Abstract
Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.
Highlights
Recent demographic studies on pancreatic cancer highlighted that, unless novel therapeutic regimens are developed, pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related death in the United States within a decade [1]
Earlier work has demonstrated that the binding of IGFBP5 to extracellular matrix components (ECM) significantly reduces its affinity for insulin-like growth factor (IGF)-I
Thereby enhancing its biological actions [64]. This was confirmed by several other experiments and showed that ECM components/heparin-binding to IGFBP5 resulted in a conformational change in the protein that decreases the affinity for IGF1 to at least 17-fold [65,66]
Summary
Recent demographic studies on pancreatic cancer highlighted that, unless novel therapeutic regimens are developed, pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related death in the United States within a decade [1]. Even though the use of FOLFIRINOX (a combination chemotherapy regimen of oxaliplatin, irinotecan, 5-fluorouracil, and L-leucovorin) as a first-line treatment in patients with advanced PC significantly prolonged overall survival and progression-free survival, the high rate of adverse events associated with its standard dosage limits its widespread use in clinical practice [6,7] This situation demands more research efforts for further improvement in PDAC. More or less normal-appearing stroma in the early PanIN lesions and dense stroma with or without inflammatory cells in the late PanIN lesions strongly suggest that progression of PDAC is integrated with progressive changes in the stroma [10,11] This disease progression is associated with several molecular alterations in the oncogenic signaling cascades in the tumor as well as stromal compartments. We discuss the emerging role of IGF signaling/IGFBPs in the mutual interactions of tumor cells and stromal cells in the PDAC microenvironment that may open new avenues in the development of novel therapeutics against PDAC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
