CD24+ Ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis

Daniela Burgos-Ojeda, Rong Wu, Karen McLean, Yu Chih Chen, Moshe Talpaz, Euisik Yoon, Kathleen R. Cho, Ronald J. Buckanovich

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere-forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells versus CD24- cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared with CD24- cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

Original languageEnglish
Pages (from-to)1717-1727
Number of pages11
JournalMolecular Cancer Therapeutics
Volume14
Issue number7
DOIs
Publication statusPublished - 2015 Jul 1

Fingerprint

Ovarian Neoplasms
Neoplasm Metastasis
Growth
Neoplasms
Phosphorylation
Population
Stem Cells
Epithelium

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Burgos-Ojeda, Daniela ; Wu, Rong ; McLean, Karen ; Chen, Yu Chih ; Talpaz, Moshe ; Yoon, Euisik ; Cho, Kathleen R. ; Buckanovich, Ronald J. / CD24+ Ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 7. pp. 1717-1727.
@article{8c6611558cd34fae9589332ed5f309b4,
title = "CD24+ Ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis",
abstract = "Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere-forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells versus CD24- cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared with CD24- cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.",
author = "Daniela Burgos-Ojeda and Rong Wu and Karen McLean and Chen, {Yu Chih} and Moshe Talpaz and Euisik Yoon and Cho, {Kathleen R.} and Buckanovich, {Ronald J.}",
year = "2015",
month = "7",
day = "1",
doi = "10.1158/1535-7163.MCT-14-0607",
language = "English",
volume = "14",
pages = "1717--1727",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

CD24+ Ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis. / Burgos-Ojeda, Daniela; Wu, Rong; McLean, Karen; Chen, Yu Chih; Talpaz, Moshe; Yoon, Euisik; Cho, Kathleen R.; Buckanovich, Ronald J.

In: Molecular Cancer Therapeutics, Vol. 14, No. 7, 01.07.2015, p. 1717-1727.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CD24+ Ovarian cancer cells are enriched for cancer-initiating cells and dependent on JAK2 signaling for growth and metastasis

AU - Burgos-Ojeda, Daniela

AU - Wu, Rong

AU - McLean, Karen

AU - Chen, Yu Chih

AU - Talpaz, Moshe

AU - Yoon, Euisik

AU - Cho, Kathleen R.

AU - Buckanovich, Ronald J.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere-forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells versus CD24- cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared with CD24- cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

AB - Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, interpatient variability, and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high-grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers, including CD24, CD44, CD90, CD117, CD133, and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere-forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells versus CD24- cells had significantly greater tumor initiation and tumor growth capacity. No preferential tumor-initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared with CD24- cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

UR - http://www.scopus.com/inward/record.url?scp=84942112364&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942112364&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-14-0607

DO - 10.1158/1535-7163.MCT-14-0607

M3 - Article

C2 - 25969154

AN - SCOPUS:84942112364

VL - 14

SP - 1717

EP - 1727

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -