Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery
Mol Imaging Biol
Selecting Tumor-Specif ic Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery
Susanna
W. L. de Geus 1
Leonora S. F. Boogerd 1
Rutger-Jan Swijnenburg 1
J. Sven D. Mieog 1
Willemieke S. F. J. Tummers 1
Hendrica A. J. M. Prevoo 1
Cornelis F. M. Sier 1
Hans Morreau 0
Bert A. Bonsing 1
Cornelis J. H. van de Velde 1
Alexander L. Vahrmeijer 1
Peter J. K. Kuppen 1
0 Department of Pathology, Leiden University Medical Center , Leiden , The Netherlands
1 Department of Surgery, Leiden University Medical Center , Albinusdreef 2, 2300 RC, Leiden , The Netherlands
Purpose: The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. Procedures: The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Results: Integrin αvβ6, carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p G 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. Conclusions: The results of this study show that integrin αvβ6, CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.
Pancreatic adenocarcinoma; Periampullary adenocarcinoma; Molecular imaging; Image-guided surgery; Immunohistochemistry; Integrin αvβ6; Carcinoembryonic antigen (CEA); Epithelial growth factor receptor (EGFR); Urokinase plasminogen activator receptor (uPAR)
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Pancreatic adenocarcinoma currently ranks the fourth
leading cause of cancer-related death in the Western
world, with a 5-year survival rate of less than 5 % [1].
Radical surgical tumor resection is imperative to curative
treatment of these patients as positive resection margins
(defined as tumor cells present at the surface of the
resection margins of the surgical specimen) are
associated with a dramatic decrease in median overall survival
[1–4]. Unfortunately, positive resection margins are
common after pancreatic surgery and reported rates vary
between 24 % and 76 % [5–7]. Adjuvant therapy cannot
retaliate the poor survival outcome associated with
residual disease [8]. The disappointing irradical resection
rates after pancreatic surgery are due to our current
inability to detect the true delineation of the tumor extent
during surgery, which is further complicated by the
intricate anatomy of the pancreas and the commonly
present peritumoral inflammatory zone in pancreatic
cancer. Conventional anatomic imaging modalities used
for preoperative diagnosis, staging, and surgical planning
include multiphase intravenous contrast-directed thin slice
computed tomography, magnetic resonance imaging,
endoscopic ultrasonography, and endoscopic retrograde
cholangiopancreatography [9, 10]. However, the
translation of these preoperative imaging techniques to the
surgical field remains challenging and in the theater, the
surgical oncologist solely has to rely on vision and
manual palpation to discriminate between malignant and
healthy pancreatic tissue, assisted by ultrasonography and
pathologic evaluation of frozen tissue sections [10].
Intraoperative tumor-specific imaging offers the
opportunity to significantly improve current practice by
increasing the capability to obtain negative resection
margins and visualize residual disease during pancreatic
surgery. This novel imaging approach uses labeled
receptor ligands, nanoparticles, antibodies, or antibody
fragments targeting cancer-specific antigens on the tumor
surface detected by positron emission tomography,
single-photon emission computed tomography,
ultrasonography, magnetic resonance, and/or near-infrared
fluorescence imaging modalities [11–13]. The feasibility of
these imaging techniques has already successfully been
proven in glioma and ovarian cancer surgery using
respectively the fluorescent agents 5-aminolevulinic acid
and folate conjugated to fluorescein isothiocyanate [11,
14]. Furthermore, the potential of image-guided surgery
in pancreatic adenocarcinoma has been demonstrated by
numerous preclinical studies using cancer-specific
contrast agents targeting integrin αvβ6, carcinoembryonic
antigen (CEA), epithelial growth factor receptor
(EGFR), human epidermal growth factor receptor
(HER2), urokinase plasminogen activator receptor
(uPAR), or vascular endothelial growth factor receptor
2 (VEGFR2) among others (Table 1). Nevertheless, the
orthotopic mouse models used in these studies are based
on a small number of pancreatic adenocarcinoma cell
lines originating from single patients and (...truncated)