Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer–stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models?
Key Points
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Desmoplastic stroma is a typical feature of pancreatic ductal adenocarcinoma (PDAC); it is either absent or much less prominent in other tumours of the pancreas
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Precursor lesions of PDAC (such as pancreatic intraepithelial neoplasms and atypical flat lesions) elicit stromal activation and extracellular matrix deposition around them
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Precursor lesions of PDAC are beneath the detection limit of conventional diagnostic methods; late diagnosis of PDAC leads to a closed therapeutic time window, thus hindering curative treatment
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The activated stroma of pancreatic cancer has an effect on the aggressiveness of the tumour as well as its resistance to therapy
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Activated stroma is a new diagnostic and therapeutic target in the treatment of PDAC
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Acknowledgements
This work was supported in part by a grant from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF] to M. Erkan, C. W. Michalski and J. Kleeff) within the “National Genome Research Network” (NGFN-Plus; 01GS08115).
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M. Erkan and C. W. Michalski contributed to all aspects of the manuscript. S. Hausmann researched data for the article and contributed to writing and reviewing/editing the manuscript. A. A. Fingerle and M. Dobritz contributed to discussion of content, writing and reviewing/editing of the manuscript. J. Kleeff and H. Friess contributed to discussion of content and reviewing/editing of the manuscript.
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Erkan, M., Hausmann, S., Michalski, C. et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9, 454–467 (2012). https://doi.org/10.1038/nrgastro.2012.115
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DOI: https://doi.org/10.1038/nrgastro.2012.115
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