Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

Local substitution of GDF-15 improves axonal and sensory recovery after peripheral nerve injury.

The growth/differentiation factor-15, GDF-15, has been found to be secreted by Schwann cells in the lesioned peripheral nervous system. To investigate whether GDF-15 plays a role in peripheral nerve regeneration, we substituted exogenous GDF-15 into 10-mm sciatic nerve gaps in adult rats and compared functional and morphological regeneration to a vehicle control group. Over a period of 11 weeks, multiple functional assessments, including evaluation of pinch reflexes, the Static Sciatic Index and of electrophysiological parameters, were performed. Regenerated nerves were then morphometrically analyzed for the number and quality of regenerated myelinated axons. Substitution of GDF-15 significantly accelerated sensory recovery while the effects on motor recovery were less strong. Although the number of regenerated myelinated axons was significantly reduced after GDF-15 treatment, the regenerated axons displayed advanced maturation corroborating the results of the functional assessments. Our results suggest that GDF-15 is involved in the complex orchestration of peripheral nerve regeneration after lesion.