Schlett, Christopher L.

There are physiological consequences of overeating that can lead to increased morbidity and mortality. The purpose of this review article is to acquaint the reader with the current state of the art in the non–cardiac-gated, noncontrast chest computed tomographic (NCCT) imaging biomarkers of the metabolic syndrome and their prognostic significance found in the lower neck and chest. NCCT imaging biomarkers associated with metabolic syndrome in the chest include premature coronary artery calcification, acceleration of large vessel arterial and valvular calcifications associated with atherosclerosis, and pulmonary arterial enlargement from pulmonary hypertension associated with sleep apnea. These easily identified imaging biomarkers have prognostic implications for major adverse cardiac events (MACE). These NCCT chest-imaging biomarkers are likely targets for artificial intelligence algorithms to harvest for longitudinal assessment of their individual and multifactorial contributions to chronic disease, MACE, and mortality. Early recognition and treatment of these common disorders may help improve patient outcomes and quality of life while decreasing medical costs.

Abstract Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993–3004. ©2016 AACR.