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Bojmar, Linda
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Wang, G., Li, J., Bojmar, L., Chen, H., Li, Z., Tobias, G. C., . . . Lyden, D. (2023). Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature, 618(7964), 374-382
Öppna denna publikation i ny flik eller fönster >>Tumour extracellular vesicles and particles induce liver metabolic dysfunction
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2023 (Engelska)Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 618, nr 7964, s. 374-382Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cancer alters the function of multiple organs beyond those targeted by metastasis(1,2). Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Ort, förlag, år, upplaga, sidor
NATURE PORTFOLIO, 2023
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:liu:diva-195777 (URN)10.1038/s41586-023-06114-4 (DOI)000994689400009 ()37225988 (PubMedID)
Anmärkning

Funding Agencies|National Cancer Institute; Thompson Family Foundation; Tortolani Foundation; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Malcolm Hewitt Weiner Foundation; Manning Foundation; Sohn Foundation; AHEPA Vth District Cancer Research Foundation; Childrens Cancer and Blood Foundation; Hartwell Foundation; National Institutes of Health; United States Department of Defense; Paul G. Allen Family Foundation; National Natural Science Foundation of China; Guangdong Foundation of Medical Science and Technology; China Scholarship Council (CSC) [CA232093, CA163117, CA207983, CA218513]; Swedish Cancer Society Pancreatic Cancer Fellowship; Lions International Postdoctoral fellowship; Sweden-America stipend; Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center of Memorial Sloan Kettering Cancer Center; NIH/NCI Cancer Center Support Grant; [R01CA234614]; [2R01AI107301]; [R01DK121072]; [R01CA237213]; [R01CA254036]; [W81XWH-21-1-0978]; [UWSC13448]; [81902730]; [A2019213]; [202008440567]; [P30 CA008748]

Tillgänglig från: 2023-06-27 Skapad: 2023-06-27 Senast uppdaterad: 2024-03-26Bibliografiskt granskad
Bojmar, L., Kim, H. S., Tobias, G. C., Pelissier Vatter, F. A., Lucotti, S., Gyan, K. E., . . . Lyden, D. (2021). Extracellular vesicle and particle isolation from human and murine cell lines, tissues, and bodily fluids. STAR protocols, 2(1)
Öppna denna publikation i ny flik eller fönster >>Extracellular vesicle and particle isolation from human and murine cell lines, tissues, and bodily fluids
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2021 (Engelska)Ingår i: STAR protocols, ISSN 2666-1667, Vol. 2, nr 1Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We developed a modified protocol, based on differential ultracentrifugation (dUC), to isolate extracellular vesicles and particles (specifically exomeres) (EVPs) from various human and murine sources, including cell lines, surgically resected tumors and adjacent tissues, and bodily fluids, such as blood, lymphatic fluid, and bile. The diversity of these samples requires robust and highly reproducible protocols and refined isolation technology, such as asymmetric-flow field-flow fractionation (AF4). Our isolation protocol allows for preparation of EVPs for various downstream applications, including proteomic profiling. For complete details on the use and execution of this protocol, please refer to Hoshino et al. (2020).

Ort, förlag, år, upplaga, sidor
Cell Press, 2021
Nyckelord
Cell Membrane; Cell culture; Cell isolation; Exomeres; Exosomes; Extracellular vesicles and particles; Isolation
Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:liu:diva-184039 (URN)10.1016/j.xpro.2020.100225 (DOI)001049318800008 ()33786456 (PubMedID)2-s2.0-85103050917 (Scopus ID)
Anmärkning

Funding agencies: he National Cancer Institute, United States CA224175 (D.L.), CA210240 (D.L.), CA232093(D.L.), CA163117 and CA207983 (D.L.), CA163120 (D.L.), CA169416 (D.L.), CA169538 (D.L.),CA218513 (D.L., H.Z.) and AI144301 (D.L., V.P.); the United States Department of Defense, UnitedStates W81XWH-13-1-0425 (D.L.), W81XWH-13-1-0427, W81XWH-13-1-0249 (D.L.), and W81XWH-14-1-0199 (D.L.); National Institutes of Health, United States/WCM CTSC, United States (NIH/NCATS (UL1TR00457) (H.Z.); NIH/NCATS (UL1TR002384) (D.L. and H.Z.); the Hartwell Foundation,United States (D.L.); the Thompson Family Foundation (D.L., D.K.); the STARR Consortium I9-A9-056(D.L., H.Z.) and I8-A8-123 (D.L.); the Pediatric Oncology Experimental Therapeutics Investigator’sConsortium (D.L., T.M.T.); Alex’s Lemonade Stand Foundation, United Sates (D.L.); the Breast Can-cer Research Foundation, United States (D.L.); the Feldstein Medical Foundation (D.L.); the TortolaniFoundation (D.L.); the Clinical & Translational Science Center (D.L., H.Z.); the Mary Kay Ash Chari-table Foundation (D.L., I.M.); the Malcolm Hewitt Weiner Foundation (D.L.); the Manning Founda-tion (DL., A.H.); the Daniel P. and Nancy C. Paduano Family Foundation (D.L); the James PaduanoFoundation (D.L.); the Sohn Foundation (D.L.); the AHEPA Vth District Cancer Research Foundation(D.L., L.B., S.L.); the Daedalus Fund Selma and Lawrence Ruben Science to Industry Bridge Award(D.L.); the Children’s Cancer and Blood Foundation, United States (D.L.); Susan G. Komen Postdoc-toral Fellowship PDF15331556, JST PRESTO, Japan 30021, and JSPS KAKENHI, Japan JP19K23743(A.H.); the National Research Foundation of Korea, South Korea (NRF) grant funded by the Korea government (MSIT) (2019R1C1C1006709, 2018R1A5A2025079, and 2020M3F7A1094093); a grantof the Korea Health Technology R&D Project through the Korea Health Industry Development Insti-tute (KHIDI), funded by the Ministry of Health & Welfare, South Korea (KHIDIHI19C1015010020);"The Alchemist Project" through the Ministry of Trade, Industry and Energy (MOTIE, Korea)(20012443), and Severance Hospital Research fund for Clinical excellence (SHRC) (C-2020-0032and C-2020-0025) (H.S.K.); The Swedish Cancer Society Pancreatic Cancer Fellowship, the Lions In-ternational Postdoctoral fellowship and the Sweden-America stipend (L.B.); the Sa ̃ o Paulo ResearchFoundation (FAPESP) Sa ̃ o Paulo, Brazil (2017/07117-7) (G.C.T); the Swiss National Science Founda-tion (SFNS), Switzerland Postdoc Mobility grant (P2SKP3_174785 and P400PB_186791) (F.A.V.); andthe DoD PRCRP Horizon Award, United States (W81XWH-19-PRCRP-HA) (S.L).

Tillgänglig från: 2022-05-16 Skapad: 2022-05-16 Senast uppdaterad: 2024-01-08
Kuninty, P. R., Bojmar, L., Tjomsland, V., Larsson, M., Storm, G., Östman, A., . . . Prakash, J. (2016). MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor. Oncotarget, 7(13), 16396-16408
Öppna denna publikation i ny flik eller fönster >>MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor
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2016 (Engelska)Ingår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 13, s. 16396-16408Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in PSCs in pancreatic cancer.

Ort, förlag, år, upplaga, sidor
Impact press, 2016
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:liu:diva-122828 (URN)10.18632/oncotarget.7651 (DOI)000375692900085 ()
Anmärkning

Funding agencies: Swedish Research Council, Stockholm, Sweden [K7/60501283]

Vid tiden för disputationen förelåg publikationen endast som manuskript

Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2024-01-17
Bojmar, L. (2015). Metastatic Mechanisms in Malignant Tumors. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Öppna denna publikation i ny flik eller fönster >>Metastatic Mechanisms in Malignant Tumors
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2015. s. 91
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1487
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:liu:diva-122830 (URN)978-91-7685-934-6 (ISBN)
Disputation
2015-12-18, Hasselqvistsalen, Ingång 76, Hus 511, Campus US, Linköping, 09:00 (Svenska)
Opponent
Handledare
Anmärkning

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

Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Bojmar, L., Zhang, H., Costa da Silva, B., Karlsson, E., Olsson, H., Vincent, T., . . . Sandström, P. (2015). miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome.
Öppna denna publikation i ny flik eller fönster >>miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
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2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast  tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.

Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:liu:diva-122829 (URN)
Tillgänglig från: 2015-11-26 Skapad: 2015-11-26 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Björnsson, B., Bojmar, L., Olsson, H., Sundqvist, T. & Sandström, P. (2015). Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver. World Journal of Gastroenterology, 21(6), 1775-1783
Öppna denna publikation i ny flik eller fönster >>Nitrite, a novel method to decrease ischemia/reperfusion injury in the rat liver
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2015 (Engelska)Ingår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, nr 6, s. 1775-1783Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

AIM: To investigate whether nitrite administered prior to ischemia/reperfusion (I/R) reduces liver injury.

METHODS: Thirty-six male Sprague-Dawley rats were randomized to 3 groups, including sham operated (n = 8), 45-min segmental ischemia of the left liver lobe (IR, n = 14) and ischemia/reperfusion (I/R) preceded by the administration of 480 nmol of nitrite (n = 14). Serum transaminases were measured after 4 h of reperfusion. Liver microdialysate (MD) was sampled in 30-min intervals and analyzed for glucose, lactate, pyruvate and glycerol as well as the total nitrite and nitrate (NOx). The NOx was measured in serum.

RESULTS: Aspartate aminotransferase (AST) at the end of reperfusion was higher in the IR group than in the nitrite group (40 ± 6.8 μkat/L vs 22 ± 2.6 μkat/L, P = 0.022). Similarly, alanine aminotransferase (ALT) was also higher in the I/R group than in the nitrite group (34 ± 6 μkat vs 14 ± 1.5 μkat, P = 0.0045). The NOx in MD was significantly higher in the nitrite group than in the I/R group (10.1 ± 2.9 μM vs 3.2 ± 0.9 μM, P = 0.031) after the administration of nitrite. During ischemia, the levels decreased in both groups and then increased again during reperfusion. At the end of reperfusion, there was a tendency towards a higher NOx in the I/R group than in the nitrite group (11.6 ± 0.7 μM vs 9.2 ± 1.1 μM, P = 0.067). Lactate in MD was significantly higher in the IR group than in the nitrite group (3.37 ± 0.18 mM vs 2.8 ± 0.12 mM, P = 0.01) during ischemia and the first 30 min of reperfusion. During the same period, glycerol was also higher in the IRI group than in the nitrite group (464 ± 38 μM vs 367 ± 31 μM, P = 0.049). With respect to histology, there were more signs of tissue damage in the I/R group than in the nitrite group, and 29% of the animals in the I/R group exhibited necrosis compared with none in the nitrite group. Inducible nitric oxide synthase (iNOS) transcription increased between early ischemia (t = 15) and the end of reperfusion in both groups.

CONCLUSION: Nitrite administered before liver ischemia in the rat liver reduces anaerobic metabolism and cell necrosis, which could be important in the clinical setting.

Ort, förlag, år, upplaga, sidor
Baishideng Publishing Group Co. Limited, 2015
Nyckelord
Ischemia-reperfusion injury; Nitrite; Liver ischemia; Liver surgery; Microdialysis; Nitric oxide; Inducible nitric oxide synthase
Nationell ämneskategori
Gastroenterologi
Identifikatorer
urn:nbn:se:liu:diva-110262 (URN)10.3748/wjg.v21.i6.1775 (DOI)000349666300010 ()25684942 (PubMedID)
Tillgänglig från: 2014-09-05 Skapad: 2014-09-05 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., . . . Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329-+
Öppna denna publikation i ny flik eller fönster >>Tumour exosome integrins determine organotropic metastasis
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2015 (Engelska)Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 527, nr 7578, s. 329-+Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Ever since Stephen Pagets 1889 hypothesis, metastatic organotropism has remained one of cancers greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2015
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-125329 (URN)10.1038/nature15756 (DOI)000365356800046 ()26524530 (PubMedID)
Anmärkning

Funding Agencies|MSK Cancer Center Support Grant/Core Grant [P30 CA008748]; National Cancer Institute [U01-CA169538]; National Institutes of Health [R01-CA169416]; United States Department of Defense [W81XWH-13-10249, W81XWH-13-1-0425]; Melanoma Research Alliance; Sohn Conference Foundation; Childrens Cancer and Blood Foundation; Manning Foundation; Hartwell Foundation; Fundacao para a Ciencia e a Tecnologia; Nancy C. and Daniel P. Paduano Foundation; Feldstein Foundation; Starr Cancer Consortium; Mary Kay Foundation; Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC); James Paduano Foundation; Beth Tortolani Foundation; Malcolm Hewitt Weiner Foundation; Theodore A. Rapp Foundation; American Hellenic Educational Progressive Association 5th District Cancer Research Foundation; Charles and Marjorie Holloway Foundation; Sussman Family Fund; Lerner Foundation; Breast Cancer Alliance; Manhasset Womens Coalition Against Breast Cancer; Ministry of Science and Technology Taiwan [101-2918-I-002-016]; JSPS Postdoctoral Fellowships; Susan G. Komen Postdoctoral Fellowship

Tillgänglig från: 2016-02-23 Skapad: 2016-02-19 Senast uppdaterad: 2017-11-30
Björnsson, B., Winbladh, A., Bojmar, L., Sundqvist, T., Gullstrand, P. & Sandström, P. (2014). Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion. World Journal of Gastroenterology, 20(28), 9506-9512
Öppna denna publikation i ny flik eller fönster >>Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion
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2014 (Engelska)Ingår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, nr 28, s. 9506-9512Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI). METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed. RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (Delta Ct: 3.44 +/- 0.57) group than in the IPC (Delta Ct: 5.86 +/- 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (Delta Ct: 1.88 +/- 0.53 to 4.81 +/- 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 +/- 2.2 to 4.7 +/- 1.2 mu mol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 +/- 2.1 to 6.4 +/- 1.5 mu mol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups. CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.

Ort, förlag, år, upplaga, sidor
Baishideng Publishing Group Co. Limited, 2014
Nyckelord
Ischemia-reperfusion injury; Preconditioning; Remote preconditioning; Liver ischemia; Liver surgery; Microdialysis; Nitric oxide; inducible nitric oxide synthase; interleukin-1 receptor
Nationell ämneskategori
Gastroenterologi
Identifikatorer
urn:nbn:se:liu:diva-109589 (URN)10.3748/wjg.v20.i28.9506 (DOI)000339389800032 ()25071345 (PubMedID)
Tillgänglig från: 2014-08-21 Skapad: 2014-08-21 Senast uppdaterad: 2017-12-05
Tjomsland, V., Bojmar, L., Sandström, P., Bratthall, C., Messmer, D., Spångeus, A. & Larsson, M. (2013). IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway. PLOS ONE, 8(8)
Öppna denna publikation i ny flik eller fönster >>IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway
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2013 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 8Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2013
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-97445 (URN)10.1371/journal.pone.0070874 (DOI)000323097300061 ()
Anmärkning

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

Tillgänglig från: 2013-09-12 Skapad: 2013-09-12 Senast uppdaterad: 2021-06-14
Pena, C., Virtudes Cespedes, M., Bradic Lindh, M., Kiflemariam, S., Mezheyeuski, A., Edqvist, P.-H., . . . Ostman, A. (2013). STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer. Cancer Research, 74(4), 1287-1297
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2013 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 4, s. 1287-1297Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.

Ort, förlag, år, upplaga, sidor
American Association for Cancer Research, 2013
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-90068 (URN)10.1158/0008-5472.CAN-12-1875 (DOI)000315029800004 ()
Anmärkning

Funding Agencies|Swedish Research Council|60016002|VINNOVA||Swedish Cancer Society|11 0371|National Health and Medical Research Council of Australia project grant||

Tillgänglig från: 2013-03-21 Skapad: 2013-03-19 Senast uppdaterad: 2017-12-06
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