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Tumors disrupt the central molecular clock; The Rich laboratory is studying the circadian running wheel behavior of mice bearing either mammary (MCa-4) or liver tumors (HCa), or a third tumor, a squamous cell cancer (SCC). They have found that running wheel behavior of a mouse decreases as the tumor grows. These tumors grow under the skin and do not infiltrate into the muscles or nerves of the hind legs which could be interpreted as causing difficulty with the measurement of running. The HCa and the SCC tumors are associated with lower running wheel activity whereas this is not seen in animals with MCa-4. They have interpreted this observation to be a form of fatigue induced in the animal by the cancer and they are looking at some of the molecular mechanisms for this finding. Candidate molecules that have been reported by others to cause a loss of running wheel activity in rodents are signaling members of the epidermal growth factor family (EGFR), TGF-a, Neuregulin-1, and prokineticin-2 (PK2) a member of the vascular endothelial growth factor (VEGF) family. The EGFR, and VEGF families are expressed frequently in human cancers and have been reported to be correlated with the symptom of fatigue. In their mouse studies they find elevated TGF-a in the HCa and SCC tumors and these elevated levels appear to be correlated with loss of running wheel behavior. They have also screening the mouse serum for over 50 other growth factors correlated with tumor induced fatigue loss of running wheel behavior. They find no differences in EGF, IL-1, IL-6 or TNF-a (preo-inflammatory cytokines). Their laboratory findings support the hypotheses that tumors can produced neurally active peptides (cytokines) that are capable of altering output of the biologic clock like the rhythmicity of running wheel behavior. The clinical application of their observations may be to help understand the causes and how to intervene more effectively in patients suffering with symptoms of cancer induced fatigue.
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