Podosome‐like structures of non‐invasive carcinoma cellsare replaced in epithelial‐mesenchymal transition by actin comet‐embedded invadopodia

Takkunen, Minna; Liljeström, Mikko; Grénman, Reidar; Virtanen, Ismo

doi:10.1111/j.1582-4934.2010.01171.x

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“…Proteomic analysis revealed that over 200 proteins were dysregulated by ≥1.5 fold in the “feet” of palladin-expressing fibroblasts relative to those of labeled control cells. These dysregulated proteins including invadopodia proteins [30] , [32] , [33] , ras related and GTP binding proteins, and proteolytic enzymes, (selected proteins, see Figure 6B ; for complete list, see Table S2 ). We were particularly interested in the invadopodia proteins, including cortactin, filamin A, beta-integrin 1, vinculin, profilin, alpha-actinin, and cofilin [32] , [33] .…”

Section: Resultsmentioning

confidence: 99%

“…These dysregulated proteins including invadopodia proteins [30] , [32] , [33] , ras related and GTP binding proteins, and proteolytic enzymes, (selected proteins, see Figure 6B ; for complete list, see Table S2 ). We were particularly interested in the invadopodia proteins, including cortactin, filamin A, beta-integrin 1, vinculin, profilin, alpha-actinin, and cofilin [32] , [33] . Nearly half of the up-regulated proteins identified in our proteomic analysis were recently reported as novel invadopodia components [34] .…”

Section: Resultsmentioning

confidence: 99%

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Arousal of Cancer-Associated Stroma: Overexpression of Palladin Activates Fibroblasts to Promote Tumor Invasion

et al. 2012

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BackgroundCancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors. These myofibroblasts promote invasion and metastasis of cancer cells. Mechanisms regulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumor invasion.Principal FindingsPalladin expression in stromal fibroblasts occurs very early in tumorigenesis. In vivo, concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (α-SMA), occurs early at the dysplastic stages in peri-tumoral stroma and progressively increases in pancreatic tumorigenesis. In vitro introduction of exogenous 90 kD palladin into normal human dermal fibroblasts (HDFs) induces activation of stromal fibroblasts into myofibroblasts as marked by induction of α-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expression in the fibroblasts enhances cellular migration, invasion through the extracellular matrix, and creation of tunnels through which cancer cells can follow. The fibroblast invasion and creation of tunnels results from the development of invadopodia-like cellular protrusions which express invadopodia proteins and proteolytic enzymes. Palladin expression in fibroblasts is triggered by the co-culture of normal fibroblasts with k-ras-expressing epithelial cells.ConclusionsOverall, palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.

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