Detection and Differentiation of Breast Cancer Sub-Types using a cPLA2α Activatable Fluorophore

Abstract

Cytosolic phospholipase A2α (cPLA2α) has been shown to be elevated in breast cancer and is a potential biomarker in the differentiation of molecular sub-types. Using a cPLA2α activatable fluorophore, DDAO arachidonate, we explore its ability to function as a contrast agent in fluorescence-guided surgery. In cell lines ranging in cPLA2α expression and representing varying breast cancer sub-types, we show DDAO arachidonate activates with a high correlation to cPLA2α expression level. Using a control probe, DDAO palmitate, in addition to cPLA2α inhibition and genetic knockdown, we show that this activation is a result of cPLA2α activity. In mouse models, using an ex vivo tumor painting technique, we show that DDAO arachidonate activates to a high degree in basal-like versus luminal-like breast tumors and healthy mammary tissue. Finally, we show that using an in vivo model, orthotopic basal-like tumors give significantly high probe activation compared to healthy mammary fat pads and surrounding tissue. Together we conclude that cPLA2α activatable fluorophores such as DDAO arachidonate may serve as a useful contrast agent for the visualization of tumor margins in the fluorescence-guided surgery of basal-like breast cancer.

Advances of the experimental models of idiopathic membranous nephropathy (Review)

“…The authors of the present review hypothesized that tumor tissues overexpress THSd7a, or Pla2r is expressed in neutrophils and lung cells, which leads to complement system activation and Mac formation (92,93,98). However, the current models do not help us answer the question of antigen production.…”

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

“…This would reduce the time course of therapy to which patients are currently submitted. A similar approach could also reduce the dosage of chemotherapeutic agents required for the treatment of aggressive types of tumors, including those that present with high metastasis and relapsing rates, such as breast cancer [77][78][79] . Finally, further work will be required to address the potential role of Ambrisentan in the treatment of cancer and to better understand the mechanisms how this drug reduces metastasis.…”

Imaging of cancer lipid metabolism in response to therapy

“…Previous studies had shown that arachidonic acid esterified to visible fluorophores such as 7‐hydroxycoumarin were highly specific for cPLA2 and displayed hydrolysis kinetics similar to those of native substrates . We adapted this caged fluorescence protocol using fluorophores that emit in the red wavelength range (660–680 nm) to create cPLA2 sensitive probes suitable for in vivo imaging . Probe selectivity could be modulated by choice of fatty acids and fluorophores, with DDAO 6,8‐dichloro‐7‐hydoxy‐9,9‐dimethylacridin‐2( 9H )‐one arachidonate performing the best in vitro, in cells, and in tumors.…”