By Figdraw.
Figure 1. 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.
3. 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)[61,62]. To 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].
3.1 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]. Relevant
clinical trials have proven that metformin is associated with better
prognosis in ovarian cancer patients. It can downregulate the activity
of IL-6/STAT3 and influence the expression of VEGF and TGF-β1. It can
enhance sensitivity to cisplatin in ovarian cancer by altering the
methylation of cancer-stem cells[65,66].
Currently, a nonrandomized phase II study combining metformin and
chemotherapy in advanced-stage ovarian cancer without diabetes has
reached promising conclusions.
3.2 Exercise and weight control
Some systematic reviews have concluded that exercise is always relevant
to better outcomes of ovarian cancer[67].
Appropriate 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[68]. The classical action mechanism is
concentrated on secretion of adipokines, insulin resistance, and chronic
inflammation[69,70]. Yueying Liu et al. 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[71]. Recent data have suggested that
exercise might contribute to the activation of M1 macrophages, which
arouse antitumor immune responses[72]. Exercise
intervention during or following ovarian cancer therapy might improve
the lives of these patients.
4. Conclusions
The 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.
Data Availability Statement
Data openly available in a public repository.
References
[1] Torre L A, Trabert B, Desantis C E, et al. Ovarian cancer
statistics, 2018[J]. CA Cancer J Clin, 2018, 68(4): 284-296.
[2] Kurman R J, Shih Ie M. The Dualistic Model of Ovarian
Carcinogenesis: Revisited, Revised, and Expanded[J]. Am J Pathol,
2016, 186(4): 733-47.
[3] Paget S. The distribution of secondary growths in cancer of the
breast. 1889[J]. Cancer Metastasis Rev, 1989, 8(2): 98-101.
[4] Akhtar M, Haider A, Rashid S, et al. Paget’s ”Seed and Soil”
Theory of Cancer Metastasis: An Idea Whose Time has Come[J]. Adv
Anat Pathol, 2019, 26(1): 69-74.
[5] Fidler I J, Poste G. The ”seed and soil” hypothesis
revisited[J]. Lancet Oncol, 2008, 9(8): 808.
[6] Wilkosz S, Ireland G, Khwaja N, et al. A comparative study of
the structure of human and murine greater omentum[J]. Anat Embryol
(Berl), 2005, 209(3): 251-61.
[7] Clark R, Krishnan V, Schoof M, et al. Milky spots promote
ovarian cancer metastatic colonization of peritoneal adipose in
experimental models[J]. Am J Pathol, 2013, 183(2): 576-91.
[8] Storti G, Scioli M G, Kim B S, et al. Mesenchymal Stem Cells in
Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A
Bridge toward Metastatic Diffusion or a New Therapeutic
Opportunity?[J]. Cells, 2021, 10(8).
[9] Chu Y, Zhu C, Wang Q, et al. Adipose-derived mesenchymal stem
cells induced PAX8 promotes ovarian cancer cell growth by stabilizing
TAZ protein[J]. J Cell Mol Med, 2021, 25(9): 4434-4443.
[10] Chu Y, You M, Zhang J, et al. Adipose-Derived Mesenchymal Stem
Cells Enhance Ovarian Cancer Growth and Metastasis by Increasing
Thymosin Beta 4X-Linked Expression[J]. Stem Cells Int, 2019, 2019:
9037197.
[11] Cao Y. Adipocyte and lipid metabolism in cancer drug
resistance[J]. The Journal of Clinical Investigation, 2019.
[12] Pascale R M, Calvisi D F, Simile M M, et al. The Warburg Effect
97 Years after Its Discovery[J]. Cancers (Basel), 2020, 12(10).
[13] Mukherjee A, Chiang C Y, Daifotis H A, et al. Adipocyte-Induced
FABP4 Expression in Ovarian Cancer Cells Promotes Metastasis and
Mediates Carboplatin Resistance[J]. Cancer Res, 2020, 80(8):
1748-1761.
[14] Gharpure K M, Pradeep S, Sans M, et al. FABP4 as a key
determinant of metastatic potential of ovarian cancer[J]. Nat
Commun, 2018, 9(1): 2923.
[15] Chen C, Chang Y C, Lan M S, et al. Leptin stimulates ovarian
cancer cell growth and inhibits apoptosis by increasing cyclin D1 and
Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt
signaling pathways[J]. Int J Oncol, 2013, 42(3): 1113-9.
[16] Ghasemi A, Hashemy S I, Aghaei M, et al. Leptin induces matrix
metalloproteinase 7 expression to promote ovarian cancer cell invasion
by activating ERK and JNK pathways[J]. J Cell Biochem, 2018, 119(2):
2333-2344.
[17] Gu F, Zhang H, Yao L, et al. Leptin contributes to the taxol
chemoresistance in epithelial ovarian cancer[J]. Oncol Lett, 2019,
18(1): 561-570.
[18] Choi J H, Lee K T, Leung P C. Estrogen receptor alpha pathway
is involved in leptin-induced ovarian cancer cell growth[J].
Carcinogenesis, 2011, 32(4): 589-96.
[19] Słomian G J, Nowak D, Buczkowska M, et al. The role of
adiponectin and leptin in the treatment of ovarian cancer
patients[J]. Endokrynol Pol, 2019, 70(1): 57-63.
[20] Choi H M, Doss H M, Kim K S. Multifaceted Physiological Roles
of Adiponectin in Inflammation and Diseases[J]. Int J Mol Sci, 2020,
21(4).
[21] Parida S, Siddharth S, Sharma D. Adiponectin, Obesity, and
Cancer: Clash of the Bigwigs in Health and Disease[J]. Int J Mol
Sci, 2019, 20(10).
[22] Tsankof A, Tziomalos K. Adiponectin: A player in the
pathogenesis of hormone-dependent cancers[J]. Front Endocrinol
(Lausanne), 2022, 13: 1018515.
[23] Filková M H M, Gay S, Senolt L. The role of resistin as a
regulator of inflammation: Implications for various human pathologies.
[J]. Clin Immunol., 2009.
[24] Parafiniuk K, Skiba W, Pawłowska A, et al. The Role of the
Adipokine Resistin in the Pathogenesis and Progression of Epithelial
Ovarian Cancer[J]. Biomedicines, 2022, 10(4).
[25] Pang L, Zhang Y, Yu Y, et al. Resistin promotes the expression
of vascular endothelial growth factor in ovary carcinoma cells[J].
Int J Mol Sci, 2013, 14(5): 9751-66.
[26] Asem M S, Buechler S, Wates R B, et al. Wnt5a Signaling in
Cancer[J]. Cancers (Basel), 2016, 8(9).
[27] Asem M, Young A M, Oyama C, et al. Host Wnt5a Potentiates
Microenvironmental Regulation of Ovarian Cancer Metastasis[J].
Cancer Res, 2020, 80(5): 1156-1170.
[28] Sica A, Saccani A, Bottazzi B, et al. Defective expression of
the monocyte chemotactic protein-1 receptor CCR2 in macrophages
associated with human ovarian carcinoma[J]. J Immunol, 2000, 164(2):
733-8.
[29] Sun C, Li X, Guo E, et al. MCP-1/CCR-2 axis in adipocytes and
cancer cell respectively facilitates ovarian cancer peritoneal
metastasis[J]. Oncogene, 2020, 39(8): 1681-1695.
[30] Furuhashi M, Hotamisligil G S. Fatty acid-binding proteins:
role in metabolic diseases and potential as drug targets[J]. Nat Rev
Drug Discov, 2008, 7(6): 489-503.
[31] Harjes U, Bridges E, Gharpure K M, et al. Antiangiogenic and
tumour inhibitory effects of downregulating tumour endothelial
FABP4[J]. Oncogene, 2017, 36(7): 912-921.
[32] Yu C, Niu X, Du Y, et al. IL-17A promotes fatty acid uptake
through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer
growth in an adipocyte-rich microenvironment[J]. Cancer Immunol
Immunother, 2020, 69(1): 115-126.
[33] Sulsky R, Magnin D R, Huang Y, et al. Potent and selective
biphenyl azole inhibitors of adipocyte fatty acid binding protein
(aFABP)[J]. Bioorg Med Chem Lett, 2007, 17(12): 3511-5.
[34] Furuhashi M, Tuncman G, Görgün C Z, et al. Treatment of
diabetes and atherosclerosis by inhibiting fatty-acid-binding protein
aP2[J]. Nature, 2007, 447(7147): 959-65.
[35] Schulze C R S a A. Lipid metabolism in cancer[J]. FFBS,
2012.
[36] Eberlé D, Hegarty B, Bossard P, et al. SREBP transcription
factors: master regulators of lipid homeostasis[J]. Biochimie, 2004,
86(11): 839-48.
[37] Ladanyi A, Mukherjee A, Kenny H A, et al. Adipocyte-induced
CD36 expression drives ovarian cancer progression and metastasis[J].
Oncogene, 2018, 37(17): 2285-2301.
[38] Tucker S L, Gharpure K, Herbrich S M, et al. Molecular
biomarkers of residual disease after surgical debulking of high-grade
serous ovarian cancer[J]. Clin Cancer Res, 2014, 20(12): 3280-8.
[39] Gharpure K M, Lara O D, Wen Y, et al. ADH1B promotes
mesothelial clearance and ovarian cancer infiltration[J].
Oncotarget, 2018, 9(38): 25115-25126.
[40] Seitz H K, Stickel F. Acetaldehyde as an underestimated risk
factor for cancer development: role of genetics in ethanol
metabolism[J]. Genes Nutr, 2010, 5(2): 121-8.
[41] Miranda F, Mannion D, Liu S, et al. Salt-Inducible Kinase 2
Couples Ovarian Cancer Cell Metabolism with Survival at the
Adipocyte-Rich Metastatic Niche[J]. Cancer Cell, 2016, 30(2):
273-289.
[42] Zhao J, Zhang X, Gao T, et al. SIK2 enhances synthesis of fatty
acid and cholesterol in ovarian cancer cells and tumor growth through
PI3K/Akt signaling pathway[J]. Cell Death Dis, 2020, 11(1): 25.
[43] Shi X, Yu X, Wang J, et al. SIK2 promotes ovarian cancer cell
motility and metastasis by phosphorylating MYLK[J]. Mol Oncol, 2022,
16(13): 2558-2574.
[44] Gyorffy B, Lánczky A, Szállási Z. Implementing an online tool
for genome-wide validation of survival-associated biomarkers in
ovarian-cancer using microarray data from 1287 patients[J]. Endocr
Relat Cancer, 2012, 19(2): 197-208.
[45] Györffy B L A, Eklund Ac, Denkert C, Budczies J, Li Q, Szallasi
Z. . An online survival analysis tool to rapidly assess the effect of
22,277 genes on breast cancer prognosis using microarray data of 1,809
patients.[J]. Breast Cancer Res Treat, 2010.
[46] Nagano H, Hashimoto N, Nakayama A, et al. p53-inducible DPYSL4
associates with mitochondrial supercomplexes and regulates energy
metabolism in adipocytes and cancer cells[J]. Proc Natl Acad Sci U S
A, 2018, 115(33): 8370-8375.
[47] Au Yeung C L, Co N N, Tsuruga T, et al. Exosomal transfer of
stroma-derived miR21 confers paclitaxel resistance in ovarian cancer
cells through targeting APAF1[J]. Nat Commun, 2016, 7: 11150.
[48] Liu H Y, Zhang Y Y, Zhu B L, et al. miR-21 regulates the
proliferation and apoptosis of ovarian cancer cells through
PTEN/PI3K/AKT[J]. Eur Rev Med Pharmacol Sci, 2019, 23(10):
4149-4155.
[49] Wang Y, Chen G, Dai F, et al. miR-21 Induces Chemoresistance in
Ovarian Cancer Cells via Mediating the Expression and Interaction of
CD44v6 and P-gp[J]. Onco Targets Ther, 2021, 14: 325-336.
[50] Alvero Ab O M D, Brown D, Kelly G, Garg M, Chen W, Rutherford
T, Mor G. . Molecular mechanism of phenoxodiol-induced apoptosis in
ovarian carcinoma cells. Cancer.[J]. Cancer, 2006.
[51] Cardenas C, Montagna M K, Pitruzzello M, et al. Adipocyte
microenvironment promotes Bcl(xl) expression and confers chemoresistance
in ovarian cancer cells[J]. Apoptosis, 2017, 22(4): 558-569.
[52] Guo T, Gu C, Li B, et al. Dual inhibition of FGFR4 and BCL-xL
inhibits multi-resistant ovarian cancer with BCL2L1 gain[J]. Aging
(Albany NY), 2021, 13(15): 19750-19759.
[53] Xue J, Schmidt S V, Sander J, et al. Transcriptome-based
network analysis reveals a spectrum model of human macrophage
activation[J]. Immunity, 2014, 40(2): 274-88.
[54] Reinartz S S T, Finkernagel F, Wortmann a, Jansen Jm, Meissner
W, Krause M, Schwörer Am, Wagner U, Müller-Brüsselbach S, Müller R.
Mixed-polarization phenotype of ascites-associated macrophages in human
ovarian carcinoma: correlation of CD163 expression, cytokine levels and
early relapse. [J]. Int J Cancer, 2014.
[55] Etzerodt A, Moulin M, Doktor T K, et al. Tissue-resident
macrophages in omentum promote metastatic spread of ovarian
cancer[J]. J Exp Med, 2020, 217(4).
[56] Krishnan V, Tallapragada S, Schaar B, et al. Omental
macrophages secrete chemokine ligands that promote ovarian cancer
colonization of the omentum via CCR1[J]. Commun Biol, 2020, 3(1):
524.
[57] Tang H, Chu Y, Huang Z, et al. The metastatic phenotype shift
toward myofibroblast of adipose-derived mesenchymal stem cells promotes
ovarian cancer progression[J]. Carcinogenesis, 2020, 41(2): 182-193.
[58] Chu Y, Tang H, Guo Y, et al. Adipose-derived mesenchymal stem
cells promote cell proliferation and invasion of epithelial ovarian
cancer[J]. Exp Cell Res, 2015, 337(1): 16-27.
[59] Nowicka A, Marini F C, Solley T N, et al. Human omental-derived
adipose stem cells increase ovarian cancer proliferation, migration, and
chemoresistance[J]. PLoS One, 2013, 8(12): e81859.
[60] Reza A, Choi Y J, Yasuda H, et al. Human adipose mesenchymal
stem cell-derived exosomal-miRNAs are critical factors for inducing
anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer
cells[J]. Sci Rep, 2016, 6: 38498.
[61] Association G O P C O C a C. Guidelines for the diagnosis and
treatment of ovarian malignancies[J]. China Oncology, 2021.
[62] China N H C O T P S R O. Guidelines for the diagnosis and
treatment of ovarian cancer[J], 2022.
[63] Friedenreich C M, Ryder-Burbidge C, Mcneil J. Physical
activity, obesity and sedentary behavior in cancer etiology:
epidemiologic evidence and biologic mechanisms[J]. Mol Oncol, 2021,
15(3): 790-800.
[64] Tebbe C, Chhina J, Dar S A, et al. Metformin limits the
adipocyte tumor-promoting effect on ovarian cancer[J]. Oncotarget,
2014, 5(13): 4746-64.
[65] Brown J R, Chan D K, Shank J J, et al. Phase II clinical trial
of metformin as a cancer stem cell-targeting agent in ovarian
cancer[J]. JCI Insight, 2020, 5(11).
[66] Yang X, Huang M, Zhang Q, et al. Metformin Antagonizes Ovarian
Cancer Cells Malignancy Through MSLN Mediated IL-6/STAT3
Signaling[J]. Cell Transplant, 2021, 30: 9636897211027819.
[67] Jones T L, Sandler C X, Spence R R, et al. Physical activity
and exercise in women with ovarian cancer: A systematic review[J].
Gynecol Oncol, 2020, 158(3): 803-811.
[68] Delort L K F, Chalabi N, Satih S, Bignon Yj, Bernard-Gallon Dj.
. Central adiposity as a major risk factor of ovarian cancer. [J].
Anticancer Res, 2009.
[69] Galic S, Oakhill J S, Steinberg G R. Adipose tissue as an
endocrine organ[J]. Mol Cell Endocrinol, 2010, 316(2): 129-39.
[70] Doyle S L, Donohoe C L, Lysaght J, et al. Visceral obesity,
metabolic syndrome, insulin resistance and cancer[J]. Proc Nutr Soc,
2012, 71(1): 181-9.
[71] Liu Y, Metzinger M N, Lewellen K A, et al. Obesity Contributes
to Ovarian Cancer Metastatic Success through Increased Lipogenesis,
Enhanced Vascularity, and Decreased Infiltration of M1
Macrophages[J]. Cancer Res, 2015, 75(23): 5046-57.
[72] Morrisson M J, Bi F, Yang K, et al. Effect of exercise on
peritoneal microenvironment and progression of ovarian cancer[J]. Am
J Cancer Res, 2021, 11(10): 5045-5062.