Effects of dietary flavonoids, luteolin and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells

Wednesday, 20/07/2011  |   Others, Pancreatic Cancer  |  no comments

Highly invasive A431-III cells, which are derived from parental A431-P cells, were originally isolated via three successive passages through a Boyden chamber using a Matrigel-coated membrane support. The greater invasion potential exhibited by A431-III cells was due to their increased ability to spread/migrate, which was associated with enhanced MMP activity. The tumor progression events evoked by A431-P cells compared to A431-III cells may help identify useful strategies for evaluating the EMT and these cell lines could be a reliable model for evaluating tumor metastasis events. Employing this approach, we evaluated the effects of luteolin and quercetin using the A431-P/A431-III EMT model. These flavonoids reversed cadherin switching, downregulated EMT markers and nullified the invasion ability of A431-III cells. Overexpression of MMP-9 resulted in induction of the EMT in A431-P cells and this could be reversed by treating with luteolin or quercetin. Co-treatment of A431-P and A431-III cells with EGF plus luteolin or quercetin resulted in a more epithelial-like morphology, led to reduced levels of the EGF-induced markers of the EMT and caused the restoration of cell-cell junctions. E-cadherin was decreased by EGF, but increased by luteolin and quercetin. Our results suggest that luteolin and quercetin are potentially beneficial agents that target and prevent the occurrence of the EMT in epidermal carcinoma cells. These chemicals also have the ability to attenuate tumor progression in A431-III cells. In conclusion, luteolin and quercetin show inherent potential as chemopreventive/anti-neoplastic agents and do this by abating tumor progression through a reversal of EMT.
Lin Y-S, Tsai P-H, Kandaswami CC, et al. Effects of dietary flavonoids, luteolin and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells. Cancer Science 2011 DOI: 10.1111/j.1349-7006.2011.02035.x

EMT and Cancer
Epithelial to mesenchymal transition (EMT) is a physiological transcriptional reprogramming event used in normal organ development, and is characterized by the combined loss of epithelial cell junctions and cell polarity, and the gain of a mesenchymal phenotype. This reprogramming event allows for organ development through de-differentiation of normal epithelial cells, their migration through an extracellular matrix, and finally re-differentiation, homotypic adhesion and organ growth. EMT and mesenchymal to epithelial transition (MET) processes are now recognized in cancer progression (AACR, 2010).
Most solid tumors are epithelial in origin, as shown in the EMT Figure panel A, above. A loss of epithelial-cell markers and gain of mesenchymal-cell markers has been observed in patient tumor samples, particularly at the leading edge or invasive front of solid tumors such as non-small cell (NSCLC), pancreatic, colorectal, and hepatocellular cancers. Such changes in phenotypic epithelial-like and mesenchymal-like cellular markers have been associated with the degree of tumor progression. The loss of epithelial-cell markers (e.g. E-cadherin, gamma catenin, others) is associated with disease progression and metastatic potential of a tumor. It has become evident that cancer cells can dedifferentiate through activation of specific biological pathways associated with EMT, thereby gaining the ability to migrate and invade. Hence, what has been observed experimentally regarding EMT and normal organ development is also thought to apply in the progression of solid tumors: transcriptional reprogramming processes whereby epithelial tumor cells lose cell polarity and cell-junction proteins and at the same time acquire protein mesenchymal-cell markers (e.g. vimentin, fibronectin, others) and signal transduction activities associated with mesenchymal cells facilitating migration and survival in an anchorage-independent environment, and ultimately metastasis at distal sites as shown in the EMT Figure Panels B and C. Mesenchymal-like tumor cells gain migratory capacity at the expense of proliferative potential. As in normal EMT, pathological EMT in tumor cells results from a transcriptional reprogramming of the cell leading to its transition into mesenchymal-like cellular phenotype, promoted by EMT-related signaling pathways driven, in part, through abnormal survival signals via receptors such as platelet derived growth factor receptor (PDGFR); fibroblast growth factor receptor (FGFR); cMET; TGFbR; IGF-1R; and regulatory kinases such as PI3K, AKT and mTOR. Cellular changes resulting in a more mesenchymal-like state driven by pathological EMT in cancer are thought to play a major role in disease progression has been associated with poor prognosis.
The reverse, Mesenchymal Epithelial Transition (MET), whereby mesenchymal tumor cells change to become more epithelial-like in phenotype, is thought to be required to regenerate a proliferative state and form macrometastases resembling the primary tumor at distant sites, as shown in the EMT Figure Panel D. It has been hypothesized that MET facilitates proliferation and growth of epithelial tumor cells at the sites distal from the primary tumor. Changes in the expression levels of epithelial-cell and mesenchymal-cell markers has allowed OSI to begin to define the EMT-status of tumors and OSI has an active research program to characterize EMT biomarkers across a variety of patient samples.

AACR (American Association for Cancer Research) 2010 Accessed July 2011

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Christfori C. New signals from an invasive front. Nature 2006; 41:444-450

Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev/Mol Cell Biol 2006; 7:131-142

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