Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2016; 22(26): 5971-6007
Published online Jul 14, 2016. doi: 10.3748/wjg.v22.i26.5971
Pancreatic cancer stem cell markers and exosomes - the incentive push
Sarah Heiler, Zhe Wang, Margot Zöller
Sarah Heiler, Zhe Wang, Margot Zöller, Tumor Cell Biology, University Hospital of Surgery, D 69120 Heidelberg, Germany
Author contributions: Zöller M wrote the first draft and the final version; Heiler S and Wang Z contributed to writing and final version approving.
Supported by Wilhelm Sander Stiftung to Zöller M, No. 2009.100.2; German Cancer Research Aid to Zöller M, No. 110836; and China Scholarship Council to Wang Z, CSC 201408080067.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dr. Margot Zöller, Tumor Cell Biology, University Hospital of Surgery, Im Neuenheimer Feld 365, D 69120 Heidelberg, Germany.
Telephone: +49-6210-565146 Fax: +49-6210-565199
Received: March 19, 2016
Peer-review started: March 22, 2016
First decision: May 30, 2016
Revised: June 3, 2016
Accepted: June 28, 2016
Article in press: June 28, 2016
Published online: July 14, 2016

Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.

Keywords: Pancreatic cancer, Cancer stem cells, Stem cell markers, Exosomes, Crosstalk

Core tip: Cancer progression relies on a small population of cancer stem cells (CSC), characterized by longevity, self renewal, drug resistance and requirement of a niche. In addition, CSC abundantly deliver exosomes (TEX) allowing CSC a long distance communication. At the descriptive level, CSC are characterized by a set of so called CSC markers. We here discuss for pancreatic cancer that the CSC markers CD44v6, c-Met, Tspan8, alpha6beta4, EpCAM, claudin7, CXCR4 and prominin1 can in a concerted activity account for all CSC features. This includes CSC TEX activity due to the engagement of CSC markers in TEX biogenesis and enrichment in TEX.