Adipocytes: active facilitators in epithelial ovarian cancer progression?

Dai, Lan; Song, Keqi; Di, Wen

doi:10.1186/s13048-020-00718-4

Cited by 35 publications

(28 citation statements)

References 140 publications

(176 reference statements)

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“…Numerous studies suggest that ADI within the omental TME may play an essential role in HGSC progression 67 by promoting the homing and invasion of cancer cells, angiogenesis and chemoresistance via the secretion of adipokines, including IL‐6, IL‐8, THF, leptin, adiponectin and resistin. 10 , 68 , 69 , 70 Our study extends these previous data by adding additional mediators to the list of adipokines expressed by omental ADI, some of them with a high degree of selectivity compared to other cell types, for example, CCL14, IGF1, PROK1, SEMA3G and THBS4 (Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

The multicellular signalling network of ovarian cancer metastases

Sommerfeld¹,

Finkernagel²,

Jansen³

et al. 2021

Clinical & Translational Med

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BackgroundTranscoelomic spread is the major route of metastasis of ovarian high‐grade serous carcinoma (HGSC) with the omentum as the major metastatic site. Its unique tumour microenvironment with its large populations of adipocytes, mesothelial cells and immune cells establishes an intercellular signaling network that is instrumental for metastatic growth yet poorly understood.MethodsBased on transcriptomic analysis of tumour cells, tumour‐associated immune and stroma cells we defined intercellular signaling pathways for 284 cytokines and growth factors and their cognate receptors after bioinformatic adjustment for contaminating cell types. The significance of individual components of this network was validated by analysing clinical correlations and potentially pro‐metastatic functions, including tumour cell migration, pro‐inflammatory signal transduction and TAM expansion.ResultsThe data show an unexpected prominent role of host cells, and in particular of omental adipocytes, mesothelial cells and fibroblasts (CAF), in sustaining this signaling network. These cells, rather than tumour cells, are the major source of most cytokines and growth factors in the omental microenvironment (n = 176 vs. n = 13). Many of these factors target tumour cells, are linked to metastasis and are associated with a short survival. Likewise, tumour stroma cells play a major role in extracellular‐matrix‐triggered signaling. We have verified the functional significance of our observations for three exemplary instances. We show that the omental microenvironment (i) stimulates tumour cell migration and adhesion via WNT4 which is highly expressed by CAF; (ii) induces pro‐tumourigenic TAM proliferation in conjunction with high CSF1 expression by omental stroma cells and (iii) triggers pro‐inflammatory signaling, at least in part via a HSP70–NF‐κB pathway.ConclusionsThe intercellular signaling network of omental metastases is majorly dependent on factors secreted by immune and stroma cells to provide an environment that supports ovarian HGSC progression. Clinically relevant pathways within this network represent novel options for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

The multicellular signalling network of ovarian cancer metastases

Sommerfeld¹,

Finkernagel²,

Jansen³

et al. 2021

Clinical & Translational Med

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“…We assume the lack of an adequate stimulus in vitro prevent tumor spheroids to attach and further spread, thereby highlighting the key role of the intraperitoneal environment for tumor progression in ovarian cancer. Thus, the key role of fibroblasts, immune, adipocytes, mesothelial, and endothelial cells for disease progression has been broadly described in the last years [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics and tumorigenicity of ascites‐derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer

et al. 2021

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Ovarian cancer disseminates primarily intraperitoneally. Detached tumor cell aggregates (spheroids) from the primary tumor are regarded as ‘metastatic units’ that exhibit a low sensitivity to classical chemotherapy, probably due to their unique molecular characteristics. We have analyzed the cellular composition of ascites from OvCa patients, using flow cytometry, and studied their behavior in vitro and in vivo . We conclude that ascites‐derived cultured cells from OvCa patients give rise to two subpopulations: adherent cells and non‐adherent cells. Here, we found that the AD population includes mainly CD90 + cells with highly proliferative rates in vitro but no tumorigenic potential in vivo , whereas the NAD population contains principally tumor cell spheroids (EpCAM + /CD24 + ) with low proliferative potential in vitro . Enriched tumor cell spheroids from the ascites of high‐grade serous OvCA patients, obtained using cell strainers, were highly tumorigenic in vivo and their metastatic spread pattern precisely resembled the tumor dissemination pattern found in the corresponding patients. Comparative transcriptome analyses from ascites‐derived tumor cell spheroids ( n = 10) versus tumor samples from different metastatic sites ( n = 30) revealed upregulation of genes involved in chemoresistance ( TGM1 , HSPAs, MT1s), cell adhesion and cell‐barrier integrity ( PKP3 , CLDNs, PPL ), and the oxidative phosphorylation process. Mitochondrial markers (mass and membrane potential) showed a reduced mitochondrial function in tumoroids from tumor tissue compared with ascites‐derived tumor spheroids in flow cytometry analysis. Interestingly, response to OXPHOS inhibition by metformin and IACS010759 in tumor spheroids correlated with the extent of mitochondrial membrane potential measured by fluorescence‐activated cell sorting. Our data contribute to a better understanding of the biology of ovarian cancer spheroids and identify the OXPHOS pathway as new potential treatment option in advanced ovarian cancer.

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“…Adipocytes are important secretory cells, that release a wide range of adipokines, including hormones, inflammatory cytokines, enzymes and other factors [ 18 , 19 ]. Many of these adipokines participate in EOC growth promotion by activating a series of signalling pathways in tumour cells [ 3 , 20 ]. Therefore, we wondered whether there might be one major mediator regulating these adipokines and signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Activation of SphK1 by adipocytes mediates epithelial ovarian cancer cell proliferation

et al. 2021

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Background Adipocytes, active facilitators of epithelial ovarian cancer (EOC) growth, have been implicated in the link between obesity and EOC. However, the current understanding of the mechanisms underlying adipocyte-induced EOC cell proliferation remains incomplete. Results We provide the first evidence showing that sphingosine kinase (SphK) 1 is critical for adipocyte-induced EOC cell proliferation. Adipocytes are capable of activating SphK1, which then leads to extracellular signal-regulated kinase (ERK) phosphorylation. Moreover, adipocyte-induced SphK1 activation is ERK dependent. Furthermore, sphingosine 1-phosphate receptor (S1PR) 1 and S1PR3, key components of the SphK1 signalling pathway, participate in adipocyte-mediated growth-promoting action in EOC cells. Conclusions Our study reveals a previously unrecognized role of SphK1 in adipocyte-induced growth-promoting action in EOC, suggesting a new target for EOC therapy.

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Adipocytes: active facilitators in epithelial ovarian cancer progression?

Cited by 35 publications

References 140 publications

The multicellular signalling network of ovarian cancer metastases

The multicellular signalling network of ovarian cancer metastases

Molecular characteristics and tumorigenicity of ascites‐derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer

Activation of SphK1 by adipocytes mediates epithelial ovarian cancer cell proliferation

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