The Endothelin-Integrin Axis Is Involved in Macrophage-induced Breast Cancer Cell Chemotactic Interactions with Endothelial Cells

Chen, Chia-Chi; Chen, Lili; Hsu, Yu-Ting; Liu, Ko‐Jiunn; Fan, Chi-Shuan; Huang, Tze-Sing

doi:10.1074/jbc.m113.528406

Cited by 20 publications

(20 citation statements)

References 48 publications

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“…Interestingly, in two of three macrophage donors, preferential transmigration across lymphatic endothelium was observed. A study has shown the effect of macrophage conditioned media on MCF7 adhesion to HUVEC which could be reduced with endothelin receptor inhibition and showed similar results for transmigration [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Storr

Safuan

Ahmad

et al. 2017

Cancer Immunol Immunother

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Lymphovascular invasion (LVI), encompassing blood and lymphatic vessel invasion, is an important event in tumourigenesis. Macrophages within the tumour microenvironment are linked to the presence of LVI and angiogenesis. This study investigates the role of macrophage-derived, caspase-1-dependent interleukin-1beta (IL-1β) in an in vitro model of LVI. IL-1β significantly augmented the adhesion and transmigration of breast cancer cell lines MCF7 and MDA-MB-231 across endothelial cell barriers. MDA-MB-231 and MCF7 showed a higher percentage of adhesion to lymphatic endothelial cells than blood endothelial cells following endothelial cell IL-1β stimulation (P < 0.001 and P < 0.0001, respectively). Supernatants from activated macrophages increased the adhesion of tumour cells to lymphatic and blood endothelium. Secretion of IL-1β was caspase-1 dependent, and treatment with caspase-1 inhibitor reduced IL-1β production by 73% and concomitantly reduced tumour cell adhesion to levels obtained with resting macrophages. Transmigration of MDA-MB-231 cells across blood and lymphatic endothelial monolayers was significantly increased following IL-1β stimulation. Furthermore, supernatants from activated macrophages increased transmigration of MDA-MB-231 cells across endothelial monolayers, which was abolished by caspase-1 inhibition. IL-1β stimulation of tumour cells significantly increased their migratory ability and a significant increase in migration was observed when MDA-MB-231 cells were stimulated with macrophage conditioned media (two of three donors). Results demonstrate that macrophage production of IL-1β plays an important role in the migration of breast cancer cells and their adhesion to, and transmigration across, blood and lymphatic endothelial cells. Results suggest that IL-1β may play a role in the adhesion to lymphatic endothelial cells in particular.

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Section: Discussionmentioning

confidence: 99%

Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Storr

Safuan

Ahmad

et al. 2017

Cancer Immunol Immunother

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“…Macrophages produce cytokines, such as IL-8 and tumor necrosis factor-α (TNF-α), to stimulate endothelin (ET) and ET receptor (ETR) expression on breast cancer cells and human umbilical vein ECs (HUVECs). The ET axis induces integrins and their counterligands on breast cancer cells and HUVECs, thus facilitating the adhesion process of cancer cells to HUVECs and also the TEM [168]. It has also been reviewed that leukocyte-cancer cell fusion facilitates chemotactic motility and metastasis [169,170].…”

Section: Modulation Of Vascular Property During Metastasismentioning

confidence: 99%

Cancer cells remodel themselves and vasculature to overcome the endothelial barrier

Shenoy

2016

Cancer Letters

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Metastasis refers to the spread of cancer cells from a primary tumor to distant organs mostly via the bloodstream. During the metastatic process, cancer cells invade blood vessels to enter circulation, and later exit the vasculature at a distant site. Endothelial cells that line blood vessels normally serve as a barrier to the movement of cells into or out of the blood. It is thus critical to understand how metastatic cancer cells overcome the endothelial barrier. Epithelial cancer cells acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT), which enables them to move toward vasculature. Cancer cells also express a variety of adhesion molecules that allow them to attach to vascular endothelium. Finally, cancer cells secrete or induce growth factors and cytokines to actively prompt vascular hyperpermeability that compromises endothelial barrier function and facilitates transmigration of cancer cells through the vascular wall. Elucidation of the mechanisms underlying metastatic dissemination may help develop new anti-metastasis therapeutics.

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“…Experimental studies in bladder cancer have also revealed an ET-1/ET A R-dependent production of pro-inflammatory mediators and infiltration of macrophages into tumors, which promotes breaching of vascular integrity and dissemination of cancer cells to the lungs (24). Macrophages also stimulate the expression of ET-1 and its receptors in breast cancer cells and EC, thus stimulating transendothelial migration of cancer cells (6).…”

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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The Endothelin-Integrin Axis Is Involved in Macrophage-induced Breast Cancer Cell Chemotactic Interactions with Endothelial Cells

Cited by 20 publications

References 48 publications

Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Cancer cells remodel themselves and vasculature to overcome the endothelial barrier

Endothelin therapeutics in cancer: Where are we?

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