Alternatively activated macrophage-derived secretome stimulates ovarian cancer spheroid spreading through a JAK2/STAT3 pathway

Fogg, Kaitlin C.; Olson, Will R.; Miller, Jamison N.; Khan, Aisha; Renner, Carine; Hale, Isaac; Weisman, Paul; Kreeger, Pamela K.

doi:10.1016/j.canlet.2019.05.029

Cited by 31 publications

(24 citation statements)

References 53 publications

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“…In the ovarian TME, MSCs as well as tumor cells, have been shown to recruit macrophages, which in turn secrete ECM components and enzymes resulting in ECM reorganization and remodeling [65], again likely influencing mechanical stimuli sensed by cancer cells. In the presence of specific factors like IL-4, IL-10, and IL-13 these macrophages become polarized and differentiate into an M2-like phenotype [66], also called tumor-associated macrophages (TAMs) or alternatively activated macrophages (AAMs), and secrete IL-4, IL-5, and IL-6 [67,68]. Multiple mechanisms including augmented c-Jun and NF-κB activity facilitate ovarian cancer cell invasion by TAMs [69].…”

Section: Interactions Between Ovarian Cancer Stem-like Cells and Omentioning

confidence: 99%

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

Bregenzer

Horst

Mehta

et al. 2019

Cancers

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Ovarian cancer is an extremely lethal gynecologic disease; with the high-grade serous subtype predominantly associated with poor survival rates. Lack of early diagnostic biomarkers and prevalence of post-treatment recurrence, present substantial challenges in treating ovarian cancers. These cancers are also characterized by a high degree of heterogeneity and protracted metastasis, further complicating treatment. Within the ovarian tumor microenvironment, cancer stem-like cells and mechanical stimuli are two underappreciated key elements that play a crucial role in facilitating these outcomes. In this review article, we highlight their roles in modulating ovarian cancer metastasis. Specifically, we outline the clinical relevance of cancer stem-like cells, and challenges associated with their identification and characterization and summarize the ways in which they modulate ovarian cancer metastasis. Further, we review the mechanical cues in the ovarian tumor microenvironment, including, tension, shear, compression and matrix stiffness, that influence (cancer stem-like cells and) metastasis in ovarian cancers. Lastly, we outline the challenges associated with probing these important modulators of ovarian cancer metastasis and provide suggestions for incorporating these cues in basic biology and translational research focused on metastasis. We conclude that future studies on ovarian cancer metastasis will benefit from the careful consideration of mechanical stimuli and cancer stem cells, ultimately allowing for the development of more effective therapies.

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Section: Interactions Between Ovarian Cancer Stem-like Cells and Omentioning

confidence: 99%

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

Bregenzer

Horst

Mehta

et al. 2019

Cancers

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“…This finding was enabled by a combination of a controlled in vitro co-culture model, bioinformatic analysis of gene expression and phenotype patterns, and rigorous tests of candidate factors identified in our screen. Combined with other studies demonstrating effects of tumor cells on monocyte recruitment, macrophage polarization, and macrophage influence on tumor cells [ 16 – 18 ], it is evident that tumor cell-macrophage interactions are complex and multi-faceted, providing multiple opportunities for intervention to slow tumor progression.…”

Section: Discussionmentioning

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-1β, HB-EGF, and leptin, resulting in increased ovarian cancer cell adhesion, proliferation, and spreading, respectively [ 16 – 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 and IL-13 treatment, resulting in a cell population that is CD68+, CD163+ [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer cells direct monocyte differentiation through a non-canonical pathway

et al. 2020

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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 7 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. TGFα 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 TGFα 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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“…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 macrophage-derived secretome stimulates ovarian cancer spheroid spreading through a JAK2/STAT3 pathway

Cited by 31 publications

References 53 publications

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

Ovarian cancer cells direct monocyte differentiation through a non-canonical pathway

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

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