| 1. |
- Aslan, Cynthia, et al.
(författare)
-
Tumor-derived exosomes: Implication in angiogenesis and antiangiogenesis cancer therapy
- 2019
-
Ingår i: Journal of Cellular Physiology. - : WILEY. - 0021-9541 .- 1097-4652. ; 234:10, s. 16885-16903
-
Forskningsöversikt (refereegranskat)abstract
- Tumor cells utilize different strategies to communicate with neighboring tissues for facilitating tumor progression and invasion, one of these strategies has been shown to be the release of exosomes. Exosomes are small nanovesicles secreted by all kind of cells in the body, especially cancer cells, and mediate cell to cell communications. Exosomes play an important role in cancer invasiveness by harboring various cargoes that could accelerate angiogenesis. Here first, we will present an overview of exosomes, their biology, and their function in the body. Then, we will focus on exosomes derived from tumor cells as tumor angiogenesis mediators with a particular emphasis on the underlying mechanisms in various cancer origins. Also, exosomes derived from stem cells and tumor-associated macrophages will be discussed in this regard. Finally, we will discuss the novel therapeutic strategies of exosomes as drug delivery vehicles against angiogenesis.
|
|
| 2. |
- Dubois, Louise, et al.
(författare)
-
Malignant Cell-Derived Extracellular Vesicles Express Different Chromogranin Epitopes Compared to Prostasomes
- 2015
-
Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 75:10, s. 1063-1073
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers.
|
|
| 3. |
- Fotouhi, Omid, et al.
(författare)
-
Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
- 2019
-
Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.
|
|
| 4. |
- Kharaziha, Pedram, et al.
(författare)
-
Functional characterization of novel germline TP53 variants in Swedish families
- 2019
-
Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 96:3, s. 216-225
-
Tidskriftsartikel (refereegranskat)abstract
- Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.
|
|
| 5. |
- Kharaziha, Pedram, et al.
(författare)
-
Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection : a phase I-II clinical trial
- 2009
-
Ingår i: European Journal of Gastroenterology and Hepathology. - 0954-691X .- 1473-5687. ; 21:10, s. 1199-1205
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage liver disease is a medical problem with high morbidity and mortality. We have investigated the feasibility, safety, and efficacy of using autologous mesenchymal stem cells (MSCs) as a treatment. METHODS: Eight patients (four hepatitis B, one hepatitis C, one alcoholic, and two cryptogenic) with end-stage liver disease having Model for End-Stage Liver Disease score > or =10 were included. Autologous MSCs were taken from iliac crest. Approximately, 30-50 million MSCs were proliferated and injected into peripheral or the portal vein. Liver function and clinical features were evaluated at baseline and 1, 2, 4, 8, and 24 weeks after injection. RESULTS: Treatment was well tolerated by all patients. Liver function improved as verified by the Model for End-Stage Liver Disease score, which decreased from 17.9±5.6 to 10.7±6.3 (P<0.05) and prothrombin complex from international normalized ratio 1.9±0.4 to 1.4±0.5 (P<0.05). Serum creatinine decreased from 114±35 to 80±18 µmol/l (P<0.05). Serum albumin changed from 30±5 to 33±5 g/l and bilirubin from 46±29 to 41±31 µmol/l. No adverse effects were noted. CONCLUSION: Our data show that MSCs injection can be used for the treatment of end-stage liver disease with satisfactory tolerability. Furthermore, this treatment may improve clinical indices of liver function in end-stage liver disease.
|
|
| 6. |
- Kharaziha, Pedram, et al.
(författare)
-
Sorafenib Has Potent Antitumor Activity against Multiple Myeloma In Vitro, Ex Vivo, and In Vivo in the 5T33MM Mouse Model
- 2012
-
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72:20, s. 5348-5362
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138(+)-enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138(+)-enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737.
|
|
| 7. |
- Kharaziha, Pedram
(författare)
-
Studies on the mechanisms of sorafenib-induced cell death
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In 2008, 26% of all deaths were cancer-related, making this group of diseases the second leading cause of death in the EU countries. Derailment of tyrosine kinase signaling is one important pre-requisite towards tumorigenesis. Small molecular inhibitors of receptor tyrosine kinases (RTKs) are a new type of targeted therapy and they are increasingly used as a core component of personalized cancer therapy. The main aim of this thesis is to investigate the anti-cancer effects of the multi tyrosine kinase inhibitor (TKI) sorafenib in hematological and solid tumors. In the first study, we found that sorafenib is particularly effective in inducing cell death in a panel of human myeloma cell lines. We investigated the mode of cell death induced by sorafenib and found that this TKI induces both caspase dependent and caspase independent cell death. Furthermore, sorafenib induces autophagy in some human myeloma cell lines, myeloma patient samples and mouse myeloma cells and co-treatment of myeloma cells with sorafenib and autophagy inhibitors potentiates the cytotoxic efficacy of sorafenib. Importantly, sorafenib induced cell death in freshly isolated CD138+ multiple myeloma cells from newly diagnosed patients chemotherapy naïve as well as bortezomib resistant patient samples. We investigated the efficacy of sorafenib in the 5T33MM mouse myeloma model and found that this TKI lead to significantly increased survival, reduced tumor growth and decreased serum M component. In the pertaining studies we investigated the efficacy of sorafenib against prostate cancer cell lines. In the second study we demonstrated that sorafenib caused a dose-dependent decrease in cell viability in two hormone refractory and one hormone responsive prostate cancer cell lines. In the third study we further investigated the signaling cascades inhibited by sorafenib leading to cell death in prostate cancer cell lines (22Rv1 and PC3). Activation of caspases and downregulation of Mcl-1 are seen in both cell lines. However we found that distinct upstream signaling cascades are activated in these two prostate cancer cell lines which are differentially affected upon treatment with sorafenib. In 22Rv1, ERK1/2 is constitutively phosphorylated and active whereas in PC3 cells it is not active. In contrast, Src and AKT were constitutively active in PC3 cells but not in 22Rv1 and treatment with sorafenib could inhibit these kinases in PC3 cells. In both cell lines, sorafenib induces autophagy and inhibition of autophagy potentiates the cytotoxic efficacy of sorafenib. PC3 and 22Rv1 cells could further be rescued from sorafenib-induced cell death when co-cultured with cancer associated fibroblasts. This protection could be overcome by co-treatment with ABT737 (a Bcl-2/Bcl-xL inhibitor), suggesting that these anti-apoptotic proteins are, at least in part, responsible for the rescuing phenotype observed upon co-culture with cancer associated fibroblasts. In a fourth study we found that even though DU145 cells do not express ATG5 they undergo autophagy upon treatment with sorafenib or bafilomycin A1. Interestingly, we showed that sorafenib-induced autophagy in DU145 cells is cytotoxic and the cell death observed could be inhibited by the exogenous re-constitution of Atg5 expression. We found that treatment with molecular or chemical inhibitors of RIPK1 suppressed the observed cell death. Collectively our data suggest that in Atg5-deficient cells autophagy is cytotoxic and the ensuing cell death is executed by the necroptotic program. In summary, these data identify some molecular mechanisms and requirements for the successful usage of sorafenib as a putative anti-cancer treatment against multiple myeloma and prostate cancer
|
|
| 8. |
- Pellegrini, Paola, et al.
(författare)
-
Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:24, s. 35703-35723
-
Tidskriftsartikel (refereegranskat)abstract
- Sustained autophagy contributes to the metabolic adaptation of cancer cells to hypoxic and acidic microenvironments. Since cells in such environments are resistant to conventional cytotoxic drugs, inhibition of autophagy represents a promising therapeutic strategy in clinical oncology. We previously reported that the efficacy of hydroxychloroquine (HCQ), an autophagy inhibitor under clinical investigation is strongly impaired in acidic tumor environments, due to poor uptake of the drug, a phenomenon widely associated with drug resistance towards many weak bases. In this study we identified salinomycin (SAL) as a potent inhibitor of autophagy and cytotoxic agent effective on several cancer cell lines under conditions of transient and chronic acidosis. Since SAL has been reported to specifically target cancer-stem cells (CSC), we used an established model of breast CSC and CSC derived from breast cancer patients to examine whether this specificity may be associated with autophagy inhibition. We indeed found that CSC-like cells are more sensitive to autophagy inhibition compared to cells not expressing CSC markers. We also report that the ability of SAL to inhibit mammosphere formation from CSC-like cells was dramatically enhanced in acidic conditions. We propose that the development and use of clinically suitable SAL derivatives may result in improved autophagy inhibition in cancer cells and CSC in the acidic tumor microenvironment and lead to clinical benefits.
|
|
