Oncotarget

Research Papers:

Ki-67 is required for maintenance of cancer stem cells but not cell proliferation

Justin Cidado, Hong Yuen Wong, D. Marc Rosen, Ashley Cimino-Mathews, Joseph P. Garay, Abigail G. Fessler, Zeshaan A. Rasheed, Jessica Hicks, Rory L. Cochran, Sarah Croessmann, Daniel J. Zabransky, Morassa Mohseni, Julia A. Beaver, David Chu, Karen Cravero, Eric S. Christenson, Arielle Medford, Austin Mattox, Angelo M. De Marzo, Pedram Argani, Ajay Chawla, Paula J. Hurley, Josh Lauring and Ben Ho Park _

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Oncotarget. 2016; 7:6281-6293. https://doi.org/10.18632/oncotarget.7057

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Abstract

Justin Cidado1,5, Hong Yuen Wong1, D. Marc Rosen1, Ashley Cimino-Mathews1, Joseph P. Garay1, Abigail G. Fessler1, Zeshaan A. Rasheed1, Jessica Hicks1, Rory L. Cochran1, Sarah Croessmann1, Daniel J. Zabransky1, Morassa Mohseni1,6, Julia A. Beaver1, David Chu1, Karen Cravero1, Eric S. Christenson1, Arielle Medford1, Austin Mattox1, Angelo M. De Marzo1, Pedram Argani1, Ajay Chawla2,3, Paula J. Hurley1, Josh Lauring1 and Ben Ho Park1,4

1 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

2 Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

3 Departments of Physiology and Medicine, University of California San Francisco, San Francisco, CA, USA

4 The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA

5 Present address: Oncology iMED, AstraZeneca, Waltham, MA, USA

6 Present address: Roche Sequencing, San Jose, CA, USA

Correspondence to:

Ben Ho Park, email:

Keywords: Ki-67, cancer stem cells, proliferation, clonogenicity, tumorigenicity

Received: December 18, 2015 Accepted: January 05, 2016 Published: January 28, 2016

Abstract

Ki-67 expression is correlated with cell proliferation and is a prognostic marker for various cancers; however, its function is unknown. Here we demonstrate that genetic disruption of Ki-67 in human epithelial breast and colon cancer cells depletes the cancer stem cell niche. Ki-67 null cells had a proliferative disadvantage compared to wildtype controls in colony formation assays and displayed increased sensitivity to various chemotherapies. Ki-67 null cancer cells showed decreased and delayed tumor formation in xenograft assays, which was associated with a reduction in cancer stem cell markers. Immunohistochemical analyses of human breast cancers revealed that Ki-67 expression is maintained at equivalent or greater levels in metastatic sites of disease compared to matched primary tumors, suggesting that maintenance of Ki-67 expression is associated with metastatic/clonogenic potential. These results elucidate Ki-67’s role in maintaining the cancer stem cell niche, which has potential diagnostic and therapeutic implications for human malignancies.


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