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FINDING AND VALIDATING MOLECULAR TARGETS IN GASTRIC TUMOR STEM CELLS FOR DEVELOPMENT OF NOVEL ANTI-CANCER THERAPEUTIC STRATEGIES.

Program: Resurse Umane
Project code: TE-100/2010
Funds: UEFISCSU
Project’s length: 36 months (August 2010 – July 2013)
Host institution: Stefan S. Nicolau Institute of Virology (www.virology.ro)
Address: Mihai Bravu 285 Ave., sector 3, Bucharest, Romania; tel/fax: 021 3242590
Project director: Dr. Mihaela CHIVU ECONOMESCU, CSIII
e-mail: mihaela.chivu@gmail.com; mihaela.chivu@virology.ro

 

Year TOTAL (lei)
2010 110000
2011 225000
2012 252000
2013 148000
TOTAL (lei) 735000


Budget: 750.000 lei

Summary of the project

Cellular heterogeneity, present in most solid tumors, represents an enormous challenge for cancer eradication. Present strategies for inducing cell death usually target only the most rapidly proliferating cells within a tumor, and are unable to destroy tumor stem cells that are more resistant to standard chemotherapeutic agents and have the ability to regenerate the tumor. It became increasingly obvious that it is necessary to develop strategies targeted to the mechanisms of survival and regeneration characteristics of tumor stem cells.

 

A recent study published in 2009,  which identify gastric tumor stem cells (gtsc) based on surface antigen cd44, opens new directions for the
management of gastric carcinoma, disease that is the second cause of death worldwide (700,000 deaths/year worldwide ; 17/6.6 m / f deaths/100000 people/year in Romania).

 

Given the opportunity to identify and isolate gtsc, and our laboratory experience in the field of stem cells and anti-tumor therapy, we intend to use small interferece rna technology to specifically inhibit certain genes overexpresed in gastric cancer which can be promoters of processes such as: cell proliferation, interaction with the matrix, motility, metastasis, angiogenesis.
 

Bibliography:
Al-Hajj M, Wicha M S, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983-3988.
Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
Chen T, Deng C. Inhibitory effect of siRNA targeting survivin in gastric cancer MGC-803 cells. Int Immunopharmacol. 2008;8(7):1006-11.
Hannon GJ, Rossi JJ.  Unlocking the potential of the human genome with RNA interference. Nature 2004; 431: 371–8
Houghton J, Stoicov C, et al. Goldenring JR, Wang TC. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306: 1568–1571.
Quante M, Wang TC. Inflammation and stem cells in gastrointestinal carcinogenesis, Physiology, 2008; 23: 350–359.
Lei XY, Zhong M, et al. Silencing of Bcl-XL expression in human MGC-803 gastric cancer cells by siRNA. Acta Biochim Biophys Sin. 2005; 37(8):555-60.
Li C, Heidt D G, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67:1030-1037
Pai SI, Lin YY, et al. Prospects of RNA interference therapy for cancer. Gene Ther 2006; 13: 464–77
Parkin DM, Bray F, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55(2):74-108
Singh S K, Clarke I D, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63:5821-5828.
Singh S K, Hawkins C, et al. Identification of human brain tumour initiating cells. Nature 2004; 432:396-401.
Takaishi S, Okumura T, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27(5):1006-20.
Valean S, Armean P,  et al. Cancer Mortality in Romania, 1955-2004. J Gastrointestin Liver Dis.,  2008;17(1):9-14.
Zhu H, Mitsuhashi N, et al. The role of the hyaluronan receptor CD44 in mesenchymal stem cell migration in the extracellular matrix. Stem Cells. 2006 Apr; 24(4):928-35.
Wang Q, Huang Y, et al. siRNA targeting midkine inhibits gastric cancer cells growth and induces apoptosis involved caspase-3,8,9 activation and mitochondrial depolarization. J Biomed Sci. 2007;14(6):783-95.


Project objectives
1. Identification, isolation and characterization gtsc. Testing their tumoral capacity on  immunodeficient animal models
2. Identification of molecular targets by testing gene expression in the gtsc, and selection of genes significantly modified
3. Specific inhibition of selected gene expression using sirna methodology
4. Analysis of molecular target therapy-induced effects on gtsc functionality.


Working plan
Phase I (15 August 2010 – 10 December 2010)
Objective: Identification, isolation and characterization of stem cells in gastric tumor cell lines and primary cultures of gastric adenocarcinoma.
Budget: 110.000 lei
Results:
Selection protocol for gastric tumor stem cells isolation.
Considerations on the performances of the proposed selection method.
An original article accepted for publication in Hepato-Gastroenterology.

Phase II (16 December 2010 – 30 November 2011)
Objective 1: Testing tumorigenic capacity of isolated gastric tumor stem cells in immunodeficient animal models.
Objective 2: Identification of molecular targets by testing gene expression in gastric tumor stem cells, and selection of genes significantly
dysregulated.
Budget: 225.000 lei

Phase III (1 December 2011 – 30 November 2012)
Objective 1: Specific inhibation of target gene expression using siRNA technology.
Objective 2: In vitro analysis of molecular target therapy effects on the functionality of gastric tumor stem cells.
Budget: 252.000 lei

Phase IV (1 December 2012 – 15 July2013)
Objective 1: In vivo analysis of molecular target therapy effects on the functionality of gastric tumor stem cells.
Objective 2: Final analysis of results and conclusions.
Budget: 148.000 lei

The research team
Mihaela CHIVU ECONOMESCU, PhD
Drd. Laura G. NECULA, PhD St
Drd. Denisa Laura DRAGU, PhD St
Cosmin Ilie STANCU, MD



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