Abstract
Metastatic disease is the leading cause of pancreatic ductal adenocarcinoma (PDAC) associated death. PDAC cells invade and enter the bloodstream early, before frank malignancy can be detected. Our objective was to develop an in vivo assay enabling the identification and quantification of circulating tumor cells (CTCs) from primary orthotopic PDAC tumors. Human PDAC cells expressing luciferase and green fluorescent protein were orthotopically injected into the pancreas of mice utilizing ultrasound guidance. Bioluminescent imaging was conducted to identify and track tumor growth. CTCs were then isolated and analyzed by flow cytometry to detect GFP-expressing cancer cells. Tumor growth as measured by bioluminescent imaging increased over time. The concentration of CTCs correlated with the strength of bioluminescent imaging signal. In addition, livers bearing macroscopic disease were harvested for further imaging under fluorescence stereomicroscopy and confocal microscopy, which confirmed the presence of metastases. This study represents an orthotopic animal model that reliably detects the presence of CTCs from PDAC. There is a positive correlation between the concentrations of CTCs with overall tumor burden.
Highlights
Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer related deaths in the United States in spite of accounting for only 3.2% of new cancer cases [1]
Even localized disease commonly recurs in distant sites following surgical resection and adjuvant chemotherapy [25], perhaps indicating both the high frequency of undetectable metastatic disease in these patients and the high level of resistance this disease has to current systemic chemotherapies
Circulating tumor cells are widely thought to be the link between primary tumor and metastatic disease [26]
Summary
Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer related deaths in the United States in spite of accounting for only 3.2% of new cancer cases [1]. Of individuals who do have disease recurrence, nearly 80% have metastases [3] The reason for this phenomenon can be attributed to the early metastatic progression of the disease, which can occur before primary tumor is detectable [5]. Some have even proposed the possibility of metastases developing prior to pathologically observable basement membrane invasion and in parallel with primary tumor development [5]. Suffice it to say, PDAC may be a systemic disease and treatment strategies must evolve to better target the systemic disease features
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