Omentum provides a special cell microenvironment for ovarian cancer

Abstract Background 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. Recent findings 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. Conclusion It is 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.

(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. 3e 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. 4Although there are several theories and hypotheses raised to challenge this concept, it is still accepted by majority nowadays. 4However, idiographic terms change constantly; for example, "seed" has been renamed cancer stem cells and "soil" has been renamed the tumor microenvironment in most cases. 5We are interested in the interaction of the omentum, which acts as "soil," and ovarian cancer cells, which play the part of "seed."Although past studies have explained the above mechanisms from various aspects, they either contained only a fraction of the cell species or explored only a fraction of the cytokines, 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.

| VARIOUS CELL COMPONENTS IN THE OMENTUM PLAY ROLES IN OVARIAN CANCER DEVELOPMENT
Wilkosz et al. 6 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, and so forth, which are also named fat-associated lymphoid clusters.Clark et al. 7 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.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. 8Remarkably, 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. 9,10Therefore, 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.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. 12Ovarian 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. 13,14e 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.

| 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 antiapoptotic factor. 15The expression of uPA induced by leptin mediates ovarian cancer cell invasion. 16Flow cytometry results have verified that leptin is associated with chemoresistance of ovarian cancer. 17veral particular mechanisms are involved in the above roles, including the MEK/ERK1/2 pathway, PI3K̸ Akt pathway, RhoA/ROCK pathway, estrogen receptor pathway, 18 and so forth.But there are some opposite conclusions.The molecule alone has no obvious effect on ovarian cancer.It is interesting that Słomian 19 combined leptin and adiponectin and used their ratio as indicator of the response to chemotherapy.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. 20There is a mountain of evidence which suggests that this factor has anti-carcinogenic effects. 21Some agents which can increase the level or stimulate the activity of adiponectin would be hopeful for the therapy of ovarian cancer. 22In fact, this has given us a meaningful tip.Besides exploring the roles of various adipocytokines, the interaction among these factors is also necessary.

| Resistin
Resistin is a novel adipocytokine that is secreted by human adipocytes and mononuclear cells. 23The 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. 24Recombinant 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

| Wnt5a
Wnt5a is a highly evolutionarily conserved noncanonical Wnt ligand 26 In the microenvironment of adipose tissue infiltration, various cell components support adipose tissue and play important roles in ovarian cancer development via their specific functions and unique characteristics.Adipocytes, as the dominant cells in this environment, can secrete many kinds of cytokines and factors to enhance ovarian cancer cell growth, invasion, migration, angiogenesis and chemoresistance.Macrophages and mesenchymal stem cells depend on their own plasticity to make the local environment more suitable for ovarian cancer cells.By Figdraw.
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+/ÀFOXP3+ 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

| MCP-1
Monocyte chemotactic protein-1 (MCP-1) is also known as chemokine (C-C motif) ligand 2 (CCL-2). 28 tor 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. 32Therefore, 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.the rate-limiting enzyme in FA synthesis. 35

| 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. 38It 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. 39In fact, acetaldehyde is toxic to cells, has carcinogenic effects, and disrupts the DNA repair and methylation processes. 40However, specific and systemic studies on ADH-1B in ovarian cancer still exhibit a large gap.

| 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. 42Adipocytes can activate SIK-2 autophosphorylation through the Ca 2+ pathway.SIK-2 can participate in fatty acid oxidation and mitochondrial respiration, which might sustain adipocyte-induced metastasis of ovarian cancer. 41Furthermore, SIK-2 can also directly phosphorylate MYLK and activate its downstream pathway to boost ovarian cancer cell motility. 43survival in ovarian cancer. 44,45Unfortunately, this factor lacks further insightful investigations in ovarian cancer. 46

| miR-21
Next-generation sequencing has revealed that RNA expression is different in exosomes from ovarian cancer cells and adipocytes and fibroblasts from normal human omental tissue and cancerassociated omental tissue.MiR-21 is the most abundant. 47Though 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. 48In addition, it is involved in the chemoresistance progress by CD44v6 pathway. 49There are still many research gaps remaining about its potential roles in ovarian cancer.

| Cancer-associated macrophages deprived from the omentum
In recent years, increasing attention has been focused on cancerassociated macrophages (CAMs).Macrophages have a variety of effects on the basis of their extreme plasticity in response to their microenvironment. 53In many previous studies, most foci are gathered in macrophages isolated from peritoneal ascites because they are abundant in thoracic and ascites of ovarian cancer patients.Relevant results have demonstrated that ascites-deprived macrophages express M1 and M2 polarization markers, which is named mixed polarization. 54In this review, we will discuss reciprocity between ovarian cancer cells and macrophages deprived from omentum adipose tissue.
Unfortunately, relevant studies are limited.Thus, whether previous results about the roles of macrophages stemming from peritoneal ascites apply to macrophages originating from omentum adipose tissue should be further verified.
Peritoneal injection into mice of the immortalized mouse ovarian epithelial cell line ID8, which is labeled with Qdots (Qtracker705), demonstrated that the area of aggregated omental macrophages attracts more ovarian cancer cells.Further single-cell RNA sequencing analysis of these macrophages indicated that common coexpressing macrophage markers are Lyve-1, Cd163, and Tim4.Only CD169 hi macrophages expressed Lyve-1 at the same time, and only CD169 hi Lyve-1 + cells expressed Cd163 and Tim4.According to their different expression status, the authors divided four subtypes: CD163 + Tim 4+ (P1), CD163 + Tim4 À (P2), CD163 À Tim4 À (P3), and CD163 À Tim4 + .The significant feature of P1 macrophages, which are distinguished from other subtypes, is they might originate from embryos rather than monocytes, which is why they cannot be replaced easily by other cell types.The specific deletion of P1 macrophages would inhibit ovarian cancer cell metastasis, and their existence would be the basis of the acquisition of invasive behavior of ovarian cancer cells. 55 addition, chemokines and their receptors form an important bridge between macrophages and cancer cells.For example, in mouse models, the expression of the chemokine ligand CCL6 presents significant changes in omental macrophages while ovarian cancer cells colonize the omentum.Similarly, CCL23, the human homolog of CCL6, was discovered in human omental macrophages.CCR1, which is highly expressed in ovarian cancer cells, can mediate ovarian cancer cell-enhanced migration and metastasis. 56Some blockers targeting at CCR1 or CCL23 might improve the clinical outcome of ovarian cancer patients.

| Cancer-associated mesenchymal stem cells deprived of omentum
In recent years, mesenchymal stem cells (MSCs) have attracted attention because of their therapeutic potential in cancer.Tang et al. 57 found that MSCs deprived of omentum adipose tissue tend to express more carcinoma-associated-fibroblast markers through the TGF-β pathway to support ovarian cancer cell growth and omental metasta- and above process was inhibited by downregulating the expression of MMP. 58Other phenotype validation experiments illustrated that MSCs deprived of omentum adipose tissue would advance invasion and chemoresistance. 59There is another perspective that ADSCdeprived exosomes could induce the apoptosis of ovarian cancer cells, and the sequencing results showed a great deal of miRNAs associated with ovarian cancer survival. 60Each conclusion provides an important disease treatment idea for ovarian cancer.

| PREVENTION AND THERAPY
Because of the lack of early detection and acquisition of drug resistance, complete victory over ovarian cancer is still extremely difficult.The current mainstream treatment includes primary debulking surgery (PDS) combined or not combined with chemotherapy or interval debulking surgery (IDS) combined with neoadjuvant chemotherapy.When patients finish primary therapy and achieve a complete clinical response or partial response, maintenance therapy is administered to improve their progression-free survival (PFS) and overall survival (OS). 61,62To unearth more latent mechanisms is significant.It is evident that omentum can provide a suitable environment for ovarian cancer cells.From the perspective of the roles of adipose cells and adipocytes, metformin might be promising for ovarian cancer therapy.
More epidemiologic evidence supports that exercise could reduce ovarian cancer risk. 63

| Metformin
Metformin is a classical hypoglycemic drug that could also be effective in several cancers, including ovarian cancer.It can inhibit the conversion of preadipocytes to adipocytes and block the biological process of adipocytes to interfere with ovarian cancer cell growth and invasion mediated by adipocytes. 64

| Exercise and weight control
Some systematic reviews have concluded that exercise is always relevant to better outcomes of ovarian cancer. 67Appropriate exercise is helpful for weight control, and increasing evidence supports that obesity, particularly the stock of visceral white adipose tissue (WAT), increases the occurrence and mortality of ovarian cancer. 68The classical action mechanism is concentrated on secretion of adipokines, insulin resistance, and chronic inflammation.

CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

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 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 T A B L E 1 Examples of adipocyte-associated factors.
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),

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 nonsmall 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 regarded CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells as a chemoresistance phenotype.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 Bcl xl , encoded by BCL2L1, is differentially expressed.On the other hand, the adipocyte-infiltrated microenvironment always upregulates the expression of Bcl xl .Bclxl-specific siRNA will achieve apoptosis of chemoresistant ovarian cancer cells.51,52 sis.Inhibition of this differentiation would be a new therapeutic target.Coculturing ovarian cancer cell lines and adipose-derived mesenchymal stem cells (ADSCs) in vitro and in mouse xenograft models reached the same conclusion: adipose-derived mesenchymal stem cells could promote ovarian cancer cell growth and migration, 69,70 Liu et al.71 confirmed that obesity and a high-fat diet influence immune cell infiltration.For example, CD45 + lymphocyte (B-cell marker), whole macrophage, and M1-polarized macrophage infiltration decreased in the obesity group while M2-polarized macrophages showed no significant change.The alteration of the immune microenvironment might open up another mechanism linking obesity and ovarian cancer.Recent data have suggested that exercise might contribute to the activation of M1 macrophages, which arouse antitumor immune responses.72Exercise intervention during or following ovarian cancer therapy might improve the lives of these patients.4| CONCLUSIONSThe omentum acts as the most frequent location where ovarian cancer cells spread for subsequent metastasis.It covers the surface of abdominal organs, and its enormous endocrine function and particular structural composition can provide a suitable and specific environment for ovarian cancer cell growth, invasion, migration and chemoresistance.Various cell compositions take part in ovarian cancer genesis and development via energy metabolism regulation, immune reactions and many other processes.All of the above molecules are just the tip of the iceberg.Investigations performed to reveal additional functions of the omentum, especially adipose tissue, might offer more effective and satisfactory therapeutic solutions for patients suffering from ovarian cancer.Further study of the roles of the tumor cell microenvironment in ovarian cancer will facilitate its immunotherapy.Some agents which targeted for the above cytokines will be hopeful for prognosis of ovarian cancer.AUTHOR CONTRIBUTIONSZeying Li: Visualization (lead); writingoriginal draft (lead).Xiaoling Fang: Writingreview and editing (lead).Sixue Wang: Visualization (supporting); writingreview and editing (supporting).ACKNOWLEDGMENTS I would first like to thank my thesis advisor Xiaoling, Fang.Her office was always open whenever I ran into a trouble spot or had a question about my research or writing.She consistently steered me in the right the direction whenever she thought I needed it.I would also like to acknowledge Sixue, Wang as the second reader of this review, and I am gratefully indebted to her for her very valuable comments on this article.Without her passionate participation and input, the article could not have been successfully conducted.Finally, I must express my very profound gratitude to my parents for providing me with unfailing support and continuous encouragement throughout my years of study and through the process of writing this article.This accomplishment would not have been possible without them.