Low-dose orthotopic cancer implantation permits measurement of longitudinal functional changes associated with cachexia

Abstract

Background: Progressive functional decline is a key element of cancer-associated cachexia. Major barriers to translating pre-clinical therapies into the clinic include lack of cancer models that accurately mimic functional decline, which develops over time, and use of non-specific measures, like grip strength, as surrogates for physical function. In this study, we aimed to extend the survival and longevity of a cancer model, in order to investigate cachexia-related function at the basic science level. Methods: Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) derived cells. 128 animals in this new model were assessed for cachexia syndrome phenotype using a battery of anatomical, biochemical, and behavioral techniques. Results: We extended the survival of the KPC orthotopic model to 8-9 weeks post-implantation using a relatively low 100-cell dose of DT10022 KPC cells (p<0.001). In this Low-dose Orthotopic (LO) model, progressive muscle wasting was detected in parallel to systemic inflammation; skeletal muscle atrophy at the fiber level was detected as early as 3 weeks post-implantation compared to controls (p<0.001). Gait speed in LO animals declined as early 2-weeks post-implantation while grip strength change was a late event. Principle component and regression analyses revealed distinct cachectic and non-cachectic animal populations, which we leveraged to show that the gait speed decline was specific to cachexia (p<0.01) while grip strength decline was not (p=0.19). Conclusion: Gait speed represents an accurate surrogate for cachexia related physical function as opposed to grip strength.