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IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
Kalmar Hospital, Sweden.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed) Published
Abstract [en]

The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

Place, publisher, year, edition, pages
Public Library of Science , 2013. Vol. 8, no 8
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-97445DOI: 10.1371/journal.pone.0070874ISI: 000323097300061OAI: diva2:647849

Funding Agencies|Swedish Research Council|AI52731|VINNMER (Vinnova)||Medical Research Council of Southeast Sweden||Swedish Society of Medicine||

Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2015-11-26
In thesis
1. Metastatic Mechanisms in Malignant Tumors
Open this publication in new window or tab >>Metastatic Mechanisms in Malignant Tumors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 91 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1487
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Cell and Molecular Biology
urn:nbn:se:liu:diva-122830 (URN)978-91-7685-934-6 (print) (ISBN)
Public defence
2015-12-18, Hasselqvistsalen, Ingång 76, Hus 511, Campus US, Linköping, 09:00 (Swedish)

The ISBN 987-91-7685-934-6 in the printed version is incorrect. The correct ISBN is  978-91-7685-934-6.

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2015-12-18Bibliographically approved

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Tjomsland, VegardBojmar, LindaSandström, PerSpångeus, AnnaLarsson, Marie
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Molecular VirologyFaculty of Health SciencesDivision of Clinical SciencesDepartment of Surgery in LinköpingInternal MedicineDepartment of EndocrinologyDivision of Microbiology and Molecular Medicine
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