Effects of infused chemotherapy on microvasculature of metastatic organs

Amanda Eakin, Gloria Allocca, Aileen Burke, Lowri Edwards, Cristina Branco*

*Corresponding author for this work

Research output: Contribution to conferencePaperpeer-review

Abstract

Introduction Metastasis cause 90% of cancer-related deaths. Few studies address the impact of chemotherapy on cells of secondary organs. Our data and others’ show a detrimental effect of cytotoxic treatment on the endothelial barrier. We hypothesise that chemotherapy effects on endothelial cells (ECs) influences the rate of extravasation as well as EC-derived organ remodelling, with impact on metastasis. This study focusses on the impact of Epirubicin (EPI) on EC function, and the downstream effect on metastasis. Using established mouse models, primary murine and human EC, we evaluate the microvascular responses and the metastatic potential following infused cytotoxic treatments. Material and Methods Human umbilical vein EC (hUVECs) were incubated with 3µg/ml and 5µg/ml of EPI for 30 minutes and allowed to recover in drug-free medium. TUNEL and tube formation assays were carried out at various time points after incubation. C57/Bl6 mice were intravenously injected with 2mg/ml EPI or saline control. Typically metastatic (brain and lung) were collected on days 1, 7 and 14 for IF analyses, and CD31, a-smooth muscle actin and MAC2 signal was quantified. Primary ECs were also isolated from specific tissues following treatment at each time point, to assess proliferation, viability and function ex vivo. Results and Discussions EPI-treated hUVECs showed increased apoptosis compared to saline controls. Angiogenesis is also impaired following EPI exposure, with reduced number of branches and junctions treated (6.533 ± 2.445, n=6) versus saline controls(34.73 ± 7.661, n=6, p<0.01). These results persist for up to 5 days in drug-free medium. Lung EC isolated from mice 7 days after injection with EPI proliferated at a lower rate. Additionally, EC from treated mice showed impaired migration, assessed by wound healing assays (15.12 %closure ± 5.0 treated vs 43.55 %closure ± 5.55, n=3, p<0.05 saline). IF staining of brain tissue shows significantly reduced pericyte:EC ratio (0.14 ± 0.02 compared to control, 0.24 ± 0.03, n=32, p<0.01), an effect that persists up to 14 days after treatment. Macrophage infiltration, assessed by MAC2 signal is also higher in treated mice. Conclusion EPI significant reduces viability and function of ECs in organs predisposed to metastatic disease in breast cancer. Further work will confirm the effects on endothelial metabolism, signalling, and metastatic success following infused chemotherapy, and whether this can be detected before formation of a secondary tumor.
Original languageEnglish
Publication statusPublished - 02 Mar 2020
EventEACR-AACR Basic and Translational Research Conference - Tumor Microenvironment: Tumor Microenvironment - Centro de Congressos de Lisboa, Lisbon, Portugal
Duration: 02 Mar 202004 Mar 2020
https://www.eaa2020.org

Conference

ConferenceEACR-AACR Basic and Translational Research Conference - Tumor Microenvironment
Country/TerritoryPortugal
CityLisbon
Period02/03/202004/03/2020
Internet address

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