TNF and neoplasm: Different mechanisms underlying the independent effects of IGFBP-3 have been shown, including the activation of the insulin receptor/TNFα pathway [27], sphingolipid signaling [29], binding to IGFBP-3 receptor [46], and the involvement of protein kinase A [31] for the regulation of cellular apoptosis, as well as inactivation of the Erk1/2 pathway for anti-angiogenic and anti-tumor activities [47].