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Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells

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World Journal of Gastroenterology 2016年第9期22卷 2678-2700页

作者： michael Friberg Bruun Nielsen michael bau mortensen Sonke Detlefsen Department of Pathology Odense University Hospital University of Southern Denmark Department of Surgery HPB Section Odense University Hospital University of Southern Denmark

Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.

关键词： Pancreatic cancer Desmoplastic stroma Cancer-associated fibroblast Inflammatory cells Pancreatic stellate cell

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Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations

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World Journal of Gastroenterology 2018年第41期24卷 4663-4678页

作者： michael Friberg Bruun Nielsen michael bau mortensen Sonke Detlefsen Department of Pathology Odense University HospitalDepartment of Clinical ResearchUniversity of Southern DenmarkOdense Pancreas Center(OPAC)Odense C 5000Denmark Department of Surgery HPB SectionOdense University HospitalDepartment of Clinical ResearchUniversity of Southern DenmarkOdense Pancreas Center(OPAC)Odense C 5000Denmark

AIM To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC). METHODS We defined four different stromal compartments in surgical specimens with PC: The juxtatumoural, peripheral, lobular and septal stroma. Tissue microarrays were produced containing all pre-defined PC compartments, and the expression of 37 fibroblast (FB) and 8 extracellular matrix (ECM) markers was evaluated by immunohistochemistry, immunofluorescence (IF), double-IF, and/or in situ hybridization. The compartment-specific mean labelling score was determined for each marker using a four-tiered scoring system. DOG1 gene expression was examined byquantitative reverse transcription PCR (qPCR). RESULTS CD10, CD271, cytoglobin, DOG1, miR-21, nestin, and tenascin C exhibited significant differences in expression profiles between the juxtatumoural and peripheral compartments. The expression of CD10, cytoglobin, DOG1, nestin, and miR-21 was moderate/strong in juxtatumoural CAFs (j-CAFs) and barely perceptible/weak in peripheral CAFs (p-CAFs). The upregulation of DOG1 gene expression in PC compared to normal pancreas was verified by qPCR. Tenascin C expression was strong in the juxtatumoural ECM and barely perceptible/weak in the peripheral ECM. CD271 expression was barely perceptible in j-CAFs but moderate in the other compartments. Galectin-1 was stronger expressed in j-CAFs vs septal fibroblasts, PDGFRβ, tissue transglutaminase 2, and hyaluronic acid were stronger expressed in lobular fibroblasts vs p-CAFs, and plectin-1 was stronger expressed in j-CAFs vs l-FBs. The expression of the remaining 33 markers did not differ significantly when related to the quantity of CAFs/FBs or the amount of ECM in the respective *** Different immune phenotypic CAF subpopulations can be identified in PC, using markers such as cytoglobin, CD271, and miR-21. Future studies should determine whether CAF subpo

关键词： Pancreatic cancer Tumour stroma Cancerassociated fibroblasts Extracellular matrix Subtyping Immunohistochemistry

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