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Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis.

ABSTRACT: The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. Whereas previous investigations have focused mostly on ET action in malignant cells, we chose a model allowing separate assessment of the effects of ETs and their receptors ET(A)R and ET(B)R in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ET(B)R deficiency, we showed significant reduction of growth and metastasis of MAT B III rat mammary adenocarcinoma cells overexpressing ET(A)R and ET-1 but negative for ET(B)R. Lack of stromal ET(B)R expression did not influence angiogenesis. However, it was correlated with diminished infiltration by tumor-associated macrophages and with reduced production of tumor necrosis factor-alpha, both known as powerful promoters of tumor progression. These effects were almost completely abolished in transgenic sl/sl rats, wherein ET(B)R function is restored by expression of an intact ET(B)R transgene. This shows that tumor growth and metastasis are critically dependent on ET(B)R function in cells of the microenvironment and suggests that successful ETR antagonist therapy should also target the stromal component of ET signaling

SUBMITTER: Binder C

PROVIDER: S-EPMC2728766 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis.

Binder Claudia C Hagemann Thorsten T Sperling Swetlana S Schulz Matthias M Pukrop Tobias T Grimshaw Matthew J MJ Ehrenreich Hannelore H

Molecular cancer therapeutics 20090811 8

The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. Whereas previous investigations have focused mostly on ET action in malignant cells, we chose a model allowing separate assessment of the effects of ETs and their receptors ET(A)R and ET(B)R in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ET(B)R deficienc ...[more]

PMID: 19671740

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Project description:Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRβD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβD849V in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.See related article by Wyss and colleagues, p. 594.

Dataset Information

Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis.

Publications

Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis.

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