Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Inhibition of FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells

Gabriela Morales-Guadarrama
ORCID logo ,
Edgar A. Méndez-Pérez
ORCID logo ,
Janice García-Quiroz
,
Euclides Avila
ORCID logo ,
María J. Ibarra-Sánchez
ORCID logo ,
José Esparza-López
,
Rocío García-Becerra
ORCID logo ,
Fernando Larrea
ORCID logo ,
Lorenza Díaz
*
Version 1 : Received: 17 July 2023 / Approved: 18 July 2023 / Online: 18 July 2023 (10:25:14 CEST)

A peer-reviewed article of this Preprint also exists.

Morales-Guadarrama, G.; Méndez-Pérez, E.A.; García-Quiroz, J.; Avila, E.; Ibarra-Sánchez, M.J.; Esparza-López, J.; García-Becerra, R.; Larrea, F.; Díaz, L. The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2023, 24, 13770. Morales-Guadarrama, G.; Méndez-Pérez, E.A.; García-Quiroz, J.; Avila, E.; Ibarra-Sánchez, M.J.; Esparza-López, J.; García-Becerra, R.; Larrea, F.; Díaz, L. The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells. Int. J. Mol. Sci. 2023, 24, 13770.

Abstract

Vasculogenic mimicry (VM), a process in which aggressive cancer cells form tube-like structures, plays a crucial role in providing nutrients and escape routes. Highly plastic tumor cells, such as those with triple-negative breast cancer (TNBC) phenotype, can develop VM. However, little is known about the interplay between cellular components of the tumor microenvironment upon TNBC cells VM-capacity. In this study, we analyzed the ability of endothelial and stromal cells to induce VM when interacting with TNBC cells, and analyzed the involvement of the FGFR/PI3K/Akt pathway in this process. VM was corroborated using fluorescently‐labeled TNBC cells. Only endothelial cells triggered VM formation, suggesting a predominant role of paracrine/ juxtacrine factors from an endothelial origin in VM development. By immunocytochemistry, qPCR and secretome analyses, we determined increased expression of proangiogenic factors as well as stemness markers in VM-forming cancer cells. Similarly, endothelial cells primed by TNBC cells showed upregulation of proangiogenic molecules, including FGF, VEGFA, and several inflammatory cytokines. The endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors.

Keywords

co-culture; tubulogenesis; vascular mimicry; breast cancer; angiogenesis array; AZD4547; LY294002

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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