Activities per year
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 language | English |
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Publication status | Published - 02 Mar 2020 |
Event | EACR-AACR Basic and Translational Research Conference - Tumor Microenvironment: Tumor Microenvironment - Centro de Congressos de Lisboa, Lisbon, Portugal Duration: 02 Mar 2020 → 04 Mar 2020 https://www.eaa2020.org |
Conference
Conference | EACR-AACR Basic and Translational Research Conference - Tumor Microenvironment |
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Country/Territory | Portugal |
City | Lisbon |
Period | 02/03/2020 → 04/03/2020 |
Internet address |
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Dive into the research topics of 'Effects of infused chemotherapy on microvasculature of metastatic organs'. Together they form a unique fingerprint.Activities
- 1 Public lecture/debate/seminar
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WVU_Cancer Centre: Microvascular Contributions to Brain Metastasis in Triple Negative Breast Cancer
Branco, C. (Invited speaker)
08 Oct 2021Activity: Talk or presentation types › Public lecture/debate/seminar