Figure 2.

A working model for genetic events that lead to multifocal ileal NETs. Notably, these alterations are not caused by point mutations, which are rare in I-NETs. Overexpression of the growth factor IGF2 across a large region of the ileum occurs due to zonal loss of imprinting, which should increase the proliferation of enterochromaffin cells (red) in a number of intestinal crypts. Chromosome 18 loss decreases expression of resident gene MIR1-2, which normally suppresses CDK4 to maintain the RB1 tumor suppressor pathway. No recurrent genetic cause for mTOR activation has been elucidated in I-NETs, but mTOR inhibitors are clinically beneficial for I-NET patients. Even after tumorigenic events occur, the growth of primary ileal NETs often remains slow, possibly due to local production of the growth inhibitor somatostatin by neighboring enteroendocrine cells, which are shown in purple.