| 1. |
- Bocci, Matteo, et al.
(författare)
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Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer
- 2019
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Ingår i: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 22:1, s. 117-131
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein (CLEC)14A as a potential downstream target of ACVRL1. Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer.
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| 2. |
- Kurzejamska, Ewa
(författare)
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Mesenchymal stem cells in vascular structure and remodeling in cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mesenchymal stem cells (MSCs) are present in vascular structure and play an important role in vessel remodeling in normal, as well as pathological conditions, such as transplant arteriosclerosis or tumor angiogenesis. Moreover, MSCs affect tumor growth and metastasis by production of chemokines, such as (C-C motif) ligand 7 (CCL7). Similar effect on tumor biology exert multiple other factors, such as CCAAT-enhancer binding protein β (C/EBPβ), which is a transcription factor playing an essential role in mammary gland development and breast cancer progression. In study I, presence of MSCs in vascular structure, as well as their role in vascular remodeling in transplant arteriosclerosis was analyzed. Specifically, rat allograft model was used to identify the predominant cell types associated with this process and to find factors crucial for their recruitment into the graft. This study identified adventitia as a potentially important source of mesenchymal stem cells that contribute to formation of intimal hyperplasia. Furthermore, monocyte chemoattractant protein-1 (MCP-1) was found as a potent chemokine for the recruitment of adventitial vascular progenitor cells to intimal lesions. Study II and III focus on the role of C/EBPβ transcription factor in breast cancer progression. Namely, in study II C/EBPβ was associated with epithelial-to-mesenchymal transition (EMT) features in triple-negative human breast cancer and invasive areas of mammary tumors in MMTV-PyMT mice. In vitro studies showed that C/EBPβ was repressed during EMT by miR-155, a breast cancer oncomiR. Moreover, C/EBPβ depletion enhanced TGFβ response towards EMT and contributed to evasion of growth inhibitory response to TGFβ. C/EBPβ loss caused potentiated invasion and metastasis of breast cancer cells to the lungs in mouse 4T1 model. In addition, C/EBPβ was shown to transcriptionally activate genes encoding epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor (CAR). Study III was focused on explaining the mechanism of C/EBPβ effect on metastasis, as well as determining the relationship between C/EBPβ expression and survival of breast cancer patients. Firstly, study showed that decrease in C/EBPβ expression was associated with shorter overall survival of breast cancer patients. Next, loss of C/EBPβ affected tumor growth, morphology and lung metastasis in murine 4T1 breast cancer model. Moreover, inhibition of C/EBPβ caused enhanced histocompatibility complex II (MHCII) expression and accumulation of CD45+, CD3+ and CD4+ lymphocytes in the tumors. Additional experiments confirmed the role of inflammation in C/EBPβ-mediated metastasis formation. Study IV involved analysis of crosstalk between MSCs and colon cancer. Results demonstrated that MSCs affect CT26 tumor cell proliferation, migration and expression of different chemokines in coculture with CT26 cells in vitro, such as (C-C motif) ligand 7 (CCL7). The next goal of the study was to analyze the effect of CCL7 overexpression on tumor progression in mouse CT26 colon cancer model. Cells overexpressing CCL7 accelerated early phase of tumor growth and led to higher lung metastasis rate in tumor-bearing mice. Lastly, higher CCR2 expression, which is a CCL7 receptor, was associated with shorter overall survival of colorectal cancer patients.
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| 3. |
- Lazarczyk, Marzena, et al.
(författare)
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Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer
- 2023
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Ingår i: Current Issues in Molecular Biology. - : MDPI. - 1467-3037 .- 1467-3045. ; 45:4, s. 3446-3461
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer is the third most frequently diagnosed cancer in the world. Despite extensive studies and apparent progress in modern strategies for disease control, the treatment options are still not sufficient and effective, mostly due to frequently encountered resistance to immunotherapy of colon cancer patients in common clinical practice. In our study, we aimed to uncover the CCL9 chemokine action employing the murine model of colon cancer to seek new, potential molecular targets that could be promising in the development of colon cancer therapy. Mouse CT26.CL25 colon cancer cell line was used for introducing lentivirus-mediated CCL9 overexpression. The blank control cell line contained an empty vector, while the cell line marked as CCL9+ carried the CCL9-overexpressing vector. Next, cancer cells with empty vector (control) or CCL9-overexpressing cells were injected subcutaneously, and the growing tumors were measured within 2 weeks. Surprisingly, CCL9 contributed to a decline in tumor growth in vivo but had no effect on CT26.CL25 cell proliferation or migration in vitro. Microarray analysis of the collected tumor tissues revealed upregulation of the immune system-related genes in the CCL9 group. Obtained results suggest that CCL9 reveals its anti-proliferative functions by interplay with host immune cells and mediators that were absent in the isolated, in vitro system. Under specific study conditions, we determined unknown features of the murine CCL9 that have so far bee reported to be predominantly pro-oncogenic.
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| 4. |
- Lazarczyk, Marzena, et al.
(författare)
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The Journey of Cancer Cells to the Brain : Challenges and Opportunities
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:4
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Forskningsöversikt (refereegranskat)abstract
- Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.
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| 5. |
- Mader, Theresa, et al.
(författare)
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Exercise reduces intramuscular stress and counteracts muscle weakness in mice with breast cancer
- 2022
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Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : John Wiley & Sons. - 2190-5991 .- 2190-6009. ; 13:2, s. 1151-1163
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with breast cancer exhibit muscle weakness, which is associated with increased mortality risk and reduced quality of life. Muscle weakness is experienced even in the absence of loss of muscle mass in breast cancer patients, indicating intrinsic muscle dysfunction. Physical activity is correlated with reduced cancer mortality and disease recurrence. However, the molecular processes underlying breast cancer-induced muscle weakness and the beneficial effect of exercise are largely unknown.METHODS: Eight-week-old breast cancer (MMTV-PyMT, PyMT) and control (WT) mice had access to active or inactive in-cage voluntary running wheels for 4 weeks. Mice were also subjected to a treadmill test. Muscle force was measured ex vivo. Tumour markers were determined with immunohistochemistry. Mitochondrial biogenesis and function were assessed with transcriptional analyses of PGC-1α, the electron transport chain (ETC) and antioxidants superoxide dismutase (Sod) and catalase (Cat), combined with activity measurements of SOD, citrate synthase (CS) and β-hydroxyacyl-CoA-dehydrogenase (βHAD). Serum and intramuscular stress levels were evaluated by enzymatic assays, immunoblotting, and transcriptional analyses of, for example, tumour necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (MAPK) signalling.RESULTS: PyMT mice endured shorter time and distance during the treadmill test (~30%, P < 0.05) and ex vivo force measurements revealed ~25% weaker slow-twitch soleus muscle (P < 0.001). This was independent of cancer-induced alteration of muscle size or fibre type. Inflammatory stressors in serum and muscle, including TNF-α and p38 MAPK, were higher in PyMT than in WT mice (P < 0.05). Cancer-induced decreases in ETC (P < 0.05, P < 0.01) and antioxidant gene expression were observed (P < 0.05). The exercise intervention counteracted the cancer-induced muscle weakness and was accompanied by a less aggressive, differentiated tumour phenotype, determined by increased CK8 and reduced CK14 expression (P < 0.05). In PyMT mice, the exercise intervention led to higher CS activity (P = 0.23), enhanced β-HAD and SOD activities (P < 0.05), and reduced levels of intramuscular stressors together with a normalization of the expression signature of TNFα-targets and ETC genes (P < 0.05, P < 0.01). At the same time, the exercise-induced PGC-1α expression, and CS and β-HAD activity was blunted in muscle from the PyMT mice as compared with WT mice, indicative that breast cancer interfere with transcriptional programming of mitochondria and that the molecular adaptation to exercise differs between healthy mice and those afflicted by disease.CONCLUSIONS: Four-week voluntary wheel running counteracted muscle weakness in PyMT mice which was accompanied by reduced intrinsic stress and improved mitochondrial and antioxidant profiles and activities that aligned with muscles of healthy mice.
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