Publications by authors named "Nataša Pavlović"

8 Publications

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Activated platelets contribute to the progression of hepatocellular carcinoma by altering the tumor environment.

Life Sci 2021 May 12;277:119612. Epub 2021 May 12.

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Electronic address:

Aim: Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in a background of chronic liver disease and prolonged inflammation. A major contributor in the complex molecular pathogenesis of HCC is the highly intertwined cross-talk between the tumor and the surrounding stromal cells, such as hepatic stellate cells, endothelial cells, macrophages and other immune cells. These tumor-stroma interactions actively fuel tumor growth and modulate the hepatic microenvironment to benefit tumor invasion and disease progression. Platelets have been reported to interact with different cell types in the tumor microenvironment, including tumor cells, stellate cells and macrophages.

Materials And Methods: Mice were treated with hepatocarcinogenic compound diethylnitrosamine for 25 weeks to induce HCC in the background of fibrosis and inflammation. From week 10, anti-platelet drug Clopidogrel was added to the drinking water and mice were given ad libitum access.

Key Findings: In this study, we show that activated platelets promote tumor cell proliferation and contribute to the adverse tumor-stroma cross-talk that fuels tumor progression. We also show that inhibiting platelet activation with the P2Y12-inhibitor Clopidogrel decreases the number of tumors in a chemically induced mouse model for HCC.

Significance: These results suggest an important role for platelets in the pathogenesis of HCC and that the use of anti-platelet drugs may be therapeutically relevant for patients with liver cancer.
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http://dx.doi.org/10.1016/j.lfs.2021.119612DOI Listing
May 2021

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype.

Int J Mol Sci 2020 Oct 31;21(21). Epub 2020 Oct 31.

Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden.

The P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 is expressed by macrophages in the liver. Using in vitro methods, we show that inhibition of P2Y12 with ticagrelor enhances tumor cell phagocytosis by macrophages and induces an anti-tumoral phenotype. Treatment with ticagrelor also increases the expression of several actors of the endoplasmic reticulum (ER) stress pathways, suggesting activation of the unfolded protein response (UPR). Inhibiting the UPR with tauroursodeoxycholic acid (Tudca) diminishes the pro-phagocytotic effect of ticagrelor, thereby indicating that P2Y12 mediates macrophage function through activation of ER stress pathways. This could be relevant in the pathogenesis of chronic liver disease and cancer, as macrophages are considered key players in these inflammation-driven pathologies.
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http://dx.doi.org/10.3390/ijms21218177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672568PMC
October 2020

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma.

Elife 2020 10 26;9. Epub 2020 Oct 26.

Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.

Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.
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http://dx.doi.org/10.7554/eLife.55865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661042PMC
October 2020

A Biomimetic Model for Liver Cancer to Study Tumor-Stroma Interactions in a 3D Environment with Tunable Bio-Physical Properties.

J Vis Exp 2020 08 7(162). Epub 2020 Aug 7.

Department of Medical Cell Biology, Uppsala University;

Hepatocellular carcinoma (HCC) is a primary liver tumor developing in the wake of chronic liver disease. Chronic liver disease and inflammation leads to a fibrotic environment actively supporting and driving hepatocarcinogenesis. Insight into hepatocarcinogenesis in terms of the interplay between the tumor stroma micro-environment and tumor cells is thus of considerable importance. Three-dimensional (3D) cell culture models are proposed as the missing link between current in vitro 2D cell culture models and in vivo animal models. Our aim was to design a novel 3D biomimetic HCC model with accompanying fibrotic stromal compartment and vasculature. Physiologically relevant hydrogels such as collagen and fibrinogen were incorporated to mimic the bio-physical properties of the tumor ECM. In this model LX2 and HepG2 cells embedded in a hydrogel matrix were seeded onto the inverted transmembrane insert. HUVEC cells were then seeded onto the opposite side of the membrane. Three formulations consisting of ECM-hydrogels embedded with cells were prepared and the bio-physical properties were determined by rheology. Cell viability was determined by a cell viability assay over 21 days. The effect of the chemotherapeutic drug doxorubicin was evaluated in both 2D co-culture and our 3D model for a period of 72h. Rheology results show that bio-physical properties of a fibrotic, cirrhotic and HCC liver can be successfully mimicked. Overall, results indicate that this 3D model is more representative of the in vivo situation compared to traditional 2D cultures. Our 3D tumor model showed a decreased response to chemotherapeutics, mimicking drug resistance typically seen in HCC patients.
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http://dx.doi.org/10.3791/61606DOI Listing
August 2020

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment.

Cell Signal 2020 08 22;72:109661. Epub 2020 Apr 22.

Dept. of Medical Cell Biology, Uppsala University, P.O. Box 571, SE-751 23 Uppsala, Sweden; Dept. of Radiology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

Fibrin is an essential constituent of the coagulation cascade, and the formation of hemostatic fibrin clots is central to wound healing. Fibrin clots are over time degraded into fibrin degradation products as the injured tissue is replaced by granulation tissue. Our goal was to study the role of the fibrin degradation product fragment E (FnE) in fibroblast activation and migration. We present evidence that FnE is a chemoattractant for fibroblasts and that FnE can potentiate TGF-β-induced myofibroblast formation. FnE forms a stable complex with αβ integrin, and the integrin β subunit is required both for FnE-induced fibroblast migration and for potentiation of TGF-β-induced myofibroblast formation. Finally, subcutaneous infusion of FnE in mice results in a fibrotic response in the hypodermis. These results support a model where FnE released from clots in wounded tissue promote wound healing and fibrosis by both recruitment and activation of fibroblasts. Fibrin fragment E could thus represent a therapeutic target for treatment of pathological fibrosis.
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http://dx.doi.org/10.1016/j.cellsig.2020.109661DOI Listing
August 2020

Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile.

Cancers (Basel) 2019 Jul 20;11(7). Epub 2019 Jul 20.

Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 µM doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.
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http://dx.doi.org/10.3390/cancers11071024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678640PMC
July 2019

Platelets as Key Factors in Hepatocellular Carcinoma.

Cancers (Basel) 2019 Jul 20;11(7). Epub 2019 Jul 20.

Department of Medical Cell Biology, Uppsala University, Box 571, Husargatan 3, 75-431 Uppsala, Sweden.

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix, and a variety of immune cells interact in highly complex and intertwined signaling pathways. A key factor in these cross-talks are platelets, whose role in cancer has gained growing evidence in recent years. Platelets have been reported to promote HCC cell proliferation and invasion, but their involvement goes beyond the direct effect on tumor cells, as they are known to play a role in pro-fibrinogenic signaling and the hepatic immune response, as well as in mediating interactions between these factors in the stroma. Anti-platelet therapy has been shown to ameliorate liver injury and improve the disease outcome. However, platelets have also been shown to play a crucial role in liver regeneration after organ damage. Therefore, the timing and microenvironmental setting need to be kept in mind when assessing the potential effect and therapeutic value of platelets in the disease progression, while further studies are needed for understanding the role of platelets in patients with HCC.
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http://dx.doi.org/10.3390/cancers11071022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678690PMC
July 2019

Anti-Stokes contribution to the SBS Stokes gain in remotely seeded bidirectional NG-PON systems.

Opt Express 2017 Jul;25(14):16182-16195

We assess the importance of Stimulated Brillouin scattering (SBS) anti-Stokes wave on reflection tolerance in remotely seeded wavelength-division multiplexing passive optical networks (WDM PON). Experimental validation of the extended model for the externally seeded SBS is presented towards assessing the conditions in which the anti-Stokes contribution becomes relevant in the variant scenario of remotely carrier-seeded PON. We identify relevant operating conditions in which the latter can no longer be reliably neglected, and analyze the remote seed power budget implications of such contribution. Considering typical launch powers in PON systems we found that, even for seed launch powers below SBS threshold, non-optimized upstream (US) power spectral density may lead to a considerable anti-Stokes contribution to the SBS gain. In effect, in order to maintain a reference optical return loss (ORL) of 32 dB in such scenario, anti-Stokes wave contribution imposed rigorous remote seed power budget restrictions depending on fiber parameters.
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http://dx.doi.org/10.1364/OE.25.016182DOI Listing
July 2017