или только на стромальные
клетки, или на компоненты сложных внутриклеточных
взаимодействий. Вместо этого нужно предпринимать
усилия для разрушения опухоли в целом, разорвав
взаимодействия между ее частями, в частности, путем
воздействия на прямые контакты между собственно
раковыми и стромальными клетками опухоли. В этом
мини-обзоре мы рассмотрим возможность использо-
вания опухоль-ассоциированных фибробластов (ОАФ)
и их взаимодействий с раковыми клетками в качестве
перспективного направления терапии рака.
К л юч е в ы е с л ов а: рак, маркер, терапия, иммуно-
терапия, строма, взаимодействия
Received 05.06.2018
_GoBack
См1
|