Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Introduction: Cachexia is a progressive metabolic disorder that affects over half of patients with head and neck cancer (HNC). Despite its prevalence, effective treatment options are lacking. Utilizing HPV(+) oropharyngeal squamous cell carcinoma rodent models, we characterize the role of Lipocalin 2 (LCN2) in mediating cachexia and assess the biological relevance of these pre-clinical studies in a cohort of HNC patients.
Methods: HPV(+) squamous cell carcinoma cells (expressing HPV16 E6/E7 and hRas) were subcutaneously implanted into wild type (WT) and Lcn2 knockout (Lcn2KO) C57BL/6J mice and cachexia measures were evaluated throughout tumor growth. Utilizing a prospective cohort of patients at a single tertiary care institution diagnosed with HNC, we assessed pre-operative LCN2 serum levels along with their correlation to standardized patient-reported cachexia measures.
Results: LCN2 was increased in the serum (1,090 v 82 ng/mL; p=0.0008) and cerebrospinal fluid (32 v 2 ng/mL; p=0.0009) in WT tumor-bearing mice compared to controls. Tumor-bearing Lcn2KO mice demonstrated improved food intake (76 v 65 g; p=0.004), skeletal muscle mass (76% v 68% [percentage of baseline lean mass]; p=0.03), cardiac mass (0.36% v 0.31%; p=0.007) and fat mass (32.5% v 8.2%; p=0.0008) compared to WT mice. Pair-feeding Lcn2KO to WT mice resulted in normalization of skeletal muscle and fat mass, while cardiac mass remained elevated (0.34% v 0.31%; p=0.007), demonstrating a nutrition-independent role of LCN2. LCN2 levels were elevated in the serum of HNC patients compared to healthy controls (418 v 141 ng/mL; p=0.001), and patients with increased LCN2 levels trended towards reduced QoL scores by standardized Functional Assessment of Anorexia/Cachexia Therapy questionnaires (r-0.25; p=0.15).
Conclusions: This study demonstrates LCN2 is robustly elevated during HNC cachexia in both pre-clinical models and humans, while genetic ablation of Lcn2 in rodents significantly mitigates debilitating features of cachexia. Collectively, our findings suggest a pathologic role for LCN2 in mediating HNC cachexia, and targeting this molecule may improve appetite, tissue wasting, and QoL during HNC cachexia.