Identification of Cancer Stem Cells in human pancreatic cancer, a small population with high tumorigenic activity and chemotherapy resistance

Masahide Kashiwagi,Hideyuki Tanaka

doi:10.4172/2157-7633.1000371

Abstract

Small populations of pancreatic cancer cells from Patient Derived Xenografts (PDXs) were demonstrated to be highly tumorigenic and chemotherapy resistant. The cancer cells isolated from the xenograft tumor tissue were sorted by the previously reported Cancer Stem Cell (CSC) markers and tested their tumorigenic activity in the limiting dilution assay by inoculating into the immuno-deficient NOD/scid mice subcutaneously. The varied correlation between the CSC marker expression and the tumorigenic activity in the NOD/scid mice among the different PDXs indicates that the CSC markers of the individual pancreatic tumor patients could be different each other. Only a part of PDX tumor samples among the six examined could show a tight correlation between the tumor initiating activity and the selectively higher expression of cell surface markers CD24, CD44 and CD133. We also demonstrated that CD133/CD44 double positive population from the one PDX shows superior tumorigenic activity and gemcitabine treatment resistance. To illuminate the characteristically expressed genes which allow them to have tumorigenic activity and chemotherapy resistance, the CD133/CD44 double positive CSC faction was subjected to the gene expression analysis. Prominently higher expression of epiregulin (11.1-fold increase compared to the double negative population), interleukin-8 and CXCL5 (8.5- and 8.0-fold increases, respectively) were observed in the CSC fraction. These gene signatures of CSC suggest several key molecular mechanisms playing important roles in CSC biology and having possibilities as drug targets for CSC therapy.

Highlights

According to Li et al [10], the pancreatic Cancer Stem Cells were identified in the clinical tumor tissue as the CD44, CD24 and EpCAM triple positive fraction, which was 0.2-0.8% of total cancer cells
Current radio- and chemotherapies are efficacious to the bulk of cancer cells, but are scarcely able to eliminate the particular population of the cancer cells so called Cancer Stem Cells (CSCs) in the tumor tissue, which are protected from anti-cancer therapies by resistant mechanisms [1]
The pancreatic tumor initiating cell fractions were isolated from patient derived xenografts (PDXs) using fluorescent activated cell sorter (FACS) depending on the cell surface markers

Summary

Introduction

According to Li et al [10], the pancreatic Cancer Stem Cells were identified in the clinical tumor tissue as the CD44, CD24 and EpCAM triple positive fraction, which was 0.2-0.8% of total cancer cells. Taking the above information into account, we tried to isolate the pancreatic Cancer Stem Cells from patient derived tumor xenografts. Current radio- and chemotherapies are efficacious to the bulk of cancer cells, but are scarcely able to eliminate the particular population of the cancer cells so called Cancer Stem Cells (CSCs) in the tumor tissue, which are protected from anti-cancer therapies by resistant mechanisms [1]. The recurrent tumors sometimes become more malignant compared to the primary tumor and turn to be resistant to radio- and chemotherapies applied as the primary treatment, which makes the prognosis for tumor patients poorer. The existence of CSCs could provide an explanation for many therapeutic failures and highlight new directions for more effective cancer therapy

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