Cachexia is the term used to describe the severe weight loss and muscle wasting seen in patients with a variety of primary disorders including cancer. Cancer cachexia is the result of active protein degradation via the ubiquitin proteasome pathway, and a decrease in protein synthesis. Despite progress in understanding the mechanisms of cachexia treatment options remain limited. We propose that successful treatment for cachexia will require a combination of strategies aimed not only at inhibiting the ongoing protein degradation and tissue destruction, but also at replacing the lost tissue by skeletal muscle regeneration. We have recently discovered a novel CD4+ T cell subset identified by their very low density of CD44 (now called precursor cells) that are depleted in mice with cancer that are cachexic. Moreover, infusion of highly purified precursor cells, but not other CD4+ T cell subsets, inhibits cachexia and cachexia-associated lymphopenia. Protection from cachexia is associated with an increase in both skeletal muscle protein and DNA suggesting that the mechanism of protection is not simply to prevent protein degradation. We propose that CD4+ precursor cells inhibit cachexia by promoting skeletal muscle regeneration. This hypothesis will be tested by i) measuring the capacity of precursor cells to induce muscle stem cell (satellite cells, SC) differentiation and muscle growth in vivo and in vitro, and by ii) testig whether SC are required for precursor cell-mediated protection from cachexia (Specific Aim 1). Using DNA expression profiling we will also test the hypothesis that pathways relevant to skeletal muscle regeneration are upregulated in muscle protected from cachexia with precursor cells compared to muscle that is cachexic (Specific Aim 2). As part of the same aim we will identify immune biomarkers specific for muscle cachexia and precursor cell-mediated protection from cachexia. As such, this study will provide novel insight into the mechanism by which the regeneration machinery responds to CD4+ precursors cells during cachexia and the overall effect of this response on activation of muscle anabolic/catabolic pathways. Importantly, CD4+ T cells that express a very low density of CD44 are present in human blood.
In Specific Aim 3 we will embark on a pilot study to test the hypothesis that cancer patients with cachexia have significantly fewer CD4+ CD44v.low cells compared to cancer patients without cachexia. We will also test whether biomarkers for cachexia identified in Specific Aim 2 are also associated with cachexia in human.
Cancer cachexia is the severe wasting caused by cancer-derived signals that promote muscle catabolism. Our limited knowledge on the cellular and molecular effectors that promote cancer cachexia has hampered the advance toward discovering effective treatments to prevent muscle breakdown in cancer patients. Thus, the potential role of CD4+ precursors cells as a source of signals that promote protection from cachexia is highly significant from a basic biology and therapeutic standpoint.