Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Shiri Klein is active.

Publication


Featured researches published by Shiri Klein.


Hepatology | 2013

Inflammation‐induced hepatocellular carcinoma is dependent on CCR5 in mice

Neta Barashi; Ido D. Weiss; Ori Wald; Hanna Wald; Michal Abraham; Shiri Klein; Daniel Goldenberg; Jonathan H. Axelrod; Eli Pikarsky; Rinat Abramovitch; Evelyne Zeira; Eithan Galun; Amnon Peled

Human hepatocellular carcinoma (HCC) is an inflammation‐induced cancer, which is the third‐leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation‐induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)‐knockout (Mdr2‐KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2‐KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2‐KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24+ oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size. Conclusions: Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment. (Hepatology 2013;53:1021–1030)


Clinical Cancer Research | 2017

The Sphingosine-1-Phosphate Modulator FTY720 Targets Multiple Myeloma via the CXCR4/CXCL12 Pathway

Evgenia Rosenberg; Hanna Bitner; Avichai Shimoni; Merav Leiba; Maya Koren-Michowitz; Elena Ribakovsky; Shiri Klein; Devorah Olam; Lola Weiss; Hanna Wald; Michal Abraham; Eithan Galun; Amnon Peled; Arnon Nagler

Purpose: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the sphingosine-1-phosphate (S1P) pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with the FTY720 modulator as a potential anti-MM therapeutic strategy. Experimental Design and Results: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with the SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 coexpression in both cell lines and primary MM bone marrow (BM) samples, suggesting regulative cross-talk between the CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathway activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells. Conclusions: Altogether, our work identifies a cross-talk between the S1P and CXCR4 pathways in MM cells and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM. Clin Cancer Res; 23(7); 1733–47. ©2016 AACR.


Cytokine | 2018

Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies

Amnon Peled; Shiri Klein; Katia Beider; Jan A. Burger; Michal Abraham

The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1/CXCL12) are important players in the cross-talk among lymphoma, myeloma and leukemia cells and their microenvironments. In hematological malignancies and solid tumors, the overexpression of CXCR4 on the cell surface has been shown to be responsible for disease progression, increasing tumor cell survival and chemoresistance and metastasis to organs with high CXCL12 levels (e.g., lymph nodes and bone marrow (BM)). Furthermore, the overexpression of CXCR4 has been found to have prognostic significance for disease progression in many type of tumors including lymphoma, leukemia, glioma, and prostate, breast, colorectal, renal, and hepatocellular carcinomas. In leukemia, CXCR4 expression granted leukemic blasts a higher capacity to seed into BM niches, thereby protecting leukemic cells from chemotherapy-induced apoptosis, and was correlated with shorter disease-free survival. In contrast, neutralizing the interaction of CXCL12/CXCR4 with a variety of antagonists induced apoptosis and differentiation and increased the chemosensitivity of lymphoma, myeloma, and leukemia cells. The role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies and the clinical therapeutic potential of CXCR4 antagonists in these diseases is discussed.


Clinical Cancer Research | 2017

Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers

Michal Abraham; Yaron Pereg; Baruch Bulvik; Shiri Klein; Inbal Mishalian; Hanna Wald; Orly Eizenberg; Arnon Nagler; Rottem Golan; Abi Vainstein; Arnon Aharon; Eithan Galun; Yoseph Caraco; Reuven Or; Amnon Peled

Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019). Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immunodeficient mice. Results: BL-8040 was found safe and well tolerated at all doses tested (0.5–1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/μL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34+ cells/kg collected were 11.6 × 106 cells/kg. The graft composition was rich in immune cells. Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790–801. ©2017 AACR.


Cancer Research | 2017

CXCR4 promotes neuroblastoma growth and therapeutic resistance through miR-15a/16-1 mediated ERK and BCL2/cyclin D1 pathways

Shiri Klein; Michal Abraham; Baruch Bulvik; Elia Dery; Ido D. Weiss; Neta Barashi; Rinat Abramovitch; Hanna Wald; Yaniv Harel; Devorah Olam; Lola Weiss; Katia Beider; Orly Eizenberg; Ori Wald; Eithan Galun; Yaron Pereg; Amnon Peled

CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.


Gastroenterology | 2017

Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues

Chofit Chai; Mila Rivkin; Liav Berkovits; Alina Simerzin; Elina Zorde-Khvalevsky; Nofar Rosenberg; Shiri Klein; Dayana Yaish; Ronen Durst; Shoshana Shpitzen; Shiran Udi; Joseph Tam; Joerg Heeren; Anna Worthmann; Christoph Schramm; Johannes Kluwe; Revital Ravid; Eran Hornstein; Hilla Giladi; Eithan Galun


Journal of Clinical Oncology | 2017

Effect of BL-8040, high-affinity CXCR4 antagonist, on T-cell infiltration, tumor growth, and synergy with immunomodulatory agents.

Michal Abraham; Inbal Mishalian; Yaniv Harel; Shiri Klein; Yaron Pereg; Galia Oberkovitz; Hanna Wald; Orly Eizenberg; Baruch Bulvik; Abi Vainstein Haras; Arnon Aharon; Amnon Peled


Blood | 2016

The High Affinity CXCR4 Inhibitor, BL-8040, Induces Apoptosis of AML Blasts and Their Terminal Differentiation By Blocking AKT/ERK Survival Signals and Downregulating BCL-2, MCL-1 and Cyclin-D1 through Regulation of Mir-15a/16-1 Expression

Michal Abraham; Shiri Klein; Baruch Bulvik; Hanna Wald; Dvora Holam; Lola Weiss; Katia Beider; Orly Eizenberg; Ori Wald; Abraham Avigdor; Ohad Benjamini; Eithan Galun; Arnon Nagler; Yaron Pereg; Amnon Peled


Clinical Lymphoma, Myeloma & Leukemia | 2015

BL-8040, A novel CXCR4 inhibitor, affects AML blasts survival and induces their terminal differentiation

Michal Abraham; Ahmed AlRawi; Yaron Pereg; Shiri Klein; Hanna Wald; Orly Eizenberg; Baruch Bulvik; Lena Russovsky; Abi Vainstein; Arnon Aharon; Teresa McQueen; Naveen Pemmaraju; Jorge Cortes; Amnon Peled; Gautam Borthakur; Michael Andreeff


Blood | 2014

S1P Modulator FTY720 Targets Multiple Myeloma Cell Proliferation and Stromal Interactions Via CXCR4/CXCL12 and mTOR Pathways

Katia Beider; Evgenia Rosenberg; Hanna Bitner; Merav Leiba; Maya Koren-Michowitz; Michal Abraham; Shiri Klein; Hanna Wald; Avichai Shimoni; Amnon Peled; Arnon Nagler

Collaboration


Dive into the Shiri Klein's collaboration.

Top Co-Authors

Avatar

Amnon Peled

Hebrew University of Jerusalem

View shared research outputs
Top Co-Authors

Avatar

Hanna Wald

Hebrew University of Jerusalem

View shared research outputs
Top Co-Authors

Avatar

Eithan Galun

Hebrew University of Jerusalem

View shared research outputs
Top Co-Authors

Avatar

Michal Abraham

Hebrew University of Jerusalem

View shared research outputs
Top Co-Authors

Avatar

Orly Eizenberg

Weizmann Institute of Science

View shared research outputs
Top Co-Authors

Avatar

Yaron Pereg

Weizmann Institute of Science

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Baruch Bulvik

Hebrew University of Jerusalem

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Michal Abraham

Hebrew University of Jerusalem

View shared research outputs
Researchain Logo
Decentralizing Knowledge