Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells

Kim, Seung Wook; Choi, Hyun Jin; Lee, Ho Jeong; He, Jie; Wu, Qiuyu; Langley, Robert R.; Fidler, Isaiah J.; Kim, Jong Hun

doi:10.1093/neuonc/nou128

Cited by 77 publications

(99 citation statements)

References 33 publications

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“…Besides the intrinsic mechanisms activated in EOC cells, acquisition of chemoresistance could be dependent also by the tumor microenvironment (44). In this regard, recent studies demonstrated that endothelial cells chemoprotect tumor cells through activation of ET-1 axis (45). Therefore, we can hypothesize that other mechanisms activated by ET B R, heterogeneously expressed on tumor cells as well as on endothelial cells, might also contribute to sensitize tumor cells to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Rosanò¹,

Cianfrocca²,

Tocci³

et al. 2014

Cancer Research

107

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The high mortality of epithelial ovarian cancer (EOC) is mainly caused by resistance to the available therapies. In EOC, the endothelin-1 (ET-1, EDN1)-endothelin A receptor (ET A R, EDNRA) signaling axis regulates the epithelial-mesenchymal transition (EMT) and a chemoresistant phenotype. However, there is a paucity of knowledge about how ET-1 mediates drug resistance. Here, we define a novel bypass mechanism through which ET A R/b-arrestin-1 (b-arr1, ARRB1) links Wnt signaling to acquire chemoresistant and EMT phenotype. We found that ET A R/b-arr1 activity promoted nuclear complex with b-catenin and p300, resulting in histone acetylation, chromatin reorganization, and enhanced transcription of genes, such as ET-1, enhancing the network that sustains chemoresistance. Silencing of b-arr1 or pharmacologic treatment with the dual ET A R/ET B R antagonist macitentan prevented core complex formation and restored drug sensitivity, impairing the signaling pathways involved in cell survival, EMT, and invasion. In vivo macitentan treatment reduced tumor growth, vascularization, intravasation, and metastatic progression. The combination of macitentan and cisplatinum resulted in the potentiation of the cytotoxic effect, indicating that macitentan can enhance sensitivity to chemotherapy. Investigations in clinical specimens of chemoresistant EOC tissues confirmed increased recruitment of b-arr1 and b-catenin to ET-1 gene promoter. In these tissues, high expression of ET A R significantly associated with poor clinical outcome and chemoresistance. Collectively, our findings reveal the existence of a novel mechanism by which ET A R/b-arr1 signaling is integrated with the Wnt/b-catenin pathway to sustain chemoresistance in EOC, and they offer a solid rationale for clinical evaluation of macitentan in combination with chemotherapy to overcome chemoresistance in this setting. Cancer Res; 74(24); 7453-64. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Rosanò¹,

Cianfrocca²,

Tocci³

et al. 2014

Cancer Research

107

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“…Astrocytes were previously shown to protect melanoma cells from chemotherapy via the endothelin-endothelin receptor signaling axis (38)(39)(40), and by direct contact through establishment of functional gap junctions via connexin 43 (41,42). However, the role of astrocytes in facilitating the primary growth of brain-metastasizing melanoma cells is unknown.…”

Section: Astrocytes Facilitate the Initial Growth Of Metastatic Melanmentioning

confidence: 99%

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

et al. 2016

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Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood-brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse.

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“…Important evidences recently defined a key role of ET-1 axis in drug resistance. In a model of brain metastasis from breast cancer, it has been demonstrated that bidirectional signaling between astrocytes and tumor cells involves upregulation and activation of ET-1 axis, which protects tumor cells from cytotoxicity induced by chemotherapeutic drugs such as taxol (15,24). Moreover, macitentan abolishes astrocyte-and endothelial cell-mediated chemoprotection (15).…”

Section: Role Of Et-1 In the Interactions Of Tumor Cells With The Micmentioning

confidence: 99%

Endothelin therapeutics in cancer: Where are we?

Rosanò¹,

Bagnato²

2016

American Journal of Physiology-Regulatory, Integrative and Comp

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In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ␤-arrestin 1 (␤-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ET AR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ␤-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.␤-arrestin; cancer; endothelin-1; endothelin-1 receptor; target therapy RECENT INVESTIGATIONS have consistently suggested that endothelin-1 (ET-1), a small bioactive peptide of 21 residues derived from longer prepro-ET-1 precursor, is an important signal messenger in different pathological conditions, including human cancers (24,35). ET-1 belongs to a family of closely related peptides that include ET-2 and ET-3, which are all similar in structure to ET-1, but are separate gene products, with tissue-specific expression. ETs act mainly via G protein-coupled receptors (GPCR) from endothelin receptor type A (ET A R) and B (ET B R) (24). The two receptors can be differentiated by agonists and antagonists binding affinity and in their cellular distributions. The ET A R binds ET-1 with the greatest affinity, whereas ET-1, ET-2, and ET-3 all have equal affinity for the ET B R.It is now well known that ET-1 receptors can activate several signaling pathways in a G protein-independent manner via complexes with ␤-arrestin (␤-arr)-1 or -2 (18, 24). The scaffold protein ␤-arr1 serves as a copilot in ET-1 signaling to organize complex networks driving tumor progression (7,23,25,26,28,30,33). Thus ET-1 axis confers pleiotropic effects on both tumor cells and microenvironment, modulating different processes by activating ␤-arr-mediated pathways (Fig. 1A). A lesson learned from various tumor models is that there are different expression profiles of the ET-1 receptors compared with normal tissues. There are cancers expres...

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Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells

Abstract: Bidirectional signaling between astrocytes and cancer cells involves upregulation and activation of the endothelin axis, which protects cancer cells from cytotoxicity induced by chemotherapeutic drugs.

Cited by 77 publications

References 33 publications

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

Endothelin therapeutics in cancer: Where are we?

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