Tumor Secreted Autocrine Motility Factor (AMF): Causal Role in an Animal Model of Cachexia

Abstract : Cancer cachexia has three clinical features: 1) loss of appetite (anorexia)1 2) nutritional mal-absorption, and 3) muscle and fat wasting caused by tumor-stimulated factors. This project focuses on muscle wastiung. A number of %factors have been proposed to cause cancer cachexia. Lack of progress in the area is unfortunate, given the tremendous benefit patients with advanced cancer would receive from effective treatment of cachexia to improve quality of life and postpone mortality. We proposed that autocrine motility factor (AMF) is released into the bloodstream from cancer sites and stimulates muscle wasting. In the second grant period we have now demonstrated that administration of recombinant AMF protein to mice results in a statistically significant loss of weight, compared to control treatment, in 24 hours. We are ready to test the species specificity of this response. We have also determined the molecular structure of the recombinant mouse protein. In the next and final research year will assess some of the molecular pathways activated in muscle by AMF, which could contribute to cachexia. These include - activation of proteasomal muscle protein degradation via the Foxo transcription factors and PI3 kinase pathways and alterations in the secreted regulators of muscle mass, IGF-1 and myostatin.