Conversion of stationary to invasive tumor initiating cells (TICs)

Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking

Jian Li, Stanley Zucker, Ashleigh Pulkoski-Gross, Cem Kuscu, Mihriban Karaayvaz, Jingfang Ju, Herui Yao, Erwei Song, Jian Cao

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxic conditions, MT1-MMP redistributed from cytoplasmic storage pools to the cell surface of TICs, which coincides with the increased cell invasion. In addition, CD44, a cancer stem-like cell marker, inversely correlated with increased cell surface MT1-MMP. Interestingly, cell surface MT1-MMP gradually disappeared when the hypoxia-treated cells were switched to normoxia, suggesting the plasticity of TICs in response to oxygen content. Furthermore, we dissected the pathways leading to upregulated MT1-MMP in cytoplasmic storage pools under normoxic conditions, by demonstrating a cascade involving Twist1-miR10b-HoxD10 leading to enhanced MT1-MMP expression in SK-3rd TICs. These observations suggest that MT1-MMP is a key molecule capable of executing conversion of stationary TICs to invasive TICs under hypoxic conditions and thereby controlling metastasis.

Original languageEnglish (US)
Article numbere38403
JournalPloS one
Volume7
Issue number6
DOIs
StatePublished - Jun 5 2012
Externally publishedYes

Fingerprint

interstitial collagenase
Matrix Metalloproteinase 14
Cell Hypoxia
Neoplastic Stem Cells
Tumors
hypoxia
metastasis
cell invasion
anaerobic conditions
Neoplasm Metastasis
normoxia
cells
neoplasm cells
neoplasms
Cell Membrane
Breast Neoplasms
Small Interfering RNA
Plasticity
breast neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Conversion of stationary to invasive tumor initiating cells (TICs) : Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking. / Li, Jian; Zucker, Stanley; Pulkoski-Gross, Ashleigh; Kuscu, Cem; Karaayvaz, Mihriban; Ju, Jingfang; Yao, Herui; Song, Erwei; Cao, Jian.

In: PloS one, Vol. 7, No. 6, e38403, 05.06.2012.

Research output: Contribution to journalArticle

Li, Jian ; Zucker, Stanley ; Pulkoski-Gross, Ashleigh ; Kuscu, Cem ; Karaayvaz, Mihriban ; Ju, Jingfang ; Yao, Herui ; Song, Erwei ; Cao, Jian. / Conversion of stationary to invasive tumor initiating cells (TICs) : Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking. In: PloS one. 2012 ; Vol. 7, No. 6.
@article{f59a8727638840e4bc6cf3f3e546c0e7,
title = "Conversion of stationary to invasive tumor initiating cells (TICs): Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking",
abstract = "Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxic conditions, MT1-MMP redistributed from cytoplasmic storage pools to the cell surface of TICs, which coincides with the increased cell invasion. In addition, CD44, a cancer stem-like cell marker, inversely correlated with increased cell surface MT1-MMP. Interestingly, cell surface MT1-MMP gradually disappeared when the hypoxia-treated cells were switched to normoxia, suggesting the plasticity of TICs in response to oxygen content. Furthermore, we dissected the pathways leading to upregulated MT1-MMP in cytoplasmic storage pools under normoxic conditions, by demonstrating a cascade involving Twist1-miR10b-HoxD10 leading to enhanced MT1-MMP expression in SK-3rd TICs. These observations suggest that MT1-MMP is a key molecule capable of executing conversion of stationary TICs to invasive TICs under hypoxic conditions and thereby controlling metastasis.",
author = "Jian Li and Stanley Zucker and Ashleigh Pulkoski-Gross and Cem Kuscu and Mihriban Karaayvaz and Jingfang Ju and Herui Yao and Erwei Song and Jian Cao",
year = "2012",
month = "6",
day = "5",
doi = "10.1371/journal.pone.0038403",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Conversion of stationary to invasive tumor initiating cells (TICs)

T2 - Role of hypoxia in membrane type 1-matrix metalloproteinase (MT1-MMP) trafficking

AU - Li, Jian

AU - Zucker, Stanley

AU - Pulkoski-Gross, Ashleigh

AU - Kuscu, Cem

AU - Karaayvaz, Mihriban

AU - Ju, Jingfang

AU - Yao, Herui

AU - Song, Erwei

AU - Cao, Jian

PY - 2012/6/5

Y1 - 2012/6/5

N2 - Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxic conditions, MT1-MMP redistributed from cytoplasmic storage pools to the cell surface of TICs, which coincides with the increased cell invasion. In addition, CD44, a cancer stem-like cell marker, inversely correlated with increased cell surface MT1-MMP. Interestingly, cell surface MT1-MMP gradually disappeared when the hypoxia-treated cells were switched to normoxia, suggesting the plasticity of TICs in response to oxygen content. Furthermore, we dissected the pathways leading to upregulated MT1-MMP in cytoplasmic storage pools under normoxic conditions, by demonstrating a cascade involving Twist1-miR10b-HoxD10 leading to enhanced MT1-MMP expression in SK-3rd TICs. These observations suggest that MT1-MMP is a key molecule capable of executing conversion of stationary TICs to invasive TICs under hypoxic conditions and thereby controlling metastasis.

AB - Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxic conditions, MT1-MMP redistributed from cytoplasmic storage pools to the cell surface of TICs, which coincides with the increased cell invasion. In addition, CD44, a cancer stem-like cell marker, inversely correlated with increased cell surface MT1-MMP. Interestingly, cell surface MT1-MMP gradually disappeared when the hypoxia-treated cells were switched to normoxia, suggesting the plasticity of TICs in response to oxygen content. Furthermore, we dissected the pathways leading to upregulated MT1-MMP in cytoplasmic storage pools under normoxic conditions, by demonstrating a cascade involving Twist1-miR10b-HoxD10 leading to enhanced MT1-MMP expression in SK-3rd TICs. These observations suggest that MT1-MMP is a key molecule capable of executing conversion of stationary TICs to invasive TICs under hypoxic conditions and thereby controlling metastasis.

UR - http://www.scopus.com/inward/record.url?scp=84861898056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861898056&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0038403

DO - 10.1371/journal.pone.0038403

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e38403

ER -