ABSTRACT
Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value < 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo. Interestingly, PD2 overexpression also resulted in enrichment of cancer stem cells (CSCs) and upregulation of oncogenes such as c-Myc and cell cycle progression marker, cyclin D1. Taken together, our results support that PD2 is overexpressed in the ducts of PDAC tissues, and results in tumorigenesis and metastasis via upregulation of oncogenes such as c-Myc and cyclin hence D1 implicating PD2 upregulation in pancreatic oncogenesis with targeted therapeutic potential.
Subject(s)
Adenocarcinoma/secondary , Carcinoma, Pancreatic Ductal/secondary , Cell Transformation, Neoplastic/pathology , Nuclear Proteins/metabolism , Pancreatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Animals , Apoptosis , Blotting, Western , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Cell Cycle , Cell Differentiation , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cells, Cultured , Female , Gene Expression Regulation, Neoplastic , Humans , Immunoenzyme Techniques , Mice , Mice, Nude , NIH 3T3 Cells , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Nuclear Proteins/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors , Xenograft Model Antitumor Assays , Pancreatic NeoplasmsABSTRACT
Several evidences suggest that a small population of cells known as cancer stem cells (CSCs) or tumor initiating stemlike cells within a tumor is capable of tumor initiation, maintenance and propagation. Recent publications have supported the existence of CSCs in pancreatic tumors. The pancreatic stem/progenitor cells, which express self-renewal markers, are identified to be present in the peribiliary gland. Based on the CSC hypothesis, mutations can lead to the transformation of stem/progenitor cells or differentiated cells into CSCs. The pancreatic CSCs express a wide array of markers such as CD44, CD24, ESA, CD133, c-MET, CXCR4, PD2/Paf1 and ALDH1. The CSCs are isolated based on surface markers or by other methods such as ALDEFLOUR assay or Hoechst 33342 dye exclusion assay. The isolated cells are further characterized by in vitro and in vivo tumorigenic assays. The most important characteristics of CSCs are its ability to self-renew and impart drug resistance towards chemotherapy. Moreover, these distinct cells display alteration of signaling pathways pertaining to CSCs such as Notch, Wnt and Shh to maintain the self-renewal process. Failure of cancer treatment could be attributed to the therapy resistance exhibited by the CSCs. Metastasis and drug resistance in pancreatic cancer is associated with epithelial to mesenchymal transition (EMT). Furthermore, mucins, the high molecular weight proteins are found to be associated with pancreatic CSCs and EMT. Understanding the underlying molecular pathways that aid in the metastatic and drug resistant nature of these distinct cells will aid in targeting these cells. Overall, this review focuses on the various aspects of pancreatic adult/stem progenitors, CSC hypothesis, its markers, pathways, niche, EMT and novel therapeutic drugs used for the elimination of pancreatic CSCs.
ABSTRACT
Recent paradigm in the field of cancer defines its origin from a small population of fast growing cells known as cancer stem cells (CSCs), and they are mainly responsible for disease aggressiveness, drug resistance and tumor relapse. The existence of CSCs has been proven in different types of cancer and possesses characteristic expression of a wide array of cell surface markers specific to the type of cancer. CSCs have been isolated and enriched using several surface markers in different cancer types. Self-renewal, drug resistance and the ability to transition from epithelial to mesenchymal phenotype are the major features attributed to this fraction of mutated stem cells. The CSC hypothesis proposes that these CSCs mimic stem cells by sharing similar pathways, such as Wnt, SHH, Notch and others. Further, the niche, which in this case is the tumor microenvironment, plays a very important role in the maintenance of CSCs. Altogether, this emerging field of research on CSCs is expected to unveil answers to the most difficult issues of one of the most dreadful diseases called cancer.
