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Neoadjuvant Chemotherapy Decreases Angiogenesis Potential and Microvascular Function in Human Breast Cancer Patients
Author(s) -
Norwood Toro Laura E.,
Linn Jasmine,
Hockenberry Joseph C.,
Kong Amanda L.,
Flister Michael J.,
Beyer Andreas M.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.845.6
Subject(s) - medicine , matrigel , in vivo , angiogenesis , ex vivo , neovascularization , chemotherapy , doxorubicin , cancer , adipose tissue , breast cancer , cancer cell , pathology , biology , microbiology and biotechnology
Rational Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells; however, CT is well established to have adverse impact on the cardiovascular (CV) system even years after cessation of treatment. Much work has been dedicated to studying the effects of CT drugs on the tumor vasculature, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is a known early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate whether previous CT treatment has any lasting effect on the human MV. Methods To study the effect of CT on the MV, flow mediated dilation (FMD) was evaluated in freshly isolated adipose microvessels from cancer patients with and without previous CT. Angiogenic potential was assessed using matrigel plug assays with samples isolated from human adipose. Effect of CT on endothelial cell (EC) and cancer cell survival was determined using MTT; EC permeability was established using FITC‐dextran in transwells with a EC monolayer. Results In cultured cells doxorubicin (dox; 100 nM) causes a decrease in MTT in human cancer, but not EC. Ex vivo treatment of the vessels with dox reduced nitric oxide (NO) mediated dilation by 90% compared to untreated controls (A). Similarly, MV FMD was severely decreased in vessels from patients with neoadjuvant CT (cessation of therapy ~ four weeks prior) compared to untreated control subjects (B). Smooth muscle dependent dilation to papaverine was not affected in either study (C). Using an ex vivo matrigel assay, we found a significant decrease in angiogenesis potential in samples treated with dox (D). In line with these findings, dox causes a decrease in EC cell permeability, suggesting a potential contributing mechanism. Conclusions Dox in clinically relevant doses causes increased lethality in cancer cells versus EC, but induces MV dysfunction, decreased angiogenic potential, and elevated EC permeability. Our studies show for the first time the effect of dox on human MV function and may lead to ways to prevent adverse CV side effects from CT without affecting cancer cell lethality. Support or Funding Information This work was supported by NIH R01 HL133029, We Care Foundation Grant; MCW‐Cardiovascular Center Pre‐PPG grant, Advancing a Healthier Wisconsin – Redox Biology Grant. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .