Platelet-activating factor promotes motility in breast cancer cells and disrupts non-transformed breast acinar structures

Abstract

A plethora of studies have demonstrated that chronic inflammatory microenvironment influences the genesis and progression of tumors. Such microenvironments are enriched with various lipid mediators. Platelet activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is one such lipid mediator that is secreted by different immune cell types during inflammation and by breast cancer cells upon stimulation with growth factors. Overexpression of PAF-receptor has also been observed in many other cancers. Here we report the possible roles of PAF in tumor initiation and progression. MCF10A, a non-transformed and non-malignant mammary epithelial cell line, when grown as 3D 'on-top' cultures form spheroids that have a distinct hollow lumen surrounded by a monolayer of epithelial cells. Exposure of these spheroids to PAF resulted in the formation of large deformed acinar structures with disrupted lumen, implying transformation. We then examined the response of transformed cells such as MDA-MB 231 to stimulation with PAF. We observed collective cell migration as well as motility at the single cell level on PAF induction, suggesting its role during metastasis. This increase in collective cell migration is mediated via PI3-kinase and/or JNK pathway and is independent of the MAP-kinase pathway. Taken together this study signifies a novel role of PAF in inducing transformation of non-tumorigenic cells and the vital role in promotion of breast cancer cell migration.

Platelet activating factor leads to initiation and promotion of breast cancer

“…On the other hand, JNK pathway inhibition resulted in inhibition of PAF stimulated enhanced motility as well as motility of unstimulated cells, confirming its role in PAF increased motility as well as inherent motility. Taken together, these results raise the possibility that PAF induced increased motility may be occurring through PI3K as well as JNK pathways [27] . Ongoing studies are being performed to dissect out the exact mechanistic pathway involved in PAF stimulated motility in cells.…”

“…In agreement with these reports we also observed increased collective cell migration of MDA-MB 231 cells upon PAF treatment in the wound healing assay. At the single cell level, PAF enhanced the velocity as well as distance traversed by the cells without change in directionality [27] . Further, to unravel the mechanistic aspect of PAF induced motility we used small molecule inhibitors of probable pathways predicted from available literature.…”

“…Investigation of the PAF-R status revealed that MDA MB-231 and MCF7 cells showed higher expression as compared to MCF10A cells, which showed a very low expression. A recent study from our lab demonstrated that PAF may play a role in cancer initiation as well as promote cancer progression [27] . Three dimensional (3D) cultures of normal breast epithelial cells as well as cancerous cells have been exploited to study the process of morphogenesis and tumorigenesis [28][29][30] .…”

“…To study the role of PAF in breast cancer progression, effect of PAF on migration was studied [27] . Metastasis of cancer cells is one of the many aspects which remain unexplored in cancer pathogenesis and effectively curtailing this phenomenon is the need of the hour [39] .…”

Cancer antigen 15-3, platelet distribution width, and fibrinogen in combination to distinguish breast cancer from benign breast disease in non-conclusive mammography patients

“…Activated platelets create a procoagulant micro-environment that enables the tumor cells to cover themselves with platelets and evade the host immune system. Anandi VL et al demonstrated that platelet-activating factor promotes motility in breast cancer cells [ 24 ]. In addition, Toth B et al confirmed the key role of platelet-derived microparticles in the microenvironment of tumor tissue in breast cancer patients [ 25 ].…”