Abstract

ABSTRACTTriple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

Highlights

  • CXCR4 is a chemokine receptor, first described in the early 1990s (Baggiolini et al, 1997; Herzog et al, 1993; Jazin et al, 1993; Nomura et al, 1993) and identified as a co-receptor for human immunodeficiency virus (HIV) entry (Feng et al, 1996)

  • Intravascular and perivascular cancer cells were found in the basilar artery (BA), branchial arches (BAs) and optic vessels in the head region (Fig. 1F-H), and in intersegmental vessels (ISVs), dorsal longitudinal anastomotic vessels (DLAVs) and the dorsal aorta (DA) and caudal vein (CV) in both the trunk and tail areas (Fig. 1I,J)

  • In which tumor cells are inoculated directly into the blood circulation to study the formation of experimental micrometastases, bypassing initial modifications in a primary tumor mass, early metastatic events coincided with tumor foci formation and expansion, tumor extravasation, with adherence to the extravascular endothelium, and invasion

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Summary

Introduction

CXCR4 is a chemokine receptor, first described in the early 1990s (Baggiolini et al, 1997; Herzog et al, 1993; Jazin et al, 1993; Nomura et al, 1993) and identified as a co-receptor for human immunodeficiency virus (HIV) entry (Feng et al, 1996). It is a seven-transmembrane G-protein-coupled receptor with a major role in. In the migration of the lateral line primordium, Cxcl scavenging by Cxcr leads to the formation of a self-generated gradient and cell migration after Cxcr activation, along tissues where Cxcl is homogeneously distributed (Boldajipour et al, 2008; Dona et al, 2013; Venkiteswaran et al, 2013)

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