Endothelial dysfunction as a complication of anti-cancer therapy

Abstract

Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.

Keywords: Cancer-therapy related cardiac dysfunction; Cardio-oncology; Chemotherapy; Endothelium; Inflammation; Microcirculation.

Figure 1:. Causes and consequences of endothelial toxicity arising from anti-cancer therapy.

Many forms of anti-cancer therapy induce endothelial damage directly through primary effects on endothelial cells and indirectly through systemic effects such as innate immune system activation. There is interplay between endothelial and systemic effects wherein changes to the endothelium exacerbate systemic factors while systemic factors amplify endothelial effects. Endothelial toxicity causes damage and dysfunction at the level of the microcirculation and conduit arteries that precedes and potentially contributes to adverse clinical outcomes in patients. _nDNA, nuclear DNA; _mtDNA, mitochondrial DNA

Figure 2:. Proposed mechanisms of endothelial toxicity arising from anti-cancer therapy (CTx).

CTx agents directly impact endothelial cells through several mechanisms that interfere with signaling pathways (e.g., tyrosine kinase inhibitors), alter gene expression, reduce nitric oxide (NO) bioavailability, and promote generation of reactive oxygen species (e.g., mitochondria-derived hydrogen peroxide). CTx-induced damage to tumor and parenchymal cells leads to the release of damage-associated molecular patterns (DAMPs), which circulate in the bloodstream and activate toll-like receptors (TLRs) in endothelial cells and immune cells. This initiates an innate immune response via transcription factors such as nuclear factor kappa B (NFκB). Systemic and local inflammation induce cytokine release and surface expression of intercellular adhesion molecules (ICAM), which promote leukocyte transmigration. Augmented vascular permeability also increases exposure of underlying tissue to CTx agents. Ultimately, CTx promotes vascular inflammation, impairs vasodilation, and increases vascular permeability. eNOS, endothelial nitric oxide synthase