CD44-Positive Cancer Stem Cells Expressing Cellular Prion Protein Contribute to Metastatic Capacity in Colorectal Cancer

Lei Du,Weili Tian,Chunyi Hao,Xin Sun,Guanhua Rao,Dean G Tang,Maryam Mehrpour,Baowei Li,Youyong Lu,Quan Chen,Leya He,Hongmin Liu,Xiuyun Tian,Brian Laffin,Hongyi Wang,Jiantao Cui,Yushan Zhu

doi:10.1158/0008-5472.can-12-3759

Abstract

Cancer stem cells are implicated in tumor progression, metastasis, and recurrence, although the exact mechanisms remain poorly understood. Here, we show that the expression of cellular prion protein (PrPc, PRNP) is positively correlated with an increased risk of metastasis in colorectal cancer. PrPc defines a subpopulation of CD44-positive cancer stem cells that contributes to metastatic capacity. PrPc(+)CD44(+) colorectal cancer stem cells displayed high liver metastatic capability, unlike PrPc(-)CD44(+) stem cells, that was inhibited by RNAi-mediated attenuation of PrPc. Notably, administration of PrPc monoclonal antibodies significantly inhibited tumorigenicity and metastasis of colorectal cancer stem cells in mouse models of orthotopic metastasis. PrPc promoted epithelial to mesenchymal transition (EMT) via the ERK2 (MAPK1) pathway, thereby conferring high metastatic capacity. Our findings reveal the function of PrPc in regulating EMT in cancer stem cells, and they identify PrPc as candidate therapeutic target in metastatic colorectal cancer.

Highlights

Cancer is a major cause of mortality, and most human cancer-related deaths are related to metastasis [1, 2]
On the basis of our previous observations that CD44 is a robust marker for CCSCs [14], we hypothesized that additional factors may exist that are coexpressed with CD44 in the promotion of migration and metastasis of cancer stem cells (CSC)
This observation was supported by examining multiple Oncomine cDNA microarray datasets, which revealed that the PRNP mRNA expression levels were significantly elevated in high-grade and advanced-stage colorectal cancer (CRC) (Supplementary Fig. S1B)

Summary

Introduction

Cancer is a major cause of mortality, and most human cancer-related deaths are related to metastasis [1, 2]. The difficulty in diagnosing and therapeutically eliminating metastasis is related to our limited understanding of the molecules expressed on the surface of metastatic cancer cells. Accumulating evidence suggests that a subset of cancer cells, operationally termed cancer stem cells (CSC) or tumor-initiating cells, possesses enhanced ability to regenerate tumors and survive anticancer therapies [3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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