Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model
| Autor: | Tulotta, C., Stefanescu, C., Beletkaia, E., Bussmann, J., Tarbashevich, K., Schmidt, T., Snaar-Jagalska, B.E. |
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| Rok vydání: | 2015 |
| Předmět: |
Receptors
CXCR4 Molecular Sequence Data lcsh:Medicine Triple Negative Breast Neoplasms Metastases Ligands Triple-negative breast cancer lcsh:Pathology Animals Humans Amino Acid Sequence Neoplasm Metastasis Zebrafish CXCR4 Sequence Homology Amino Acid IT1t Xenograft lcsh:R CXCL12 Disease Models Animal Inter-species crosstalk Heterografts Female lcsh:RB1-214 Research Article |
| Zdroj: | Disease Models & Mechanisms Disease Models and Mechanisms, 9(2), 141-153 Disease Models & Mechanisms, Vol 9, Iss 2, Pp 141-153 (2016) |
| ISSN: | 1754-8411 |
| Popis: | Triple-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. Summary: CXCR4-expressing human tumor cells respond to zebrafish cognate ligands and initiate metastatic events in a zebrafish xenograft model. The CXCR4 antagonist IT1t has promising tumor inhibitory effects. |
| Databáze: | OpenAIRE |
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