Pancreatic cancer stem cells: New insight into a stubborn disease

Highlights

• We summarized recent studies focused on pancreatic cancer stem cells (PCSCs).

• PCSCs are responsible for invasion, metastasis and drug resistance.

• Signal pathways, miRNAs, EMT and microenvironment are involved in regulation of PCSCs.

• PCSCs may provide potential therapeutic targets for pancreatic cancer.

Abstract

Resistance to conventional therapy and early distant metastasis contribute to the unsatisfactory prognosis of patients with pancreatic cancer. The concept of cancer stem cells (CSCs) brings new insights into cancer biology and therapy. Many studies have confirmed the important role of these stem cells in carcinogenesis and the development of hematopoietic and solid cancers. Recent studies have shown that CSCs regulate aggressive behavior, recurrence, and drug resistance in pancreatic cancer. Here, we review recent advances in pancreatic cancer stem cells (PCSCs) research. Particular attention is paid to the regulation mechanisms of pancreatic cancer stem cell functions, such as stemness-related signaling pathways, microRNAs, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment, and the development of novel PCSCs targeted therapy. We seek to further understand PCSCs and explore potential therapeutic targets for pancreatic cancer.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and has low overall survival [1], [2]. Resection is the only radical treatment for this aggressive malignancy. Unfortunately, only 15–20% of patients can be resected, due to the low rate of early diagnosis. Resistance to chemotherapy and radiation therapy also contributes to the dismal prognosis [3], [4], [5]. Only 9.4% of patients with metastatic pancreatic cancers acquired partial response, and 34.5% experienced disease progression during chemotherapy with gemcitabine [3].

During the past decades, the carcinogenesis and pathogenesis of pancreatic cancer (PC) have been thoroughly described. However, the overall survival of patients with pancreatic cancer has not significantly improved. An in-depth investigation of the mechanisms of carcinogenesis, progression, and drug resistance that is based on the theory of cancer stem cells (CSCs) might help to improve pancreatic cancer prognosis.

CSCs have been confirmed in hematopoietic and solid tumors, which have the capacity of self-renewal and can differentiate into other cell types of cancer cells [6]. These types of cells promote tumor growth, invasion, metastasis, and therapeutic resistance [7], [8], [9]. Pancreatic cancer stem cells (PCSCs) were first identified by Li et al. in 2007 [10]. Later studies revealed that PCSCs could self-renew, differentiate, and divide asymmetrically, like normal stem cells; the critical role of PCSCs in regulating pancreatic cancer progression, metastasis, and drug resistance has since been confirmed [11], [12]. However, some critical questions still remain to be answered, including the identification of specific PCSCs, the signaling pathways involved in regulating PCSCs, and the regulatory roles of PCSCs in pancreatic cancer. In this article, we reviewed the recent advances regarding the regulating roles and mechanisms of CSCs in pancreatic cancer, paying particular attention to the metastasis, drug resistance, and prognostic functions of these cells.