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

Abstract

Progressive functional decline is a key element of cancer-associated cachexia. Major barriers to translating preclinical therapies into the clinic include lack of cancer models that accurately mimic functional decline, which develops over time, and use of nonspecific measures, like grip strength, as surrogates for physical function. In this study, we aimed to extend the survival and longevity of a cancer model, to investigate cachexia-related function at the basic science level. Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-ras^LSL.G12D/+; Trp53^R172H/+; Pdx-1-Cre (KPC)-derived cells. One hundred twenty-eight animals in this new model were assessed for cachexia syndrome phenotype using a battery of anatomical, biochemical, and behavioral techniques. We extended the survival of the KPC orthotopic model to 8-9 wk postimplantation 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 wk postimplantation compared with controls (P < 0.001). Gait speed in LO animals declined as early as 2 wk postimplantation, whereas grip strength change was a late event. Principal component and regression analyses revealed distinct cachectic and noncachectic animal populations, which we leveraged to show that the gait speed decline was specific to cachexia (P < 0.01), whereas grip strength decline was not (P = 0.19). Gait speed represents an accurate surrogate for cachexia-related physical function as opposed to grip strength.NEW & NOTEWORTHY Previous studies of cancer-induced cachexia have been confounded by the relatively rapid death of animal subjects. Using a lower dose of cancer cells in combination with a battery of behavioral, structural, histological, and biochemical techniques, we show that gait speed is actually the best indicator of functional decline due to cachexia. Future studies are required to define the underlying physiological basis of these findings.