Pancreatic cancer

Abstract

In recent years, it has become clear that the current standard therapeutic options for pancreatic cancer are not adequate and still do not meet the criteria to cure patients suffering from this lethal disease. Although research over the past decade has shown very interesting and promising new therapeutic options for these patients, only minor clinical success was achieved. Therefore, there is still an urgent need for new approaches that deal with early detection and new therapeutic options in pancreatic cancer. To provide optimal care for patients with pancreatic cancer, we need to understand better its complex molecular biology and thus to identify new target molecules that promote the proliferation and resistance to chemotherapy of pancreatic cancer cells. In spite of significant progress in curing cancers with chemotherapy, pancreatic cancer remains one of the most resistant solid tumour cancers and many studies suggest that drug-resistant cancer cells are the most aggressive with the highest relapse and metastatic rates. In this context, activated Notch signalling is strongly linked with chemoresistance and therefore reflects a rational new target to circumvent resistance to chemotherapy in pancreatic cancer. Here, we have focused our discussion on the latest research, current therapy options and recently identified target molecules such as Notch-2 and the heparin-binding growth factor midkine, which exhibit a wide range of cancer-relevant functions and therefore provide attractive new therapeutic target molecules, in terms of pancreatic cancer and other cancers also.

Linked articles: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.

Keywords: Notch; PDAC; chemotherapy resistance; gemcitabine; midkine; pancreatic cancer; therapy; tumour.

Figure 1

Elevated MK expression promotes activation of Notch signalling and chemoresistance in pancreatic cancer. Expression of the heparin-binding growth factor MK is frequently up-regulated in PDAC. MK expression is inducible by chemotherapy with gemcitabine (yellow dots), accompanied by its elevated secretion in chemoresistant cells. Secreted MK activates extracellular Notch-2 in a paracrine/autocrine fashion, followed by ADAM/TACE cleavage and shedding of the extracellular domain and subsequent γ–secretase-mediated generation of the soluble Notch-2 intracellular domain and its translocation into the nucleus to activate transcription of target genes. Secreted MK-mediated Notch-2 activation is highly linked to epithelial-mesenchymal transition (EMT), chemoresistance and migration of PDAC cells, whereas MK depletion reverses EMT to mesenchymal–epithelial transition, a reversal strongly linked to increased chemosensitivity and decreased migratory potential of chemoresistant cells. Notch signalling contributes to regulation of cell death through crosstalk with NF-κB signalling. Blockade of the secreted MK–Notch-2 interaction or MK down-regulation is therefore a rational new strategy to circumvent chemoresistance in PDAC.