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Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

ABSTRACT: The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo. Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation.

SUBMITTER: Pausch TM

PROVIDER: S-EPMC7096431 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

Pausch Thomas M TM Aue Elisa E Wirsik Naita M NM Freire Valls Aida A Shen Ying Y Radhakrishnan Praveen P Hackert Thilo T Schneider Martin M Schmidt Thomas T

Scientific reports 20200325 1

The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases followin ...[more]

PMID: 32214219

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Project description:ObjectivesIn chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis.DesignAngiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36.ResultsContrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis.ConclusionsInflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis.

Dataset Information

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

Publications

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

Similar Datasets

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