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The potentiating effect of HGF c Met on IL 6 signaling may be explained by two mechanisms: IL 6 improved the level of c Met about the cell surface of myeloma cells creating cells much more sensitive to HGF, and IL 6 relied on HGF c Met to entirely activate the RasMAPK pathway possibly by means of Shp2 activation.

This really is in line with other reports indicating that enhance of c Met expression enhances each the biologic effects of HGF and c Met signaling in a variety of cell types. A current publication also indicates that the level of c Met expression is essential for your survival of myeloma cells as partly downregulation of c Met lead to myeloma cell death. In addition, in vivo induction Cabozantinib of the IGF 1 receptor has been reported in the murine myeloma model 5T33MM, and this induction was necessary for biological effects of IGF 1 in these experiments. Inhibiting c Met had substantial effects on IL 6induced proliferation in four out of nine primary samples, although the frequency of this mechanism in primary myeloma patients is hard to estimate due to the low numbers of samples.

Further studies are necessary to see, NSCLC if hyperdiploid patients with high HGF and IL 6 expression are subjected to synergy between IL 6 and HGF, and if they can benet from c Met inhibition. The potentiating effect of c Met signaling in IL 6induced p44 42 MAPK activation in ANBL 6 cells was intriguing and a novel observation. Neither HGF nor IL 6 alone could induce Ras MAPK signaling, but the combination of HGF and IL 6 was necessary to activate this pathway. The Ras MAPK pathway is a major regulator of cell proliferation, and has previously been shown to be important for myeloma cell proliferation in vitro and in vivo. However, the role of c Met as a regulator of IL 6 induced Ras MAPK signaling has to our knowledge not been shown in myeloma cells before.

The results presented here indicate that both IL 6 and c Met activation may be required for full catalytic activity of Shp2. Shp2 activation appeared to be necessary for the activation of p44 42 MAPK as the novel SHP2 inhibitor NSC 87877 abrogated cytokine mediated MAPK phosphorylation in ANBL 6.