Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer‐initiating cells

Pancreatic adenocarcinoma (PaCa) being the deadliest cancer is partly due to early metastatic spread. Thus, we searched for PaCa‐initiating cell (PaCIC) markers with emphasis on markers contributing to metastatic progression. PaCIC were enriched from long‐term and freshly established lines by repeat...

Full description

Saved in:
Bibliographic Details
Published in:International journal of cancer 2013-07, Vol.133 (2), p.416-426
Main Authors: Wang, Haobin, Rana, Sanyukta, Giese, Nathalia, Büchler, Markus W., Zöller, Margot
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - metabolism
Animal tumors. Experimental tumors
Animals
Biological and medical sciences
Biomarkers
Biomarkers, Tumor - blood
Cancer
cancer‐initiating cells
CD44 variant isoforms
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cells
Exosomes - metabolism
Experimental tumors, general aspects
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic
holoclones
Humans
Hyaluronan Receptors - blood
Integrin alpha6beta4 - blood
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical diagnosis
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Neoplasm Transplantation
Pancreatic cancer
Pancreatic Neoplasms - metabolism
spheroid growth
tetraspanins
Tetraspanins - blood
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Pancreatic adenocarcinoma (PaCa) being the deadliest cancer is partly due to early metastatic spread. Thus, we searched for PaCa‐initiating cell (PaCIC) markers with emphasis on markers contributing to metastatic progression. PaCIC were enriched from long‐term and freshly established lines by repeated selection for spheroid or holoclone growth in advance of evaluating PaCIC markers. Sphere and holoclone formation steeply increased by recloning and remained stable thereafter. Cells not forming spheres or holoclones died on recloning. PaCIC enrichment in spheres and holoclones was accompanied by increased motility, anchorage independence and upregulated CXCR4 expression. After subcutaneous injection in NOD/SCID mice tumorigenicity and, impressively, recovery of metastasizing tumor cells in peripheral blood, spleen, bone marrow, lung and pancreas was strongly increased in spheres and holoclones. PaCIC enrichment in spheres and holoclones was accompanied, besides CXCR4, by upregulated CD44v6, alpha6beta4, weakly CD133 and tetraspanin Tspan8 expression. Notably, CD44v6, alpha6beta4, CXCR4 and Tspan8 expressing PaCa cells had a growth advantage in vivo and became dominating in migrating and in distant organs settled tumor cells. This is the first report showing that CD44v6, alpha6beta4, Tspan8 and CXCR4 are biomarkers in PaCIC allowing for long‐term survival, expansion and migration in immunocompromised mice. The stability of the percentage of PaCIC in long‐term and freshly established lines after a roughly 8‐fold enrichment by cloning indicates PaCIC, though required for long‐term survival, concomitantly depending on support by non‐CIC. What's new? An effective method for the early diagnosis of pancreatic cancer, a rapidly progressing disease, is urgently needed. While one possible approach entails the development of an exosome‐based serum test, suitable markers have yet to be identified and characterized. Here, four pancreatic cancer initiating cell (PaCIC) markers, CD44v6, alpha6beta4, CXCR4, and Tspan8, were found to be up‐regulated in locally growing tumors in NOD/SCID mice and in metastasizing tumor cells cultured ex vivo. The markers' strong expression on PaCIC and their recovery in exosomes suggests that they may be useful for pancreatic cancer diagnosis.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.28044