Abstract
There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years.
Highlights
pancreatic cancer (PC) is one of the most malignant and chemotherapy-resistant tumors
Multiple mechanisms are involved in PC chemoresistance, including aberrant gene expression, deregulation of key signaling pathways, development of the epithelial-mesenchymal transition (EMT), cancer stem cells and desmoplasia [1]
I involves of Notch receptors transduces the pathway independent of RBP-Jk, and Type II, which involves the activation of Notch target genes completely signaling [38]
Summary
PC is one of the most malignant and chemotherapy-resistant tumors. That is mainly due to the lack of effective diagnosis at an early stage of tumor development and ineffective therapy. Notch signaling is required for pancreatic tissue formation and maintenance of undifferentiated epithelial cells. Low expression of activated Notch induces undifferentiation of progenitor cells of the pancreatic epithelium [8]. Pancreatic neuroendocrine tumors (NET) (Figure 1E) represent 3–5% of PCs with a 5-years survival rate of 42% [12]. In sharp contrast to normal pancreatic tissue, the activation of Notch signaling is linked to the development of PC. PanIN shows high expression of Hes1 [17] and PC overexpress Notch pathway components [22]. Normal pancreas shows acini and interlobular ducts and pancreatic neuroendocrine tumors (NET). (e) The high magnification (40×) photo shows a well differentiated NET of the pancreas; the cells are small to medium in size, with eosinophilic to amphiphilic and finely granular cytoplasm. The nuclei are monotonous, uniform, eccentrically located, round-to-oval, with “salt and pepper” (finely stippled) chromatin and no conspicuous nucleoli
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