Research Papers:

Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts

Balaji Krishnamachary, Ioannis Stasinopoulos, Samata Kakkad, Marie-France Penet, Desmond Jacob, Flonne Wildes, Yelena Mironchik, Arvind P. Pathak, Meiyappan Solaiyappan and Zaver M. Bhujwalla _

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Oncotarget. 2017; 8:17981-17994. https://doi.org/10.18632/oncotarget.14912

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Balaji Krishnamachary1,*, Ioannis Stasinopoulos1,*, Samata Kakkad1, Marie-France Penet1,2, Desmond Jacob1, Flonne Wildes1, Yelena Mironchik1, Arvind P. Pathak1,2, Meiyappan Solaiyappan1, Zaver M. Bhujwalla1,2

1JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD 21205, USA

2Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

*These authors have contributed equally to this work

Correspondence to:

Zaver M. Bhujwalla, email: [email protected]

Keywords: COX-2, cancer associated fibroblasts, collagen 1 fibers, macromolecular transport, metastasis

Received: August 04, 2016    Accepted: December 27, 2016    Published: January 31, 2017


Cyclooxygenase-2 (COX-2) is a critically important mediator of inflammation that significantly influences tumor angiogenesis, invasion, and metastasis. We investigated the role of COX-2 expressed by triple negative breast cancer cells in altering the structure and function of the extracellular matrix (ECM). COX-2 downregulation effects on ECM structure and function were investigated using magnetic resonance imaging (MRI) and second harmonic generation (SHG) microscopy of tumors derived from triple negative MDA-MB-231 breast cancer cells, and a derived clone stably expressing a short hairpin (shRNA) molecule downregulating COX-2. MRI of albumin-GdDTPA was used to characterize macromolecular fluid transport in vivo and SHG microscopy was used to quantify collagen 1 (Col1) fiber morphology. COX-2 downregulation decreased Col1 fiber density and altered macromolecular fluid transport. Immunohistochemistry identified significantly fewer activated cancer associated fibroblasts (CAFs) in low COX-2 expressing tumors. Metastatic lung nodules established by COX-2 downregulated cells were infrequent, smaller, and contained fewer Col1 fibers.

COX-2 overexpression studies were performed with tumors derived from triple negative SUM-149 breast cancer cells lentivirally transduced to overexpress COX-2. SHG microscopy identified significantly higher Col1 fiber density in COX-2 overexpressing tumors with an increase of CAFs. These data expand upon the roles of COX-2 in shaping the structure and function of the ECM in primary and metastatic tumors, and identify the potential role of COX-2 in modifying the number of CAFs in tumors that may have contributed to the altered ECM.

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