Fig. 2

Under-recognized molecular interactions of IR-, IGF-1R- and IR/IGF-1R- expressing pancreatic cancer cells and stromal cells. IGF ligands and IGFBPs are produced by the liver in response to growth hormone (GH) secretion from the anterior pituitary gland. IGF ligands and IGFBPs circulate in the body, and when free IGFs reach the tissues such as the pancreas that express IR, IGF-1R or IR/IGF-1R receptors, they induce activation of the target signaling pathways. Endocrine part of the pancreas secretes insulin, which is also involved in the regulation of IGFs that are secreted by the liver. Insulin does not only affect the pancreas in an autocrine and paracrine manner, but also regulates energy metabolism of the body. In PDAC, IR, IGF-1R and IR/IGF-1R receptors and IGF-1 are overexpressed in cancer cells. Moreover, cancer cells that harbor the mutated oncogenic Kras pre-dominantly secrete sonic hedgehog (Shh) that activates (myo-) fibroblasts that reside in the tumor stroma. Activated (myo-) fibroblasts that secrete IGF-1 in response to Shh activation induce IGF-1R signaling on cancer cells. Moreover, secreted proteins of activated fibroblasts, e.g. hepatocyte growth factor/HGF and CCL5, augment the migration of cancer cells and anti-tumor immunity via IGF-1R on cancer cells. On the other hand, the actual impact of altered IGF-1 levels and enhanced Insulin/IGF-1R signaling in PDAC tumor stroma, and on the endocrine β-cell function is yet to be discovered. Targeting stroma-derived IGF signalling, but also the levels of IGFBPs, can be novel tailored therapy options in PDAC