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.
Highlights
Angiogenesis, the formation of new blood vessels from pre-existing ones, is typically dormant in adults
Combining cyano-4-hydroxycinnamic acid (CHC) or AZD3965, the generation monocarboxylate transporter 1 (MCT1) inhibitor, with angiogenesis inhibitor (AI), might render hard-to-treat malignancies more susceptible to therapy and is conceptually a very promising anticancer approach. By applying this treatment strategy, we aimed to evaluate the applicability of the ex ovo chorioallantoic membrane (CAM) assay as an animal-free experimental setup in an anti-cancer approach
The current study aimed to evaluate the applicability of the ex ovo chorioallantoic membrane (CAM) assay as an animal-free experimental setup by targeting, individually and simultaneously, both aerobic and hypoxic compartments of model tumors through anti-vascular endothelial growth factor (VEGF) and lactate import blocking anti-MCT1 intervention strategies, respectively
Summary
Angiogenesis, the formation of new blood vessels from pre-existing ones, is typically dormant in adults. Active angiogenesis represents a hallmark of many pathological progressions, including diabetic retinopathy, rheumatoid arthritis, cardiac ischemia, psoriasis or tumor growth and spread [1]. New capillaries are required for growth of the primary nodule beyond constraints (i.e. size of ~1–2 mm3) [2]. The non-productive angiogenesis seen in solid malignancies notoriously yields tortuous, dilated vessels with highly erratic blood flow. Treating human and canine tumor grafts on chick embryo chorioallantoic membranes
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