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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2017
Autoren:
Melissa García-Caballero, Jenny Paupert, Silvia Blacher, Maureen Van de Velde, Ana Rodríguez Quesada, Miguel Angel Medina, Agnès Noël
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-017-0484-1) contains supplementary material, which is available to authorized users.

Abstract

Background

Lymphatic metastasis is one of the leading causes of death in patients with different types of cancer and is the main prognostic factor for the disease survival. The formation of new lymphatic vessels (lymphangiogenesis) in primary tumors facilitates tumor cell dissemination to regional lymph nodes and correlates with distant metastases. Lymphangiogenesis has thus emerged as a suitable therapeutic target to block metastases, but no anti-lymphangiogenic compounds have been approved for clinical use to date. Therefore, new or improved therapies blocking lymphatic metastases are urgently required.

Methods

We established murine breast tumors to assess the effect of AD0157 on tumor growth, lymphangiogenesis, and lymphatic dissemination. Then, a battery of in vivo (mouse corneal neovascularization and ear sponges), ex vivo (mouse lymphatic rings and rat mesentery explants), and in vitro (proliferation, tubulogenesis, wound-healing, Boyden chambers, and spheroids) assays was used to give insight into the lymphangiogenic steps affected by AD0157. Finally, we investigated the molecular pathways controlled by this drug.

Results

AD0157 was found to inhibit the growth of human breast cancer xenografts in mice, to strongly reduce tumor-associated lymphangiogenesis and to block metastatic dissemination to both lymph nodes and distant organs. The high anti-lymphangiogenic potency of AD0157 was further supported by its inhibitory activity at low micromolar range in two in vivo pathological models and in two ex vivo assays. In addition, AD0157 inhibited lymphatic endothelial cell proliferation, migration and invasion, cellular sprouting, and tube formation. Mechanistically, this compound induced apoptosis in lymphatic endothelial cells and decreased VEGFR-3/-2, ERK1/2, and Akt phosphorylations.

Conclusions

These findings demonstrate the suitability of AD0157 to suppress tumor-associated lymphangiogenesis. Beyond discovering a new potent anti-lymphangiogenic drug that is worth considering in future clinical settings, our study supports the interest of designing anti-lymphangiogenic therapies to avoid distant metastatic processes.

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Zusatzmaterial
Additional file 1: Figure S1. Chemical structure of AD0157. (PS 139 kb)
13045_2017_484_MOESM1_ESM.ps
Additional file 2: Figure S2. AD0157 reduces LYVE-1 mRNA expression in mammary tumors and in draining LNs. Analyses of LYVE-1 expression by qRT-PCR, normalized to GADPH expression, in mammary MDA-MB-231/Luc+ tumors and LNs resected from control and AD0157-treated mice. Values are expressed as mean ± s.e.m. and Wilcoxon-Mann-Whitney significance tests were used to compare the differences between control and AD0157 treatments. *p < 0.05, **p < 0.01, ***p < 0.001 (n = 12). (PS 296 kb)
13045_2017_484_MOESM2_ESM.ps
Additional file 3: Figure S3. AD0157 inhibits LEC and MDA-MB-231/Luc+ cell proliferation. Representative curves showing the dose-dependent effect of AD0157 on the in vitro growth of LEC and MDA-MB-231/Luc+ cells. Cell proliferation is represented as a percentage of untreated cells. Each point represents the mean of quadruplicates; SD values were typically lower than 10% of the mean values and are omitted for clarity. The half-maximal inhibitory concentration (IC50) value was calculated from dose-response curves as the concentration of compound yielding 50% of control cell survival. It is expressed as means ± s.e.m. of five independent experiments. (PS 415 kb)
13045_2017_484_MOESM3_ESM.ps
Additional file 4: Figure S4. Effect of AD0157 on MDA-MB-231/Luc+ cell migration and apoptosis. (a) Closure of the initial scratched area by MDA-MB-231/Luc+ cells after 48 h in the absence or presence of different AD0157 doses. Broken lines in pictures indicate the initial (time 0) wound edges. Scale bars represent 100 μm. (b) Graph shows the percentage of the initial cell-free area recovered by tumor cells. (c) Representative pictures showing the effect of AD0157 on MDA-MB-231/Luc+ cell chromatin condensation after 14 h of treatment. Scale bars represent 100 μm. (d) Percentages of control and AD0157-treated tumor cells with condensed chromatin (total cells were counted by using bright field). (e) Percentages of subG1, G1, and S/G2/M MDA-MB-231/Luc+ cell subpopulations analyzed by flow cytometry after AD0157 treatment. (PS 17413 kb)
13045_2017_484_MOESM4_ESM.ps
Literatur
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