Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine‐resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC‐1 cells. Gemcitabine‐resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere‐forming activity than parental cells. After high‐dose gemcitabine treatment to eliminate most of the cells, CD44⁺ cells proliferated and reconstituted the population of resistant cells. CD44⁺CD24⁺ESA⁺ cells remained as a small subset in the resistant cell population. Among ATP‐binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose‐dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44‐positive tumors showed poor prognosis. These data indicate that cancer stem‐like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. © 2009 UICC

Goals The aims of this study were to determine the clinical use of 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) in the differential diagnosis of patients with suspected pancreatic cancer and in the determination of tumor response after concurrent chemoradiotherapy for pancreatic cancer. Background Despite advances in diagnostic tools for pancreatic cancer, it is difficult to differentiate pancreatic cancer from mass-forming pancreatitis. Even with current imaging modalities, it is also difficult to assess tumor response to therapeutic intervention. Study One hundred two patients with suspected pancreatic cancer were selected for this study. Dynamic computerized tomography (CT) scan and ¹⁸FDG-PET were used sequentially to diagnose pancreatic cancer. After diagnostic confirmation their diagnostic yields were compared. We also evaluated the treatment response in 15 patients who underwent chemoradiation therapy with dynamic CT scan and ¹⁸FDG-PET and compared their results. Results In 93 out of 102 patients, pancreatic cancer was confirmed. ¹⁸FDG-PET showed higher diagnostic accuracy than CT scan (95.1% vs. 76.5%). ¹⁸FDG-PET was also superior to CT in the detection of liver metastasis. ¹⁸FDG-PET detected treatment response in 5 out of 15 cases after chemoradiation therapy, whereas CT could not detect any treatment response. Comparing responder and nonresponder, ¹⁸FDG-PET was able to predict significantly different prognosis (399 vs. 233 d, P<0.05). Conclusions ¹⁸FDG-PET is a very useful tool in diagnosing pancreatic cancer. ¹⁸FDG-PET may be also used as an adjunct for determining the treatment modality of pancreatic cancer and evaluating tumor response to chemoradiation therapy.

Background & Aims: Although the cell of origin for pancreatic cancer remains unknown, prior studies have suggested that pancreatic neoplasia may be initiated in progenitor-like cells. To examine the effects of oncogene activation within the pancreatic progenitor pool, we devised a system for real-time visualization of both normal and oncogenic KRAS-expressing pancreatic progenitor cells in living zebrafish embryos. Methods: By using BAC transgenes under the regulation of ptf1a regulatory elements, we expressed either extended green fluorescent protein (eGFP) alone or eGFP fused to oncogenic KRAS in developing zebrafish pancreas. Results: After their initial specification, normal eGFP-labeled pancreatic progenitor cells were observed to actively migrate away from the forming endodermal gut tube, and subsequently underwent characteristic exocrine differentiation. In contrast, pancreatic progenitor cells expressing oncogenic KRAS underwent normal specification and migration, but failed to differentiate. This block in differentiation resulted in the abnormal persistence of an undifferentiated progenitor pool, and was associated with the subsequent formation of invasive pancreatic cancer. These tumors showed several features in common with the human disease, including evidence of abnormal Hedgehog pathway activation. Conclusions: These results provide a unique view of the tumor-initiating effects of oncogenic KRAS in a living vertebrate organism, and suggest that zebrafish models of pancreatic cancer may prove useful in advancing our understanding of the human disease.