Topology impacts TRAIL therapy: Differences in primary cancer growth and liver metastasis between orthotopic and subcutaneous xenotransplants of pancreatic ductal adenocarcinoma cells

作     者：Bastian Kettler Anna Trauzold Christian Röder Jan-Hendrik Egberts Holger Kalthoff Bastian Kettler;Anna Trauzold;Christian R?der;Jan-Hendrik Egberts;Holger Kalthoff

作者机构：Clinic for General-Abdominal-and Transplant-SurgeryMedical School HannoverCarl-Neuberg-Str.130625 HannoverGermany Institute for Experimental Cancer ResearchUniversity of Kiel and University Clinic of Schleswig-HolsteinCampus KielHs.U30Arnold-Heller-Str.324105 KielGermany Clinic for GeneralVisceralThoracicTransplantation-and Pediatric SurgeryUniversity Clinic of Schleswig-HolsteinCampus KielHs.CArnold-Heller-Str.324105 KielGermany 

出 版 物：《Hepatobiliary & Pancreatic Diseases International》 (国际肝胆胰疾病杂志（英文版）)

年 卷 期：2021年第20卷第3期

页      面：279-284页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by an intramural grant from UKSH Kiel to H. Kalthoff 

主　　题：Pancreatic cancer Animal models Immunohistochemistry Subcutaneous metastasis 

摘      要：Background: To study novel treatment modalities for pancreatic ductal adenocarcinoma(PDAC), we need to transfer the knowledge from in vitro to in vivo. It is important to mirror the clinical characteristics of the typically local invasive growth of pancreatic cancer and the distant spread resulting in liver metastasis. Notably, for xenotransplant studies using human specimen, two models, i.e. subcutaneous(s.c.) and orthotopic(o.t.) transplantation are widely used. Methods: The subcutaneously and orthotopically inoculated Colo357 Bcl-x L cell-derived tumors were directly compared with and without TNF-related apoptosis inducing ligand(TRAIL) treatment. The size of primary tumors, number of liver metastasis and the histologic markers Ki67, M30, TNF-α and CD31 were assessed. Results: Upon TRAIL treatment, the primary tumors did not change their size, neither in the s.c. nor in the o.t. approaches. But when s.c. was compared to o.t., the size of the s.c. tumors was more than twofold bigger than that of the o.t. tumors( P0.01). However, mice with orthotopically inoculated PDAC cells developed liver metastasis upon TRAIL treatment much more frequently( n=13/17) than mice with subcutaneously inoculated PDAC cells( n=1/11)( P0.01). As a likely driving force for this increased metastasis, a higher TNF-α staining intensity in the o.t. tumors was observed by immunohistochemistry. Conclusions: These data from a direct side-by-side comparison underline the importance of the proper inoculation site of the PDAC cells. Local invasion and liver metastases are a hallmark of PDAC in the clinic;the o.t. model is clearly superior in reflecting this setting. Moreover, a serious side-effect of a possible new therapeutic compound became obvious only in the o.t. model.