An Immunohistochemical Evaluation of Tumor-Associated Glycans and Mucins as Targets for Molecular Imaging of Pancreatic Ductal Adenocarcinoma.

Ruben D Houvast,Bert A Bonsing,Jesse V Groen,Lindy G Durrant,Alexander L Vahrmeijer,Cornelis F M Sier,Jiaxin Chua,Kira Thijse,A Stijn L P Crobach,J Sven D Mieog,Mireille Vankemmelbeke,Peter J K Kuppen

doi:10.3390/cancers13225777

Abstract

Simple SummaryDistinguishing pancreatic cancer from healthy tissue before and during surgery can be enhanced by using molecular tracers directed at molecules on tumor cells allowing high-contrast visualization of tumor tissue, eventually improving diagnosis and surgical removal. Albeit sugar molecules and proteins carrying a large amount of sugars-mucins- have gained significant interest as tumor-specific targets, their relative presence on structures surrounding tumor tissues and lymph node metastases is unknown. The current study shows that the presence of several, but not all, investigated sugar molecules and mucins on pancreatic cancer cells is higher compared to surrounding tissues. Moreover, given their abundance on tumor cells in lymph nodes and their absence on normal lymph nodes, all investigated targets are high-potential targets for visualization of lymph node metastases. This study paves the way for the development of molecular tracers against the targets evaluated herein to allow improvement of pancreatic cancer treatment. Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Lea/c/x, sdi-Lea, sLea, sLex, sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained significant interest as targets for PDAC imaging. To evaluate their PDAC molecular imaging potential, biomarker expression was determined using immunohistochemistry on PDAC, (surrounding) chronic pancreatitis (CP), healthy pancreatic, duodenum, positive (LN+) and negative lymph node (LN−) tissues, and quantified using a semi-automated digital image analysis workflow. Positive expression on PDAC tissues was found on 83% for Lea/c/x, 94% for sdi-Lea, 98% for sLea, 90% for sLex, 88% for sTn, 96% for MUC1 and 67% for MUC5AC, where all were not affected by the application of neoadjuvant therapy. Compared to PDAC, all biomarkers were significantly lower expressed on CP, healthy pancreatic and duodenal tissues, except for sTn and MUC1, which showed a strong expression on duodenum (sTn tumor:duodenum ratio: 0.6, p < 0.0001) and healthy pancreatic tissues (MUC1 tumor:pancreas ratio: 1.0, p > 0.9999), respectively. All biomarkers are suitable targets for correct identification of LN+, as well as the distinction of LN+ from LN− tissues. To conclude, this study paves the way for the development and evaluation of Lea/c/x-, sdi-Lea-, sLea-, sLex- and MUC5AC-specific tracers for molecular imaging of PDAC imaging and their subsequent introduction into the clinic.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancerrelated mortality in the Western world, with a dismal 5-year survival of only 9% [1]
Tissues from 53 patients primarily diagnosed with PDAC and 9 patients diagnosed with chronic pancreatitis (CP) were obtained
Tissue blocks containing 48 PDAC, 28 CP, 31 healthy pancreatic, 10 healthy duodenal, 27 LN+ and 41 LN− tissues derived of 62 patients (53 PDAC and 9 CP patients) were included in the study

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancerrelated mortality in the Western world, with a dismal 5-year survival of only 9% [1]. As 80–90% of patients present with locally advanced or metastatic disease, radical surgical resection, which is the only curative therapy, is often not feasible. Considering the abundance of desmoplasia in both PDAC and CP, which may be further induced by the application of neoadjuvant therapy (NAT), distinguishing malignant from healthy or benign tissue is challenging in both a preoperative and real-time intraoperative setting [8,9,10]. By facilitating high-contrast visualization of tumor cells, targeted molecular imaging may play a key role in overcoming these challenges, potentially avoiding resection for benign and irresectable disease, while simultaneously aiming to increase radical resection rates in resectable patients

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