Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy-induced toxicities.
Johan K E SpetzMary H C FloridoCameron S FraserXingping QinJonathan ChoiniereStacey J YuRumani SinghMax FriesenLee L RubinJoe-Elie SalemJavid J MoslehiKristopher A SarosiekPublished in: Science advances (2022)
Although major organ toxicities frequently arise in patients treated with cytotoxic or targeted cancer therapies, the mechanisms that drive them are poorly understood. Here, we report that vascular endothelial cells (ECs) are more highly primed for apoptosis than parenchymal cells across many adult tissues. Consequently, ECs readily undergo apoptosis in response to many commonly used anticancer agents including cytotoxic and targeted drugs and are more sensitive to ionizing radiation and BH3 mimetics than parenchymal cells in vivo. Further, using differentiated isogenic human induced pluripotent stem cell models of ECs and vascular smooth muscle cells (VSMCs), we find that these vascular cells exhibit distinct drug toxicity patterns, which are linked to divergent therapy-induced vascular toxicities in patients. Collectively, our results demonstrate that vascular cells are highly sensitive to apoptosis-inducing stress across life span and may represent a "weakest link" vulnerability in multiple tissues for development of toxicities.
Keyphrases
- cell cycle arrest
- induced apoptosis
- cell death
- endothelial cells
- endoplasmic reticulum stress
- oxidative stress
- high glucose
- stem cells
- pi k akt
- vascular smooth muscle cells
- gene expression
- diabetic rats
- drug induced
- signaling pathway
- cell proliferation
- drug delivery
- newly diagnosed
- angiotensin ii
- young adults
- mesenchymal stem cells
- tandem mass spectrometry
- replacement therapy
- simultaneous determination
- liquid chromatography
- lymph node metastasis