Diabetic hyperglycemia-induced glycation regulates tumor vasculature integrity via NF-κB-mediated GM-CSF secretion by tumor cells

To identify the mechanism by which tumor cell secretions in response to glycation result in impaired endothelial barrier function, we conducted bulk RNA sequencing on control, diabetic, and diabetic tumors treated with ALT711. FVB/N-Tg(MMTV-PyVT)634Mul/J (MMTV- PyMT) female mice were utilized in this study. All mice were maintained following a protocol approved by the Vanderbilt University Institutional Animal Care and Use Committee (Protocol # M1700029-01). Female MMTV-PyMT mice of the FVB strain background (Jackson Laboratory, Bar Harbor, ME, USA) were fed with D12492 high-fat diet (NC0004611, research diet Inc, New Brunswck, NJ, USA) starting at 4 weeks of age. To induce diabetes, mice were given 5 consecutive daily doses of streptozotocin (STZ, MilliporeSigma) through intraperitoneal injection at 70 mg/kg body weight as described previously15. The control group of mice were injected with citrate buffer (0.1 mmol/L, pH 4.5; MilliporeSigma) as vehicle control. For STZ-injected mice receiving aminoguanidine, mice were treated with 3 mg/kg body weight aminoguanidine (MilliporeSigma) in drinking water until the study endpoint. For STZ-injected mice receiving alagebrium (ALT711) treatment, mice were treated with 1 mg/kg body weight alagebrium (MedChemExpress, Monmouth Junction, NJ, USA) injected daily intraperitoneally until study endpoint. Seven weeks after STZ injection, the mice were humanely sacrificed by CO2 asphyxiation and necropsied.