Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells

Carroll, Molly J.; Fogg, Kaitlin C.; Patel, Harin A.; Krause, Harris B.; Mancha, Anne-Sophie; Patankar, Manish S.; Weisman, Paul; Barroilhet, Lisa; Kreeger, Pamela K.

doi:10.1158/0008-5472.can-17-3341

Cited by 62 publications

(66 citation statements)

References 47 publications

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“…The elevated EGFR, in tumors, further activates the VEGF/VEGFR pathway in neighboring tumor cells, and thus supports cell proliferation and metastasis. M2-like macrophages facilitate the cell adhesion of ovarian cancer cells to mesothelial cells by causing the mesothelial cells to over-express P-selectin [ 35 ]. This mechanism likely supports the epithelial ovarian cancer spread, along the mesothelial-lined peritoneal cavity.…”

Section: Bipolar Macrophagesmentioning

confidence: 99%

Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy

Gupta

Yull

Khabele

2018

Cancers

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Ovarian cancer, a rare but fatal disease, has been a challenging area in the field of gynecological cancer. Ovarian cancer is characterized by peritoneal metastasis, which is facilitated by a cross-talk between tumor cells and other cells in the tumor microenvironment (TME). In epithelial ovarian cancer, tumor-associated macrophages (TAMs) constitute over 50% of cells in the peritoneal TME and malignant ascites, and are potential targets for therapy. Here, we review the bipolar nature of TAMs and the evolving strategies to target TAMs in ovarian cancer.

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Section: Bipolar Macrophagesmentioning

confidence: 99%

Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy

Gupta

Yull

Khabele

2018

Cancers

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“…The activation of apoptosis is regulated by multiple signalling pathways, of which the PI3K/AKT pathway is one of the most important (20). The PI3K/AKT pathway regulates a number of malignant phenotypes, including anti-apoptotic, cell growth and proliferation phenotypes (21,22). In this pathway, AKT activation inhibits cell cycle arrest and angiogenesis, and promotes tumour invasion and metastasis via phosphorylation of the protein kinase mTOR (23,24).…”

Section: Discussionmentioning

confidence: 99%

JTC‑801 inhibits the proliferation and metastasis of the Hep G2 hepatoblastoma cell line by regulating the phosphatidylinositol 3‑kinase/protein kinase B signalling pathway

Zhao

2018

Oncol Lett

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The increased worldwide mortality rate due to liver cancer may be attributed to the aggressive nature of the disease. Signal transduction through G-protein-coupled receptors (GPCRs) can affect a number of aspects of cancer biology, including invasion, migration and vascular remodelling. JTC-801, a novel GPCR antagonist, has demonstrated promising anticancer effects in adenocarcinoma and osteosarcoma cells. In the present study, the effect of JTC-801 on the proliferation and migration of hepatoblastoma Hep G2 cells was investigated. The Cell Counting Kit-8 assay revealed that JTC-801 markedly suppressed the growth of the Hep G2 cells. Additionally, JTC-801 significantly inhibited cell invasion and migration in a Transwell assay. Furthermore, the expression of anti-apoptotic protein B-cell lymphoma 2 decreased and the expression of the pro-apoptotic proteins active caspase-3 and apoptosis regulator BAX increased in the Hep G2 cells following JTC-801 treatment. Additionally, JTC-801 suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in the Hep G2 cells. Therefore, the present study revealed that JTC-801 can induce the apoptosis of Hep G2 cells by regulating the PI3K/AKT signalling pathway, which suggests that JTC-801 may be a potential novel drug target for clinical liver cancer treatment. phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Bcl-2, B-cell lymphoma 2; Bax, apoptosis regulator BAX; P70S6K, P70S6 kinase; CCK-8, Cell Counting Kit-8; FITC, fluorescein isothiocyanate; PI, propidium iodide

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“…For some experiments, HGSOC cells were cultured on coverslips in the device without monocytes. AAM control monocultures were generated as previously described (16).…”

Section: In Vitro Micro-culture Devicementioning

confidence: 99%

“…In vivo, a resident population of omental CD163+ macrophages has been shown to be essential for metastatic spread in a mouse model of ovarian cancer (15). Using in vitro models of HGSOC, we have previously demonstrated that AAMs secrete soluble factors such as MIP-1, HB-EGF, and leptin, resulting in increased ovarian cancer adhesion, proliferation, and spreading, respectively (16)(17)(18). In these studies, AAMs were generated by differentiating naïve monocytes into macrophages with MCSF and then polarizing towards the alternative phenotype through IL-4…”

Section: Introductionmentioning

confidence: 99%

Ovarian Cancer Cells Direct Monocyte Differentiation Through a Non-canonical Pathway

Fogg

Miller

Liu

et al. 2020

Preprint

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Background: Alternatively-activated macrophages (AAMs), an anti-inflammatory macrophage subpopulation, have been implicated in the progression of high grade serous ovarian carcinoma (HGSOC). Increased levels of AAMs are correlated with poor HGSOC survival rates, and AAMs increase the attachment and spread of HGSOC cells in vitro. However, the mechanism by which monocytes in the HGSOC tumor microenvironment are differentiated and polarized to AAMs remains unknown. Methods: Using an in vitro co-culture device, we cultured naïve, primary human monocytes with a panel of five HGSOC cell lines over the course of seven days. An empirical Bayesian statistical method, EBSeq, was used to couple RNA-seq with observed monocyte-derived cell phenotype to explore which HGSOC-derived soluble factors supported differentiation to CD68+ macrophages and subsequent polarization towards CD163+ AAMs. Pathways of interest were interrogated using small molecule inhibitors, neutralizing antibodies, and CRISPR knockout cell lines. Results: HGSOC cell lines displayed a wide range of abilities to generate AAMs from naïve monocytes. Much of this variation appeared to result from differential ability to generate CD68+ macrophages, as most CD68+ cells were also CD163+. Differences in tumor cell potential to generate macrophages was not due to a MCSF-dependent mechanism, nor variance in established pro-AAM factors. TGFa was implicated as a potential signaling molecule produced by tumor cells that could induce macrophage differentiation, which was validated using a CRISPR knockout of TGFA in the OVCAR5 cell line. Conclusions: HGSOC production of TGFa drives monocytes to differentiate into macrophages, representing a central arm of the mechanism by which AAMs are generated in the tumor microenvironment.

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Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells

Cited by 62 publications

References 47 publications

Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy

Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy

JTC‑801 inhibits the proliferation and metastasis of the Hep G2 hepatoblastoma cell line by regulating the phosphatidylinositol 3‑kinase/protein kinase B signalling pathway

Ovarian Cancer Cells Direct Monocyte Differentiation Through a Non-canonical Pathway

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