The mechanisms eliciting
cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the
clinical deterioration in
cancer patients and for the ability to tolerate
cancer treatment. Studies done on animals suggest that nuclear factor of kappa B (
NF-kappaB) signalling is important in the progression of muscle wasting due to several types of tumours. However, there are no published studies in humans on the role of
NF-kappaB in
cancer cachexia. In this project, we studied the rectus abdominis muscle in patients with gastric tumours (n=14) and in age-matched control subjects (n=10) for markers of
NF-kappaB activation. Nuclear levels of p65, p50 and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in the muscles of
cancer patients. In addition, expression of the inhibitor of kappa B alpha (
IkappaBalpha) was decreased by 25% in
cancer patients. Decreased expression of
IkappaBalpha reflects its degradation by one of the
IkappaBalpha kinases and is a marker of
NF-kappaB activation. Interestingly, there was no correlation between the stage of
cancer and the extent of
IkappaBalpha decrease, nor was there a correlation between the degree of
cachexia and decreased
IkappaBalpha levels. This suggests that the activation of
NF-kappaB is an early and sustained event in
gastric cancer. The work implicates the
NF-kappaB signalling in the initiation and progression of
cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends
NF-kappaB signalling as a therapeutic target for the amelioration of
cachexia as has been suggested from studies done on rodents.