Subscribe to RSS
Tumor Recurrence and Drug Resistance Properties of Side Population Cells in High Grade Ovary Cancer
received 18 March 2014
accepted 10 April 2014
11 December 2014 (online)
Introduction: The presence of subset of cancer stem cells (CSCs) called “Side population” (SP) cells has been identified in several solid tumors, responsible for treatment failure especially chemotherapy, and cancer relapse. The present study was aimed to isolate and characterize cancer stem like cells side population cells from high grade ovarian cancer.
Methods: The collected cancer samples were analyzed for presence of SP cells by FACS using Hoechst 33342 exclusion technique. Further the FACS sorted SP and non-SP cells were subjected to analysis of stem cell surface protein expression by western blot and immunocytochemistry, drug resistance and sphere formation assay.
Results: By FACS, we have identified 3.7% of cancer stem cell like side population cells in ovarian cancer whose prevalence was reduced to 0.5% upon treatment with verapamil an inhibitor of ABC transporter. Further, these sorted SP cells showed over expression of ABCG2 (ABC transporter), stem cell proteins such as CD144, CD44, EpCAM and antiapoptotic factor Bcl-2. Also the SP cells showed high resistance to chemotherapy drugs, have high survival rate and they are highly potential to form tumor spheres.
Conclusion: Our data suggest that ovarian cancer contain small sub-population of side population cells which shares some characteristics of stem cells. The co-expression of ABC transporters and stem cells surface markers in SP cells may associate with resistance to chemotherapeutic agents, apoptosis and also supports a role for these cells in tumor recurrence, metastasis and invasion.
* These authors contributed equally to this work.
- 1 Lengyel E. Ovarian cancer development and metastasis. Am J Pathol 2010; 177: 1053-1064
- 2 Kurman RJ, Shih I. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer – shifting the paradigm. Hum Pathol 2011; 42: 918-931
- 3 Kurman RJ, Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34: 433-443
- 4 Cannistra SA. Cancer of the ovary. N Eng J Med 2004; 351: 2519-2529
- 5 Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer 2005; 15: 3-11
- 6 Challen GA, Little MH. A side order of stem cells: the SP phenotype. Stem Cells 2006; 24: 3-12
- 7 Ramachandran C, Melnick SJ. Multidrug resistance in human tumors molecular diagnosis and clinical significance. Mol Diagn 1999; 4: 81-94
- 8 Ford JM, Hait WN. Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 1990; 42: 155-199
- 9 Sánchez-García I, Vicente-Dueñas C, Cobaleda C. The theoretical basis of cancer-stem-cell-based therapeutics of cancer: can it be put into practice?. Bioessays 2007; 29: 1269-1280
- 10 Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 2004; 101: 781-786
- 11 Hirschmann-Jax C, Foster AE, Wulf GG et al. A distinct side population of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad USA 2004; 101: 14228-14233
- 12 He QZ, Luo XZ, Wang K et al. Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas. Cell Physiol Biochem 2014; 33: 173-184
- 13 Yanamoto S, Kawasaki G, Yamada S et al. Isolation and characterization of cancer stem-like side population cells in human oral cancer cells. Oral Oncol 2011; 47: 855-860
- 14 Baccelli I, Trumpp A. The evolving concept of cancer and metastasis stem cells. J Cell Biol 2012; 198: 281-293
- 15 Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011; 17: 313-319
- 16 Patrawala L, Calhoun T, Schneider-Broussard R et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 2005; 65: 6207-6219
- 17 Robey RW, Shukla S, Finley EM et al. Inhibition of Pgp (ABCB1) and MDR associated protein-1 (ABCC1) mediate transport by the orally administered inhibitor CBT-1. Biochemical Pharmacol 2008; 75: 1032-1042
- 18 Tirino V, Desiderio V, Paino F et al. Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. Faseb J 2013; 27: 13-24
- 19 Baba T, Convery PA, Matsumura N et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 2009; 28: 209-218
- 20 Silva IA, Bai S, McLean K et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 2011; 71: 3991-4001
- 21 Yanamoto S, Kawasaki G, Yoshitomi I et al. Clinicopathologic significance of EpCAM expression in squamous cell carcinoma of the tongue and its possibility as a potential target for tongue cancer gene therapy. Oral Oncol 2007; 43: 869-877