The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer

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.

Keywords: Notch; RBP-Jk; chemoresistance; leptin; pancreatic cancer.

Figure 1

Representative pictures from hematoxylin and eosin staining of normal pancreatic parenchyma, chronic pancreatitis (CP), pancreatic adenocarcinoma (PA), mucinous pancreatic cyst and pancreatic neuroendocrine tumors (NET). (A) Normal pancreas shows acini and interlobular ducts (exocrine) and islets of Langerhans (endocrine) (10×) (B) CP shows loss of acini and ductal tissue, as well as periductal fibrosis (10×). (b) The thumb image is a lower magnification of CP, depicting residual islets and interlobular ducts with flattened epithelium (40×). (C) PA is composed of small glands and malignant cell clusters with hyperchromatic nuclei invading in a desmoplastic stroma (10×). (c) The high magnification (40×) of a moderately differentiated PA shows glands composed of tall columnar cells with abundant cytoplasm. Perineural invasion, one of the characteristics of PA, is also seen here. The tumoral nuclei are large, with irregular nuclear membrane, frequently vesiculated chromatin, with numerous chromocenters and occasional proeminent, cherry red nucleoli. (D) The pancreatic mucinous cyst is composed of cells which contain intracytoplasmic mucin and fibrosed stroma (10×). (d) The high magnification (40×) shows mucin secreting glandular cells lining a benign mucinous cyst of pancreas (40×). (E) NET is composed of cells forming trabeculae, cords and ribbons of neoplastic cells (10×). (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.

Figure 2

Notch canonical and non-canonical signaling pathways and PC. Notch canonical signals require the activation of membrane-bound Notch receptors via ligand binding and production of Notch intracellular domain (NICD), which binds to RBP-Jk repressor complex to induce transcription of Notch targets (Hes, Hey, Cyclin D, etc.) [4,5,18,20,22]. Notch non-canonical Type I signals require NICD involvement to activate NF-κB, Hedgehog, JAK/STAT. TGF-β or Wnt. In contrast, Notch non-canonical Type II signals triggered by diverse factors (i.e., FGF2, HIF-1α, Hedgehog) do not require NICD or RBP-Jk involvement [30,31,32,33,34,35,36]. Notch and KRAS activation show synergic effects to induce PC development and chemoresistance [21]. Leptin binding to its receptor induces the expression of Notch in PC [37] Shh: Sonic Hedgehog; Dhh: Desert Hedgehog; Smo: Smoothened protein; OB-R: leptin receptor.