Transforming Growth Factor-Alpha Levels in the Serum and Ascites of Patients withAdv anced Epithelial Ovarian Cancer

Saltzman, Andrew K.; Hartenbach, Ellen M.; Carter, Jonathan; Contreras, Diana; Twiggs, Leo B.; Carson, Linda F.; Ramakrishnan, S.

doi:10.1159/000010095

Cited by 16 publications

(6 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…be elevated in the ascites fluid of patients with stage III/IV ovarian cancer compared to stage I/II(49). Additionally, histological examinations of the epithelial portion of ovarian tumors(50) and characterization of ovarian cancer lines(51) have shown that some ovarian cancer cells produce TGFα, consistent with our findings here.…”

supporting

confidence: 90%

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

Fogg

Miller

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

supporting

confidence: 90%

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

Fogg

Miller

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…For example, TGFa levels have been shown to be elevated in the ascites fluid of patients with stage III/IV ovarian cancer compared to stage I/II(49). Additionally, histological examinations of the epithelial portion of ovarian tumors(50) and characterization of ovarian cancer lines(51) have shown that some ovarian cancer cells produce TGFα, consistent with our findings here.…”

supporting

confidence: 89%

Ovarian Cancer Cells Direct Monocyte Differentiation Through A Non-Canonical Pathway

Fogg

Miller

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…Accumulation of malignant ascites in the peritoneal cavity is common, particularly in women with late-stage EOC. Thus metastasizing EOC cells exist in a milieu rich in inflammatory cells [88] and growth/signalling factors, including VEGF [89–91], EGF [11,92], TGFα, TGFβ [93,94] and LPA [23,95], providing ample opportunity for cross-talk between signalling networks. Ascites accumulation also modifies peritoneal mechanobiology, altering the force environment of both metastatic tumour cells and peritoneal mesothelium [96,97].…”

Section: Microenvironmental Activation Of the Wnt Pathwaymentioning

confidence: 99%

Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment

Barbolina

Burkhalter

Stack

2011

Biochemical Journal

View full text Add to dashboard Cite

Wnt signalling pathways have been shown to play key roles in both normal development and tumorigenesis. Progression of many human cancers is associated with defined mutations in Wnt pathway components that result in dysregulated β-catenin-mediated gene transcription. Although Wnt pathway mutations are rare in epithelial ovarian cancer (with the exception of the endometrioid histotype), accumulating evidence supports a role for Wnt signalling in ovarian tumorigenesis in the absence of genetic mutations. The present review summarizes evidence in support of activated Wnt signalling in ovarian tumours and discusses alternative mechanisms for Wnt pathway activation in the ovarian tumour microenvironment.

show abstract

Transforming Growth Factor-Alpha Levels in the Serum and Ascites of Patients withAdv anced Epithelial Ovarian Cancer

Cited by 16 publications

References 11 publications

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

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

Ovarian Cancer Cells Direct Monocyte Differentiation Through A Non-Canonical Pathway

Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment

Contact Info

Product

Resources

About