Omentum provides a special cell
microenvironment for ovarian cancer
Zeying, Li; Xiaoling, Fang; Sixue, Wang
Author Information
Zeying, Li: the first author. The second xiangya hospital of central
south university, Email: 447868162@qq.com.
Xiaoling, Fang: Corresponding author. The second xiangya hospital of
central south university, Email:fxlfxl0510@csu.edu.cn.
Sixue, Wang: The second xiangya hospital of central south university,
Email: 168212281@csu.edu.cn.
Author contribution
Zeying, Li: visualization, writing - original draft.
Xiaoling, Fang: writing - review and editing.
Sixue, Wang: visualization, writing - review and editing.
Funding
There is no specific funding for this review article.
Conflicts of interest
The authors have nothing to declare.
Abstract
Ovarian cancer seriously threatens women’s health because of its poor
prognosis and high mortality. Due to the lack of efficient early
detection and screening methods, when patients seek doctors’ help with
complaints of abdominal distension, back pain and other nonspecific
signs, the clinical results always hint at the widespread metastasis of
disease. When referring to the metastasis of this disease, the omentum
always takes precedence. The distinguishing feature of the omentum is
adipose tissue, which satisfies the energy demand of cancer cells and
supplies a more aggressive environment for ovarian cancer cells. In this
review, we mainly focus on three important cell types: adipocytes,
macrophages and mesenchymal stem cells. Besides, several mechanisms
underlying cancer-associated adipocytes (CAA)-facilitated ovarian cancer
cell development have been revealed, including their capacities for
storing lipids and endocrine function, and the release of hormones,
growth factors, and adipokines. Blocking the reciprocity among cancer
cells and various cells located on the omentum might contribute to
ovarian cancer therapy. The inhibition of hormones, growth factors and
adipokines produced by adipocytes will be a novel therapeutic strategy.
However, a sufficient number of trials has not been performed. In spite
of this, the therapeutic potential of metformin and the roles of
exercise in ovarian cancer will be worth mentioning. It’s almost
impossible to overcome completely ovarian cancer at the moment. What we
can do is trying our best to improve these patients’ prognoses. In this
process, adipocytes may bring promising future for the therapy of
ovarian cancer.
Keywords: ovarian cancer, omentum, adipocyte, metformin, exercise
1. Introduction
Ovarian cancer has a 1.3% probability of occurrence in women. Although
the specific pathogenesis of the disease is poorly elucidated, many
results have pointed out that multiple birth history, use of oral
contraceptives, avoidance of menopausal hormone use, and ligation of the
oviduct reduce the risk of developing ovarian
cancer[1]. Epithelial ovarian cancer (EOC) is the
most common type. High-grade serous carcinoma (HGSC) is the most common
epithelial subtype[2]. Most HGSC patients are
diagnosed at stage III or IV, which is consistent with their poor 5-year
survival, compared with other subtypes of ovarian
cancer[3].
The omentum, which is encompassed mainly by adipose tissue, is the site
where ovarian cancer is most prone to metastasis. In 1889, Paget first
introduced the “seed and soil” principle in terms of cancer
metastasis[4]. Although there are several theories
and hypotheses raised to challenge this concept, it’s still accepted by
majority nowadays[4]. However, idiographic terms
change constantly; for example, “seed” has been renamed cancer stem
cells and “soil” has been renamed the tumor microenvironment in most
cases[5]. We are interested in the interaction of
the omentum, which acts as “soil”, and ovarian cancer cells, which
play the part of “soil”. Although past studies have explained the
above mechanisms from various aspects, an integrative review has not
been performed. Thus, in this review, we provide a systematic overview
of these processes in the context of adipose tissue, particularly
adipocytes and macrophages that promote the biological behavior of
ovarian cancer cells, and discuss the roles of obesity in ovarian cancer
from an overall perspective. It is obvious that a comprehensive
understanding of the above constants is necessary for clinical and basic
research.
2. Various cell components in the
omentum play roles in ovarian cancer development
Sylwia Wilkosz et al. concluded that the human greater omentum is
composed of an adipose-rich region and is translucent and membranous by
means of phase contrast microscopy, scanning electron microscopy (SEM),
and transmission electron microscopy (TEM). The former contains a great
deal of milky spots, a cluster of stromal cells and immune cells,
including B cells, T cells, NK cells, macrophages, etc. which are also
named fat-associated lymphoid clusters[6]. Robert
Clark et al. proposed a two-step model to clarify the roles of milky
spots and adipocytes: Milky spots participate in the location of ovarian
cancer cells, and adipocytes play part in the subsequent migration and
invasion. Neither T cells nor B cells can assist ovarian cancer cell
infiltration, however, macrophages play opposing
roles[7]. Mesenchymal stem cells can be found
widely in various tissues. They can boost the progression and metastasis
of ovarian cancer by their multipotent differentiation ability,
self-renewal potential, immunomodulatory and secretion
function[8]. Remarkably, mesenchymal stromal cells
(MSCs) deprived of omentum adipose tissue show distinctive
characteristics when compared with mesenchymal stromal cells deprived of
adipose tissue from other sites. Existing experimental results have
demonstrated that adipose-derived mesenchymal stem cells would enhance
the growth, migration and invasion[9,10].
Therefore, the concrete roles and mechanisms of adipocytes, macrophages
and stromal cells in ovarian cancer will be discussed below. Figure 1
has shown the relationship among these cells and ovarian cancer.
2.1 Cancer-associated adipocytes
deprived of omentum
Cancer-associated adipocytes (CAAs) might directly influence ovarian
cancer cell malignant behaviors by infiltrating into tumor cells, other
adipocytes are located around cancer cells and influence cancer cells
indirectly. And a cluster of adipocytes remodeled by tumor cells have
roles akin to magic[11].
Generally, we have reached a consensus that the oxidative metabolism
deregulated in cancer cells. They tend to utilize glycolysis to produce
energy, which is different from healthy cells. This characteristic is
named the Warburg effect[12]. Ovarian cancer cells
are no exception. However, while coculturing adipocytes and ovarian
cancer cells, the alterations in lipid metabolism in ovarian cancer
cells deserve attention. Regardless of whether adipocytes are cocultured
with ovarian cancer cell lines in vitro or cancer cells adjacent
to the omentum in vivo , an increase in lipid peroxidation in
ovarian cancer cells to meet their surge in energy demand is observed,
and this process mainly depends on adipocytes, which act as a “lipid
library”. Some factors produced or regulated by adipocytes also support
cancer cell lipid metabolism reprogramming from lipid synthesis to
catabolism. For example, mass spectrometry of the proteins regulated by
coculturing with adipocytes and a comparison of data for primary and
metastatic tumors from a public dataset revealed the same changes, in
which CD36, FABP4 and ADH-1 were significantly upregulated under the
influence of adipocytes[13,14].
The complex and vital functions and mechanisms involved in modulating
ovarian cancer cell growth and progression will be summarized. In this
part, we mainly refer to some hormones, adipokines and other factors
that are released or associated with adipocytes. And the roles of these
factors are summarized in the table 1.
2.1.1 Leptin and leptin to adiponectin (L:A) ratio
Leptin is a kind of adipocyte-secreted hormone and plays different roles
in ovarian cancer. It can promote ovarian cancer cell growth through
cyclin D1, a cancer cell growth sensor, and Mcl-1, an anti-apoptotic
factor[15]. The expression of uPA induced by
leptin mediates ovarian cancer cell invasion[16].
Flow cytometry results have verified that leptin is associated with
chemoresistance of ovarian cancer[17]. Several
particular mechanisms are involved in the above roles, including the
MEK/ERK1/2 pathway,PI3K̸Akt pathway, RhoA/ROCK pathway, estrogen receptor
pathway[18], etc. But there are some opposite
conclusions. The molecule alone has no obvious effect on ovarian cancer.
It’s interesting that Słomian GJ combined leptin and adiponectin and
used their ratio as indicator of the response to
chemotherapy[19]. Adiponectin is another adipokine
produced by adipocytes. It acts different roles in various cells. For
example, it can take part in the cell differentiation and regulate the
endocrine function of adipose tissue[20]. There’s
a mountain of evidence which suggests that this factor has
anti-carcinogenic effects[21]. Some agents which
can increase the level or stimulate the activity of adiponectin would be
hopeful for the therapy of ovarian cancer[22]. In
fact, this has given us a meaningful tip. Besides exploring the roles of
various adipocytokines, the interaction among these factors is also
necessary.
2.1.2 Resistin
Resistin is a novel adipocytokine that is secreted by human adipocytes
and mononuclear cells[23]. The exiting results
have revealed that the higher level of resistin, the poorer prognosis of
ovarian cancer. It can enhance the angiogenesis process,
epithelial-mesenchymal transition and stemness of ovarian cancer
cells[24]. Recombinant human resistin enhanced the
expression of VEGF in a time- and dose-dependent manner in human ovarian
cancer cell lines. The PI3K/Akt-Sp1 pathway mediates the above effects
of resistin. However, additional in vivo studies on the
functional network among these factors are
lacking[25].
2.1.3 Wnt5a
Wnt5a is a highly evolutionarily conserved noncanonical Wnt
ligand[26] that is involved in ovarian cancer
metastasis. It is mainly produced by peritoneal mesothelial cells and
visceral adipose tissue. In ex vivo experiments, ovarian cancer
cell lines acquire greater adhesion and migration ability under the
influence of recombinant wnt5a. WNT5A knockout mice achieved by crossing
WNT5A-floxed mice (Wnt5afl/fl) with UBC-Cre/ERT2 mice were distinguished
from the control tumor group at the cytokine level, including cytokines
that regulate immune cell chemotaxis. Practically speaking, knocking out
WNT5A will contribute to a higher CD8+/−FOXP3+ ratio and M1/M2
macrophage ratio, and both of them indicate better disease prognosis.
Further studies show that the Src family kinase Fgr is its downstream
effector. Some selective inhibition of Fgr kinase activity might be
exerted to treat ovarian cancer[27].
2.1.4 MCP-1
Monocyte chemotactic protein-1 (MCP-1) is also known as chemokine (C-C
motif) ligand 2 (CCL-2)[28]. MCP-1 produced by
omental adipocytes can bind to its receptor CCR-2 to regulate the
expression of VEGF-A via the PI3K/AKT/mTOR pathway. In vitromigration and invasion assays, this axis also helped ovarian cancer
cells gain more aggressive characteristics. Either MCP-1 neutralization
antibody or CCR-2 antagonist could weaken the
effects[29].
2.1.5 FABP4
FABP4 is mainly produced by adipocytes and macrophages and participates
in the regulation of intracellular lipids by binding and redistributing
them normally[30]. However, adipocyte-induced
FABP4 expression can promote ovarian cancer cell proliferation and
metastasis both in vivo and in vitro . The inhibition of
FABP4 by CRISPR and siRNA reduced the capacity of adipocyte cocultured
ovarian cancer cells to accumulated lipids,and with the impact of this,
adipocyte-relevant β-oxidation, ROS generation and lipid peroxidation
were affected. It often increases ATP-production by glycolysis and
reduces mitochondrial ATP production. Some addition of glycolysis
process products might cycle arrest. U Harjes et al. discovered that
silencing FABP through siRNA contributes to the inhibition of
angiogenesis, growth and metastasis in
vivo [31]. Furthermore, this factor can be
regulated by some cytokines. For example, IL-17A, a vital
proinflammatory cytokine, has been found to upregulate FABP4 to realize
more fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to
help ovarian cancer cell growth and metastasis in an adipose-rich
environment[32]. Therefore, some molecular
inhibitors targeting FABP4 might block its function and bring a
promising future for ovarian cancer therapy, such as BMS309403, which
was initially used to treat atherosclerosis and type 2 diabetes and has
been proven to increase platinum-based drug sensitivity in
vivo [13,33,34].
2.1.6 CD36
Adipocytes from human greater omentum can induce the expression of CD36
in ovarian cancer cells, which is a unique feature distinguishing it
from other omental cell types, including fibroblasts and macrophages.
The expression of CD36 can increase the uptake of fatty acids and lipid
accumulation, as measured by fluorescently labeled fatty acid analogs
and immunofluorescent staining for neutral lipids. The inhibition of
this factor would cripple its abovementioned roles. At the same time,
the results of gene expression analysis demonstrated the downregulation
of acetyl-CoA carboxylase (ACACA), the rate-limiting enzyme in FA
synthesis[35]. Transcription factor analysis
revealed that several lipogenic genes were also downregulated, such as
Sterol Regulatory Element Binding Transcription Factors (SREBPF1 and
SREBPF2). Sterol regulatory element binding proteins (SREBPs) are the
most important transcription factors in lipid homeostasis. It has three
isoforms, SREBP-1a, SREBP-1c and SREBP-2. SREBP-1c mainly regulates
fatty acid synthesis, and SREBP-2 is specifically involved in
cholesterol synthesis[36]. All these facts
indicate that omental adipocytes can alter ovarian cancer metabolism by
CD36; they can not only promote exogenous lipid uptake rather than
endogenous lipid synthesis but also enhance anaerobic glucose metabolism
while suppressing glucose oxidation. Furthermore, in vitroexperiments, CyQuant cell proliferation assays and transwell assays
showed that CD36 can promote ovarian cancer cell proliferation, invasion
and migration. SKOV3ip1 and OVCAR8 xenograft mouse models also indicate
that CD36 regulates the metastasis of ovarian
cancer[37].
2.1.7 ADH-1B
Analyses of data from public datasets have shown that ADH-1B (alcohol
dehydrogenase 1B) is one of the candidates for forecasting residual
ovarian cancer[38]. It can fuel the progression
and infiltration of ovarian cancer cells in vivo and in
vitro . ADH-1B mainly mediates ethanol conversion to acetaldehyde.
Therefore, with the upregulation of ADH-1B, acetaldehyde may accumulate
gradually[39]. In fact, acetaldehyde is toxic to
cells, has carcinogenic effects, and disrupts the DNA repair and
methylation processes[40]. However, specific and
systemic studies on ADH-1B in ovarian cancer still exhibit a large gap.
2.1.8 SIK-2
Dysregulation of fatty acid and cholesterol synthesis plays an important
role in ovarian cancer. Salt-inducible kinase 2 (SIK2) is overexpressed
in adipocyte-rich metastases[41] and can enhance
the expression of FASN (one of the rapid-limiting enzymes in fatty acid
synthesis) and HMGCR (one of key enzymes in cholesterol synthesis) to
promote ovarian cancer cell multiplication and metastasis in
vitro and in vivo [42]. Adipocytes can
activate SIK-2 autophosphorylation through the Ca2+pathway. SIK-2 can participate in fatty acid oxidation and mitochondrial
respiration, which might sustain adipocyte-induced metastasis of ovarian
cancer[41]. Furthermore,SIK-2 can also directly
phosphorylate MYLK and activate its downstream pathway to boost ovarian
cancer cell motility[43].
2.1.9 DPYSL4
RNA sequencing and chromatin immunoprecipitation (ChIP)-sequence
analyses have shown that dihydropyrimidinase-like 4 (DPYSL4) is a
regulator of downstream of P53. Metabolome analysis verified higher
concentrations of glycolysis intermediates in HCT116 human non-small
cell lung cancer cells without P53 expression, in accordance with tumor
cells preferentially using glycolysis rather than OXPHOS to meet their
rapid energy demand. 2D Blue Native SDS polyacrylamide gel
electrophoresis (BN/SDS/PAGE) was used to confirm that DPYSL4 is
associated with mitochondrial supercomplexes I, III, and IV. The oxygen
consumption rate (OCR) and the NAD+/NADH ratio also indicate that DPYSL4
plays roles in mitochondrial respiration, which rescues the Warburg
effect in cancer cells. The function of DPYSL4 in tumor cell energy
metabolism provides a novel angle of view for antitumor metabolism. For
ovarian cancer, Kaplan–Meier survival analyses have shown that DPYSL4
is associated with poor survival in ovarian
cancer[44,45]. Unfortunately, this factor lacks
further insightful investigations in ovarian
cancer[46].
2.1.10 miR-21
Next-generation sequencing has revealed that RNA expression is different
in exosomes isolated from ovarian cancer cells and adipocytes and
fibroblasts from normal human omental tissue and cancer-associated
omental tissue. MiR-21 is the most abundant[47].
Though influencing the activity of PI3K/AKT mediated by PTEN, the
upregulation of miR-21 will promote ovarian cancer cell proliferation
and inhibit cancer cell apoptosis[48]. In
addition, it’s involved in the chemoresistance progress by CD44v6
pathway[49]. There are still many research gaps
remaining about its potential roles in ovarian cancer.
2.1.11 Bclxl
Carlos Cardenas et al. regarded CD44+/MyD88+ epithelial ovarian cancer
(EOC) stem cells as a chemoresistance
phenotype[50]. The Bcl2 family members show
evident variation in chemoresistance models and can determine cancer
cell survival or apoptosis. Gene expression microarray analysis revealed
that BCL2L1 is the most differentially expressed gene in
chemotherapy-resistant ovarian cancer cells compared with
chemotherapy-sensitive ovarian cancer cells, and the western blot
results also prove that Bclxl, encoded by BCL2L1, is
differentially expressed. On the other hand, the adipocyte-infiltrated
microenvironment always upregulates the expression of
Bclxl. Bclxl-specific siRNA will achieve apoptosis of
chemoresistant ovarian cancer cells[51,52].
Table 1