Targeting neovascularization and respiration of tumor grafts grown on chick embryo chorioallantoic membranes

Hyrije Ademi; Dheeraj A Shinde; Max Gassmann; Daniela Gerst; Hassan Chaachouay; Johannes Vogel; Thomas A Gorr

doi:10.1371/journal.pone.0251765

Targeting neovascularization and respiration of tumor grafts grown on chick embryo chorioallantoic membranes

PLoS One. 2021 May 17;16(5):e0251765. doi: 10.1371/journal.pone.0251765. eCollection 2021.

Authors

Hyrije Ademi^{1

2}, Dheeraj A Shinde¹, Max Gassmann^{1

3}, Daniela Gerst¹, Hassan Chaachouay^{4

5}, Johannes Vogel¹, Thomas A Gorr¹

Affiliations

¹ Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
² Center for Clinical Studies at the Vetsuisse Faculty of the University of Zurich, Zurich, Switzerland.
³ Zurich Centre for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
⁴ Division of Radiation Oncology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
⁵ Bioactives, Health & Environment Laboratory, Epigenetics, Health & Environment Unit, Faculty of Science and Techniques, Moulay Ismail University, Errachidia, Morocco.

Abstract

Since growing tumors stimulate angiogenesis, via vascular endothelial growth factor (VEGF), angiogenesis inhibitors (AIs, blockers of the VEGF signaling pathway) have been introduced to cancer therapy. However, AIs often yielded only modest and short-lived gains in cancer patients and more invasive tumor phenotypes in animal models. Combining anti-VEGF strategies with lactate uptake blockers may boost both efficacy and safety of AIs. We assessed this hypothesis by using the ex ovo chorioallantoic membrane (CAM) assay. We show that AI-based monotherapy (Avastin®, AVA) increases tumor hypoxia in human CAM cancer cell xenografts and cell spread in human as well as canine CAM cancer cell xenografts. In contrast, combining AVA treatment with lactate importer MCT1 inhibitors (α-cyano-4-hydroxycinnamic acid (CHC) or AZD3965 (AZD)) reduced both tumor growth and cell dissemination of human and canine explants. Moreover, combining AVA+AZD diminished blood perfusion and tumor hypoxia in human explants. Thus, the ex ovo CAM assay as an easy, fast and cheap experimental setup is useful for pre-clinical cancer research. Moreover, as an animal-free experimental setup the CAM assay can reduce the high number of laboratory animals used in pre-clinical cancer research.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology*
Animals
Cell Line, Tumor
Chick Embryo
Chorioallantoic Membrane* / blood supply
Chorioallantoic Membrane* / metabolism
Chorioallantoic Membrane* / pathology
Dogs
Humans
Mice
Monocarboxylic Acid Transporters / antagonists & inhibitors
Monocarboxylic Acid Transporters / metabolism
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Neoplasms, Experimental* / blood supply
Neoplasms, Experimental* / drug therapy
Neoplasms, Experimental* / metabolism
Neoplasms, Experimental* / pathology
Neovascularization, Pathologic* / drug therapy
Neovascularization, Pathologic* / metabolism
Neovascularization, Pathologic* / pathology
Oxygen Consumption / drug effects*
Pyrimidinones / pharmacology*
Symporters / antagonists & inhibitors
Symporters / metabolism
Thiophenes / pharmacology*
Xenograft Model Antitumor Assays

Substances

AZD3965
Angiogenesis Inhibitors
Monocarboxylic Acid Transporters
Neoplasm Proteins
Pyrimidinones
Symporters
Thiophenes
monocarboxylate transport protein 1

Grants and funding

TAG: Krebsliga Zürich and Marie-Louise von Muralt-Stiftung für Kleintiere HA: Swisslife MG: Stiftung für wissenschaftliche Forschung an der Universität Zürich The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.