Ricerc@Sapienza

Neurohypophyseal hormones (vasopressin, AVP, and oxytocin, OT) are powerful regulators of myogenic differentiation and muscle homeostasis. Cultured myogenic cells activate a rich orchestra of intracellular signals in response to either AVP or OT, and differentiate and hypertrophy in response to such stimuli. In vivo, receptors for neurohypophyseal hormone are constitutively expressed in murine skeletal muscle and up-regulated during regeneration.
Cancer cachexia is an extremely severe form of muscle atrophy, implies increased morbidity and mortality, worsens the patients¿ quality of life and interferes with the feasibility and efficacy of chemotherapy. Proinflammatory cytokines and tumor-released factors are the best-established players triggering muscle wasting during cancer progression and activating catabolic processes in muscle while inhibiting regeneration, thereby profoundly altering muscle homeostasis. In particular, TNF mimics the tumor presence and causes severe muscle atrophy by activating muscle catabolism and inhibiting regeneration. Notably, i.m. administration of neurohypophyseal hormones or overexpressing their receptors counteracts the atrophying effect of TNF.
On these bases, we propose to investigate (also in the prospect of a pre-clinical study) the feasibility of experiments aimed to inhibit the onset and / or progression of muscle wasting in tumor-bearing animals by administering neurohypophyseal hormones.
Purposes of this pilot study are: a) due to the short in vivo half-life of the neurohypophyseal hormones, it will be necessary to design and set up a system for the continuous infusion of OT/AVP; b) experimentally determine the concentrations of OT/AVP to be administered, in order to increase the circulating level of the hormone avoiding systemic or local toxicity effects; c) obtain preliminary data on the effectiveness of the hormonal treatment in antagonizing the tumor-dependent muscle wasting.