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; Ben Ho Park

doi:10.18632/oncotarget.7057

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 ArganiAjay Chawla, Paula J. Hurley, Josh Lauring, Ben Ho Park

School of Medicine

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English (US)
Pages (from-to)	6281-6293
Number of pages	13
Journal	Oncotarget
Volume	7
Issue number	5
DOIs	https://doi.org/10.18632/oncotarget.7057
State	Published - 2016

Keywords

Cancer stem cells
Clonogenicity
Ki-67
Proliferation
Tumorigenicity

ASJC Scopus subject areas

Oncology

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Cidado, J., Wong, H. Y., Marc Rosen, D., Cimino-Mathews, A., Garay, J. P., Fessler, A. G., Rasheed, Z. A., Hicks, J., Cochran, R. L., Croessmann, S., Zabransky, D. J., Mohseni, M., Beaver, J. A., Chu, D., Cravero, K., Christenson, E. S., Medford, A., Mattox, A., De Marzo, A. M., ... Park, B. H. (2016). Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget, 7(5), 6281-6293. https://doi.org/10.18632/oncotarget.7057

Cidado, J, Wong, HY, Marc Rosen, D, Cimino-Mathews, A, Garay, JP, Fessler, AG, Rasheed, ZA, Hicks, J, Cochran, RL, Croessmann, S, Zabransky, DJ, Mohseni, M, Beaver, JA, Chu, D, Cravero, K, Christenson, ES, Medford, A, Mattox, A, De Marzo, AM , Argani, P, Chawla, A, Hurley, PJ, Lauring, J & Park, BH 2016, 'Ki-67 is required for maintenance of cancer stem cells but not cell proliferation', Oncotarget, vol. 7, no. 5, pp. 6281-6293. https://doi.org/10.18632/oncotarget.7057

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title = "Ki-67 is required for maintenance of cancer stem cells but not cell proliferation",

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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AU - Cidado, Justin

AU - Wong, Hong Yuen

AU - Marc Rosen, D.

AU - Cimino-Mathews, Ashley

AU - Garay, Joseph P.

AU - Fessler, Abigail G.

AU - Rasheed, Zeshaan A.

AU - Hicks, Jessica

AU - Cochran, Rory L.

AU - Croessmann, Sarah

AU - Zabransky, Daniel J.

AU - Mohseni, Morassa

AU - Beaver, Julia A.

AU - Chu, David

AU - Cravero, Karen

AU - Christenson, Eric S.

AU - Medford, Arielle

AU - Mattox, Austin

AU - De Marzo, Angelo M.

AU - Argani, Pedram

AU - Chawla, Ajay

AU - Hurley, Paula J.

AU - Lauring, Josh

AU - Park, Ben Ho

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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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KW - Clonogenicity

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KW - Proliferation

KW - Tumorigenicity

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

Abstract

Keywords

ASJC Scopus subject areas

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