Nachwuchsgruppe Dr. rer. nat. Irina Nazarenko

Exosomen, Stammzellen und Tumorprogression 

Tumorzellen nutzen natürliche Wege der interzellulären Kommunikation und verändern dadurch systemische Prozesse des Körpers zu eigenem Nutzen. Induktion der Entzündungsprozesse, Immunschwäche, Verbrauchskoagulopathie sind einige Beispiele dieser Wirkung. Außerdem spielt die interzelluläre Kommunikation für die Absiedlung der Tumore in entfernten Organen, genannt Metastasierung, eine wichtige Rolle.

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Wir erforschen einen besonderen Typ der interzellulären Kommunikation mittels sogenannter Mikrovesikel (Exosomen). Es sind Membranvesikel, die wie eine Art "Message in the Bottle" fungieren. Sie werden von Zellen freigesetzt und transportieren mit dem Blutstrom über den Gesamtkörper Signalmoleküle: Proteine und Nukleinsäure zu entfernt-liegenden Organen.

Mittlerweile ist es anerkannt, dass Tumore eine erhöhte Menger der Mikrovesikel produzieren. Sie aktivieren Neubildung der Blutgefäße, sind an der Metastasierung und Regulation des Immunsystems beteiligt. Das Ziel unserer Forschung ist die Mechanismen dieser Kommunikation zu entschlüsseln und basierend darauf neue Strategien für Krebsdiagnostik und Therapie zu entwickeln.

 

Ein der Projekte beschäftig sich mit der Rolle von Exosomen und von anderen Typen der extrazellulären Vesikel in der Regulation von Stamm- und Vorläuferzellen unter physiologischen (während Embryogenese) und pathologischen (in verschiedenen Stadien der Tumorprogression) Bedingungen. 

Grundlegende Mechanismen der Exosomenfunktion: Regulation der Aufnahme bestimmter Proteine, mRNA, miRNA und DNA in die Exosomen, Freisetzung, Reichweite und Verteilung im Körper, Interaktion mit Zielzellen und schließlich die lokalen und systemische Effekte der Exosomen sind weitere Forschungsfragen, die wir in Kooperation mit interdisziplinären Teams angehen. Teil dieser Projekte sind integriert in BiF (Biointerfaces Programm) und KNMF (Karlsruhe Nano Micro Faculty) Programme des KIT. 

 

Presse und Preise

Curt Meyer-Gedächtnispreis 2008 von Berliner Krebsgesellschaft
für Dr. rer.nat Irina Nazarenko
Titel of the Work: "Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells"

 

 

Science Editor`s Choice 10-Apr-2007 Apoptosis The Mechanism of Action of the Tumor Suppressor HRSL3 

 

Public release 5-Oct-2006 A  tumor suppressor that promotes cancer cell growth? EurekAlert

 

 

 Unsere Forschung wird unterstützt:

 

Nachwuchsgruppe Dr. rer. nat. Irina Nazarenko

Exosomes are extracellular nanovesicles produced by various types of cells. We know that exosomes are vesicles with a diameter of 40-100 nm derived from the endosomal compartment and are released upon exocytotic fusion of multivesicular bodies with the plasma membrane.
They assure a lateral transfer of signalling proteins and RNA species over long distances and are involved in many physiological and pathological processes1. Increasing evidence suggests a pivotal role for exosomes in tumourigenesis, for example in the horizontal propagation of oncogenes between tumour cells and in the cross-talk between the malignant tissue and its microenvironment. Furthermore, tumour-associated systemic effects such as immunosuppression, induction of angiogenesis and thrombosis, and possibly the formation of a pre-metastatic niche, are thought to be mediated by tumour-derived exosomes2.

 

 

Atomic Forse Microscopy (Cooperation with Clemens Franz, CFN, KIT)

Despite the evidence implicating exosomes in manifold physiological and pathological processes, the mechanisms of their functions are still far from understanding. We are interested in several aspects of the exosomes action such as regulation of their specificity toward different cell types, or temporal and spatial resolution of their function in vivo. Contribution of exosomes to tumour progression is one of the central questions of our research.
Our recent findings and works of other groups indicated that not only mature host cells, but also bone marrow-derived and tissue-resident stem and progenitor cells are regulated by exosomes derived from tumour cells2,3,4. In view of the emerging evidences supporting a contribution of stem cells to tumour progression, this observation is particularly important and is further investigated in different tumour models in vivo and in vitro.

 

 

Primary tumours produce growth factors, cytokines, exosomes and other types of vesicles, which are distributed with the blood stream to different organs and contribute to the activation of stem and progenitor cells in the bone marrow and potentially tissue resident progenitors. Activated stem cells can be recruited in to the blood stream and migrate to the sites of primary tumour and so called pre-metastatic niches, contributing herewith to the different aspects of tumour progression such as growth and vascularization of primary tumour, tumour cells dissemination and metastatic spread.

 


Literature

1. Burnier,L., Fontana,P., Kwak,B.R. & Angelillo-Scherrer,A. Cell-derived microparticles in haemostasis and vascular medicine. Thromb. Haemost. 101, 439-451 (2009).
2. Nazarenko I et al. Molecular pathways of exosome-induced regulation of endothelial cells and the contribution of the tetraspanin Tspan8. Cancer Research. Accepted 2009.
3. Baj-Krzyworzeka,M. et al. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp. Hematol. 30, 450-459 (2002).
4. Xiang,X. et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int. J. Cancer 124, 2621-2633 (2009).
   

 

Nachwuchsgruppe Dr. rer. nat. Irina Nazarenko

 

Do all roads lead to Rome? Routes to metastasis development. Sleeman J. Nazarenko I. Thiele W. Int. J. of Cancer (accepted)

 

2010

Activation-induced internalization differs for the tetraspanins CD9 and Tspan8: Impact on tumor cell motility.

Rana S, Claas C, Kretz CC, Nazarenko I, Zoeller M.Int J Biochem Cell Biol. 2010 Oct 16. [Epub ahead of print]

 

Atypical PKCzeta exhibits a proapoptotic function in ovarian cancer.

Nazarenko I*, Jenny M, Keil J,Gieseler C, Weisshaupt K, Sehouli J, Legewie S, Herbst L, Weichert W, Darb-Esfahani S, Dietel M, Schafer R, Ueberall F, Sers C. Mol Cancer Res. 2010 Jun; 8(6):919-34 (IF 5.20).

 

Cell Surface Tetraspanin Tspan8 Contributes to Molecular Pathways of Exosome-Induced Endothelial Cell Activation.

Nazarenko I*, Rana S, Baumann A., McAlear J., Hellwig A, Trendelenburg M, Lochnit G., Preissner KT., Zöller M.Cancer Res. 2010 Feb 15;70(4):1668-78. Epub 2010 Feb 2. (IF 7.98)

 

2008

CD44 and EpCAM: Cancer-Initiating Cell Markers. 

Marhaba R, Klingbeil P, Nuebel T, Nazarenko I, Buechler MW, Zoeller M. Curr Mol Med. 2008 Dec;8(8):784-804.

 

Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction.

Marhaba R*, Nazarenko I*, Knoefler D, Reich E, Voronov E, Vitacolonna M, Hilderbrand D, Elter E, Apte R, Zoller M. Int J Cancer. 2008 Jul 1;123(1):134-45. (* Authors with equal contribution) (IF 4.66)

 

Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.

Nazarenko I*, Marhaba R*, Reich E, Voronov E, Vitacolonna M, Hildebrand D, Elter E, Rajasagi M, Apte RN, Zoller M.  Neoplasia. 2008 Jun;10(6):549-62. (* Authors with equal contribution) (IF 5.19)

 

2007

CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene.

Fries F, Nazarenko I, Hess J, Claas A, Angel P, Zoller M. Int J Cancer. 2007 May 15;120 (10):2135-47. (IF 4.66)

 

Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells.

Nazarenko I, Schafer R, Sers C. J Cell Sci. 2007 Apr 15;120(Pt 8):1393-404. (IF 6.25)

 

Impact of {alpha}1-adrenoceptor expression on contractile properties of vascular smooth muscle cells.

Gericke A, Martinka P, Nazarenko I, Persson PB, Patzak A. Am J Physiol Regul Integr Comp Physiol. 2007 Jun 6. (IF 3.27)

 

Geranylgeranylation but not GTP-loading determines Rho migratory-function in T cells.

Waiczies S, Bendix I, Prozorovski T, Ratner M, Nazarenko I, Pfueller CF, Brandt AU, Herz J, Brocke S, Ullrich O, Zipp F. J Immunol. 2007 Nov 1;179(9):6024-32 (IF 6.17)

 

2002-2006

H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling.

Nazarenko I, Kristiansen G, Fonfara S, Guenther R, Gieseler C, Kemmner W, Schafer R, Petersen I, Sers C. Am J Pathol. 2006 Oct;169(4):1427-39. (IF 6.2)

 

Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen-activated kinase-dependent and -independent mechanisms.

Lotz K, Kellner T, Heitmann M, Nazarenko I, Noske A, Malek A, Gontarewicz A, Schafer R, Sers C.  Int J Cancer. 2005 Oct 10;116(6):894-902. (IF 4.66)

 

The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNgamma-induced cell death in human ovarian carcinoma cells.

Sers C, Husmann K, Nazarenko I, Reich S, Wiechen K, Zhumabayeva B, Adhikari P, Schroder K, Gontarewicz A, Schafer R. Oncogene. 2002 Apr 25;21(18):2829-39. (IF 7.22)