A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells

Gargi D. Basu, Winnie S. Liang, Dietrich A. Stephan, Lee T. Wegener, Christopher R. Conley, Barbara A Pockaj, Pinku Mukherjee

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Abstract

Introduction: Cyclo-oxygenase (COX)-2 expression correlates directly with highly aggressive and metastatic breast cancer, but the mechanism underlying this correlation remains obscure. We hypothesized that invasive human breast cancer cells that over-express COX-2 have the unique ability to differentiate into extracellular-matrix-rich vascular channels, also known as vasculogenic mimicry. Vascular channels have been associated with angiogenesis without involvement of endothelial cells, and may serve as another mechanism by which tumor cells obtain nutrients to survive, especially in less vascularized regions of the tumor. Methods: To determine whether COX-2 regulates vascular channel formation, we assessed whether treatment with celecoxib (a selective COX-2 inhibitor) or silencing COX-2 synthesis by siRNA inhibits vascular channel formation by breast cancer cell lines. Cell lines were selected based on their invasive potential and COX-2 expression. Additionally, gene expression analysis was performed to identify candidate genes involved in COX-2-induced vascular channel formation. Finally, vascular channels were analyzed in surgically resected human breast cancer specimens that expressed varying levels of COX-2. Results: We found that invasive human breast cancer cells that over-express COX-2 develop vascular channels when plated on three-dimensional matigel cultures, whereas non-invasive cell lines that express low levels of COX-2 did not develop such channels. Similarly, we identified vascular channels in high-grade invasive ductal carcinoma of the breast over-expressing COX-2, but not in low-grade breast tumors. Vascular channel formation was significantly suppressed when cells were treated with celecoxib or COX-2 siRNA. Inhibition of channel formation was abrogated by addition of exogenous prostaglandin E2. In vitro results were corroborated in vivo in tumor-bearing mice treated with celecoxib. Using gene expression profiling, we identified several genes in the angiogenic and survival pathways that are engaged in vascular channel formation. Conclusion: Antivascular therapies targeting tumor cell vasculogenic mimicry may be an effective approach to the treatment of patients with highly metastatic breast cancer.

Original languageEnglish (US)
Article numberR69
JournalBreast Cancer Research
Volume8
Issue number6
DOIs
StatePublished - Dec 11 2006

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Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Blood Vessels
Breast Neoplasms
Celecoxib
Cell Line
Small Interfering RNA
Neoplasms
Carcinoma, Ductal, Breast
Cyclooxygenase Inhibitors
Gene Expression Profiling
Dinoprostone
Genes
Extracellular Matrix
Therapeutics
Endothelial Cells
Gene Expression
Food
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Basu, G. D., Liang, W. S., Stephan, D. A., Wegener, L. T., Conley, C. R., Pockaj, B. A., & Mukherjee, P. (2006). A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. Breast Cancer Research, 8(6), [R69]. https://doi.org/10.1186/bcr1626

A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. / Basu, Gargi D.; Liang, Winnie S.; Stephan, Dietrich A.; Wegener, Lee T.; Conley, Christopher R.; Pockaj, Barbara A; Mukherjee, Pinku.

In: Breast Cancer Research, Vol. 8, No. 6, R69, 11.12.2006.

Research output: Contribution to journalArticle

Basu, Gargi D. ; Liang, Winnie S. ; Stephan, Dietrich A. ; Wegener, Lee T. ; Conley, Christopher R. ; Pockaj, Barbara A ; Mukherjee, Pinku. / A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells. In: Breast Cancer Research. 2006 ; Vol. 8, No. 6.
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AB - Introduction: Cyclo-oxygenase (COX)-2 expression correlates directly with highly aggressive and metastatic breast cancer, but the mechanism underlying this correlation remains obscure. We hypothesized that invasive human breast cancer cells that over-express COX-2 have the unique ability to differentiate into extracellular-matrix-rich vascular channels, also known as vasculogenic mimicry. Vascular channels have been associated with angiogenesis without involvement of endothelial cells, and may serve as another mechanism by which tumor cells obtain nutrients to survive, especially in less vascularized regions of the tumor. Methods: To determine whether COX-2 regulates vascular channel formation, we assessed whether treatment with celecoxib (a selective COX-2 inhibitor) or silencing COX-2 synthesis by siRNA inhibits vascular channel formation by breast cancer cell lines. Cell lines were selected based on their invasive potential and COX-2 expression. Additionally, gene expression analysis was performed to identify candidate genes involved in COX-2-induced vascular channel formation. Finally, vascular channels were analyzed in surgically resected human breast cancer specimens that expressed varying levels of COX-2. Results: We found that invasive human breast cancer cells that over-express COX-2 develop vascular channels when plated on three-dimensional matigel cultures, whereas non-invasive cell lines that express low levels of COX-2 did not develop such channels. Similarly, we identified vascular channels in high-grade invasive ductal carcinoma of the breast over-expressing COX-2, but not in low-grade breast tumors. Vascular channel formation was significantly suppressed when cells were treated with celecoxib or COX-2 siRNA. Inhibition of channel formation was abrogated by addition of exogenous prostaglandin E2. In vitro results were corroborated in vivo in tumor-bearing mice treated with celecoxib. Using gene expression profiling, we identified several genes in the angiogenic and survival pathways that are engaged in vascular channel formation. Conclusion: Antivascular therapies targeting tumor cell vasculogenic mimicry may be an effective approach to the treatment of patients with highly metastatic breast cancer.

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