CANCER STEM CELL RESEARCH LABORATORY
Director: Galina Botchkina, PhD.
Key Words: Cancer; Stem cells; Colon Carcinoma; Prostate Carcinoma; Genomics; Anti-Cancer Drug Development; Establishment of CSC lines; Single-Cell Array Methodology.
During the last six decades, cancer has moved from the category of invariably fatal to the category of chronic diseases. However, advanced metastatic epithelial cancers remain to be incurable by mainstream treatment modalities. This failure was attributed to the existence of rare, highly drug- and radiation-resistant cells within the tumor. This hypothesis was firmly confirmed by the recent discovery of tumor-initiating cells with stem-like properties, called cancer stem cells (CSCs), in all major types of human cancers and, importantly, in undisturbed tumors. This discovery has dramatically improved our understanding of tumor development and made clear the necessity to develop novel effective therapies targeting these exceptionally resistant cells. The CSC-focused research and CSC-targeted drug development is widely accepted now as a new concept of carcinogenesis and new paradigm of cancer treatment strategies.
Current research in my laboratory is focused on studying the prostate and colon tumor-initiating cells, establishment of CSC cell lines and CSC-targeted drug development based on 3D and single-cell array methodologies. We have established the two CSC-enriched spontaneously immortalized cell lines, obtained their biologic and genomic characteristics, and developed 3D in vitro CSC single-cell array-based culture systems. These systems are more relevant both clinically and physiologically. We investigate CSC-targeted activities of several new-generation taxoids against prostate and colon CSCs. We have identified several members of this family which significantly affect a stemness state of the prostate and colon CSCs ( Botchkina et al., 2010 ). Our experience in stem cell research and accumulated data allow for fruitful collaboration on many aspects of tumor and stem cell biology.
I. Cancer Stem Cells
We have identified several candidate phenotypic populations of the tumor-initiating cells and obtained their genome-wide and pathway-specific characteristics (Rowehl et al., 2008; Botchkina et al., 09; Song et al., 09; Botchkina et al., 2010). We have developed 3D in vitro CSC culture systems, including the single-cell array-based methodology (Botchkina et al., 2015), which are more clinically and physiologically relevant. We have established the two CSC-enriched spontaneously immortalized cell lines ((Rowehl et al., 2014; Botchkina et al., 2013). Our experience in stem cell research and accumulated data allow for fruitful collaboration on many aspects of the tumor and stem cell biology.
II. CSC-Targeted Drug Development
We investigate CSC-targeted activities of several new-generation taxoids against prostate and colon CSCs. We have identified several members of this family which significantly affect a stemness state of the prostate and colon CSCs (Botchkina et al., 2010; 2013; 2015).
III. Development of the Bench-top Instruments for Early Cancer Detection
My long-term collaboration with the Department of Electrical & Computer Engineering, Sensor CAT and BioPhotonics Inc. resulted in the development of the two novel technologies for early cancer detection and analysis, the SBU Telomerase Analyzer and the Integrated Real-Time PCR/Capillary Electrophoresis System funded by two NIH SBIR/STTR ( R42CA106193-04 and R43CA113188-01) and 3 NYSTAR grants.
IV. Mathematic modeling of the stem cell proliferation and responses to drugs
In collaboration with the Department of Electrical & Computer Engineering, we are working on mathematical modeling of stem cell proliferation, signal processing, and responses to drugs (Bugallo M et al. (2011) A stochastic compartmental approach to modeling and simulation of cancer spheroid formation and evolution. ICASSP, 6000-6003. Bugallo MF et al. (2010) A stochastic model of proliferation of cancer stem cells and its estimation by particle filtering. ICASSP, 529-533.)
V. Development of Single-Cell Array-Based Methodology
In collaboration with the JS Celom Center (Bar Ilan University, Israel), we have developed the innovative tools: micro-chamber arrays (MCAs)for single-cell-based protracted cell culturing and drug-response screening (Botchkina et al, 2015). Two proposals (DOD PCRP and NIH R21) are pending
1. Botchkina GI, Zurgil N, Afrimzon E, Shafran Y, Sobolev M, Ravid-Hermesh O, Deutsch M. Novel live cell array-based methodology for multiplex single cell analyses of tumor heterogeneity and differential drug responses in 3D and monolayer cell cultures. Biomaterials 2015 (submitted).
2. Botchkina GI. Cancer Stem Cells Targeted Drug Development. Encyclopedia of Cancer (2015) Springer-Verlag Berlin Heidelberg 2014; DOI 10.1007/978-3-642-27841-9_7162-4
3. Rowehl RA, Burke S, Bialkowska BA,Pettet DW III, Rowehl L, Li E, Antoniou E, Zhang Y, Bergamaschi R, Shroyer KR, Ojima I and Botchkina GI. (2014) Establishment of Highly Tumorigenic Human Colorectal Cancer Cell Line (CR4) with Properties of Putative Cancer Stem Cells. PLoS ONE 9(6): e99091. doi:10.1371/journal.pone.0099091
4. Botchkina GI, Zuniga ES, Rowehl RH,Park R, Bhalla R, Bialkowska AB, Zhang Y, Johnson F, Golub LM, Ojima I, and Shroyer KR. (2013) Prostate Cancer Stem Cell-Targeted Efficacy of a New-Generation Taxoid,SBT-1214 and Novel Polyenolic Zinc-Binding Curcuminoid, CMC2.24. PLoS ONE 8(9): e69884. doi:10.1371/journal.pone.0069884
5. Botchkina GI. (2012)Colon Cancer Stem Cells: From Basic to Clinical Application. (Invited Review) Cancer Letters; Special Issue: Cancer Stem Cells 10.1016/j.canlet.2012.04.006, ISSN: 03043835.
6. Botchkina GI & Ojima I. (2011) Prostate and colon cancer stem cells as a target for anti-cancer drug development. Invited Chapter in the book “ Cancer Stem Cells”, InTech Open Access Publisher, Vienna, Austria, ISBN: 978-953-307-225-8.
7. BotchkinaGI, Wang Y, Savitt AG, Rowehl RA, Leyfman L, Wang H, Zhu S, Ju J and Ojima I. (2010)New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in three-dimensional cancer spheroids induced by two phenotypic subpopulations of colon tumor-initiating cells. Molecular Cancer, 9: 192-204.
Galina I. Botchkina
Associate Professor of Pathology