An intensified systemic trafficking of bone marrow‐derived stem/progenitor cells in patients with pancreatic cancer

Abstract

Various experimental studies indicate potential involvement of bone marrow (BM)-derived stem cells (SCs) in malignancy development and progression. In this study, we comprehensively analysed systemic trafficking of various populations of BM-derived SCs (BMSCs), i.e., mesenchymal, haematopoietic, endothelial stem/progenitor cells (MSCs, HSCs, EPCs respectively), and of recently discovered population of very small embryonic/epiblast-like SCs (VSELs) in pancreatic cancer patients. Circulating CD133+/Lin−/CD45−/CD34+ cells enriched for HSCs, CD105+/STRO-1+/CD45− cells enriched for MSCs, CD34+/KDR+/CD31+/CD45− cells enriched for EPCs and small CXCR4+CD34+CD133+ subsets of Lin−CD45− cells that correspond to VSELs were enumerated and sorted from blood samples derived from 29 patients with pancreatic cancer, and 19 healthy controls. In addition, plasma levels of stromal-derived factor-1 (SDF-1), growth/inhibitory factors and sphingosine-1-phosphate (S1P; chemoattractants for SCs), as well as, of complement cascade (CC) molecules (C3a, C5a and C5b-9/membrane attack complex – MAC) were measured. Higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (P < 0.05 and 0.01 respectively). This trafficking of BMSCs was associated with significantly elevated C5a (P < 0.05) and C5b-9/MAC (P < 0.005) levels together with S1P concentrations detected in plasma of cancer patients, and seemed to be executed in a SDF-1 independent manner. In conclusion, we demonstrated that in patients with pancreatic cancer, intensified peripheral trafficking of selected populations of BMSCs occurs. This phenomenon seems to correlate with systemic activation of the CC, hepatocyte growth factor and S1P levels. In contrast to previous studies, we demonstrate herein that systemic SDF-1 levels do not seem to be linked with increased mobilization of stem cells in patients with pancreatic cancer.

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

“…Among the usually examined BMSC populations, researchers share a common view that the population of BM-derived MSCs seems to be especially involved into the development and progression of (pancreatic) cancer, whereas the contributions of EPCs and HSPCs remain less evident and are rather indirect (supplemental online Table 1) [68][69][70][71][72][73][74][75][76]. These experimental observations are in agreement with our previous clinical studies of patients with gastric neoplasms and pancreatic cancer, indicating a very selective mobilization of BMSCs, mainly of VSELs and MSCs, in patients with these types of cancers [21,24].…”

“…Interestingly, in our recent studies, we observed an intensified systemic trafficking of BMSCs in patients with gastric and pancreatic cancer. This process did not seem to be associated with the clinical stage of the disease and occurred in patients presenting with both early and advanced disease [21,24].…”

“…This is associated with higher activity of proteolytic enzymes such as metalloproteinases, which are present both at the systemic and local levels [29,30] and may result in the inactivation of BMSC chemoattractants. Thus, researchers focused their efforts on other substances-mainly immune-related molecules, bioactive lipids, and growth factors-because these are involved in the formation of an immune-modulated microenvironment in pancreatic cancer, contribute to the development and/or progression of pancreatic malignancies, and, therefore, might potentially affect BMSC homeostasis and function [24,28,31]. Based on these studies, several substances that seemed to participate in a biochemical crosstalk between the BM and the developing pancreatic cancer have been identified.…”

“…Based on these studies, several substances that seemed to participate in a biochemical crosstalk between the BM and the developing pancreatic cancer have been identified. These involved anaphylatoxins of the complement cascade and/or biomolecules, such as C5a and C5b-9/membrane attack complex (MAC), sphingosine-and ceramide-derivatives, HGF, and cytokines (mainly interleukin [IL]-6 and IL-8) [24,28]. The exact function of these substances on the regulation of BMSC homeostasis has not been fully examined.…”

Human and Murine Very Small Embryonic-Like Cells Represent Multipotent Tissue Progenitors, In Vitro and In Vivo

“…Given that several independent groups can isolate VSEL cells and have confirmed the in vitro differentiation data [18,[31][32][33], we believe that the reasons for the differences in experimental results are of a technical nature. These differences that are outlined in great detail in a recent publication are most likely due to inadequate isolation procedures [34][35][36]. Nevertheless, some of the critiques of the VSEL cell field are valid; more systematic studies are needed.…”