Concise Review: Pancreatic Cancer and Bone Marrow-Derived Stem Cells

Abstract

Pancreatic adenocarcinoma remains one of the most challenging diseases of modern gastroenterology, and, even though considerable effort has been put into understanding its pathogenesis, the exact molecular mechanisms underlying the development and/or systemic progression of this malignancy still remain unclear. Recently, much attention has been paid to the potential role of bone marrow-derived stem cells (BMSCs) in this malignancy. Hence, herein, we comprehensively review the most recent discoveries and current achievements and concepts in this field. Specifically, we discuss the significance of identifying pancreatic cancer stem cells and novel therapeutic approaches involving molecular interference of their metabolism. We also describe advances in the current understanding of the biochemical and molecular mechanisms responsible for BMSC mobilization during pancreatic cancer development and systemic spread. Finally, we summarize experimental, translational, and/or clinical evidence regarding the contribution of bone marrow-derived mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem/progenitor cells, and pancreatic stellate cells in pancreatic cancer development/progression. We also present their potential therapeutic value for the treatment of this deadly malignancy in humans.

Significance: Different bone marrow-derived stem cell populations contribute to the development and/or progression of pancreatic cancer, and they might also be a promising "weapon" that can be used for anticancer treatments in humans. Even though the exact role of these stem cells in pancreatic cancer development and/or progression in humans still remains unclear, this concept continues to drive a completely novel scientific avenue in pancreatic cancer research and gives rise to innovative ideas regarding novel therapeutic modalities that can be safely offered to patients.

Keywords: Bone marrow; Cancer; Pancreas; Stem cells.

Figure 1.

Simplified illustration of biochemical signals influencing molecular crosstalk between pancreatic cancer and the bone marrow environment. After development/progression of pancreatic adenocarcinoma, local hypoxia and proinflammatory microenvironment stimulate expression of the hypoxia-inducible factor-1 gene and activation of the (innate) immune system, which in turn results in intensified synthesis of multiple substances, such as complement cascade-derived anaphylatoxins/molecules (C5a and C5b-9), stromal-derived factor-1, sphingosine-1-phosphate, growth factors (such as HGF), and cytokines. These seem to create sufficient biochemical balance that induces bone marrow-derived stem cell egress from the bone marrow environment. However, their systemic levels are also influenced by activity of proteolytic enzymes, which may (at least partially) deactivate various protein substances and lead to a situation that their systemic levels in humans may not significantly increase after development/progression of pancreatic adenocarcinoma. Abbreviations: BMSCs, bone marrow-derived stem cells; HGF, hepatocyte growth factor; S1P, sphingosine-1-phosphate; SDF-1, stromal-derived factor-1.

Figure 2.

Simplified illustration of molecular interactions/pathways responsible for execution of the effects of selected chemoattractants, growth factors, and interleukins on (patho)physiology and function of bone marrow-derived stem cells. Various types of bone marrow-derived stem cells (BMSCs) express receptors for major substances regulating their function. In terms of complement-derived anaphylatoxins (C5aR), S1P, and selected interleukins (CXCR1/2), these are G-coupled protein receptors, whereas other substances have different specific types of their receptors, such as c-Met receptor tyrosine kinase for hepatocyte growth factor, built from highly glycosylated extracellular α-subunit and a transmembrane β-subunit linked together by a disulfide bridge, or IL-6 complex protein receptor (also known as CD126) consisting of an IL-6 receptor subunit and IL-6 signal transducer glycoprotein 130. Via multiple intermediate stages, stimulation of these receptor(s) finally leads to activation of various intracellular signaling molecules, such as extracellular signal-regulated kinases 1/2, Akt, and/or p38. Afterward, these translocate to the nucleus and lead to phosphorylation of various transcription factors, such as, for example, Elk, which influence function of BMSCs on a (epi)genetic level. All these signals are responsible for regulation of multiple processes related to BMSC homeostasis, including protection from apoptosis, tissue transdifferentiation, migration, and/or maintenance of stemness. Abbreviations: ERK, extracellular signal-regulated kinase; HGF, hepatocyte growth factor; IL-6, interleukin 6; IL-8, interleukin 8; p, phosphoryl group; S1P, sphingosine-1-phosphate.