Aldehyde Dehydrogenase (ALDH) Activity Segregates Murine Pancreatic Cancer Stem Cells into Distinct Phenotypic Subtypes Which Dictate Histopathologic Tumor Grade.
Daniel A Winer, Scott E Seeley, William W Tseng, Jacob M Zahn, Michael N Alonso, Shawn Winer, Hweixian Leong, Mana Kvezereli, Hanlee Ji, Andrew M Lowy, Edgar G Engleman. Stanford University, Palo Alto, CA; University Health Network, Toronto, ON, Canada; Moores Cancer Center, University of California at San Diego
Background: Recent evidence suggests that the growth of tumors is driven by distinct cells with the ability to self renew and differentiate, called cancer stem cells (CSCs). Phenotypic diversity within the cancer stem cell (CSC) pool may account for the emergence of distinct patterns of tumor progression and drug resistance. However, because robust models for studying such diversity are lacking, fundamental aspects of CSC biology remain unknown.
Design: Cancer stem cells were isolated directly from pancreatic tumors and from three cell lines (primary tumor and liver metastases) derived from the commonly studied LSL-KrasG12D/+; LSL-p53R172H/+; Pdx-1-Cre mouse model of pancreatic cancer. These cells were analyzed using a comprehensive stem cell surface marker and genomic mRNA expression profiling approach and then partitioned according to ALDH functional activity using the Aldefluor assay. The resulting subsets of cells were studied in vitro and in vivo in the presence of an intact immune system for tumorigenic and stem cell properties.
Results: Epithelial cancer cells isolated from the LSL-KrasG12D/+; LSL-p53R172H/+; Pdx-1-Cre mouse model of pancreatic cancer are highly enriched in CSCs. When these cells are partitioned according to ALDH activity levels, they yield poorly tumorigenic ALDH negative (ALDHneg) cells and highly tumorigenic ALDH positive (ALDHpos) cells. ALDHpos cells are further partitioned into ALDHdim CSCs, which give rise to high grade poorly-differentiated carcinomas that metastasize rapidly, and ALDHbright CSCs, which give rise to low grade well-differentiated glandular carcinomas with reduced metastatic potential. Relative to their ALDHbright counterparts, ALDHdim CSCs exhibit morphological features and transcriptional alterations consistent with epithelial to mesenchymal transition (EMT).
Conclusions: These findings demonstrate the existence of multiple, pathology-defining pancreatic CSC subpopulations in a common mouse model, and provide highly tractable systems for their further characterization.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 241, Monday Morning