IGF2 and cancer: In addition, the therapeutic responses to the monoclonal antibodies were disappointing, and this was attributed to several potential factors including: (i) a compensatory feedback mechanism that leads to increased IGF production due to increased growth hormone release [44], (ii) IR-A signalling that can be initiated by IGF-II (the main plasma IGF-IR ligand in human) and leads to mitogenic signaling; and (iii) cancer cell resistance due to activation of compensatory RTK signaling [36,45,46].