CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness

Grass, G. Daniel; Tolliver, Lauren B.; Bratoeva, Momka; Toole, Bryan P.

doi:10.1074/jbc.m113.497685

Cited by 91 publications

(105 citation statements)

References 82 publications

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“…Previous studies have suggested a role for CD44 in invadopodia (Chabadel et al, 2007;Grass et al, 2013;Vikesaa et al, 2006). However, whether specific isoforms of CD44 are functionally crucial in invadopodia in cancer cells has not been determined.…”

Section: Discussionmentioning

confidence: 99%

The CD44s splice isoform is a central mediator for invadopodia activity

Zhao

Wei

et al. 2016

Journal of Cell Science

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The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh) RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

The CD44s splice isoform is a central mediator for invadopodia activity

Zhao

Wei

et al. 2016

Journal of Cell Science

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“…The induction of MMP expression in fibroblasts in response to CD147 stimulation was shown to be dependent on downstream MAPK p38 signaling (Lim et al 1998). In addition to homotypic interactions between CD147 molecules on tumor cells and fibroblasts, it was proposed that up-regulation of CD147 in noninvasive breast cancer cells is sufficient to induce an invasive phenotype associated with high MT1-MMP activity in invadopodia (Grass et al 2012) as a result of enhanced EGFR-Ras-ERK signaling that is initiated through a signaling complex between CD147 and CD44 (Grass et al 2013).…”

Section: Pericellular Proteolysis In the Tumor Microenvironmentmentioning

confidence: 99%

Pericellular proteolysis in cancer

2014

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Pericellular proteases have long been associated with cancer invasion and metastasis due to their ability to degrade extracellular matrix components. Recent studies demonstrate that proteases also modulate tumor progression and metastasis through highly regulated and complex processes involving cleavage, processing, or shedding of cell adhesion molecules, growth factors, cytokines, and kinases. In this review, we address how cancer cells, together with their surrounding microenvironment, regulate pericellular proteolysis. We dissect the multitude of mechanisms by which pericellular proteases contribute to cancer progression and discuss how this knowledge can be integrated into therapeutic opportunities.

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“…41,67 In normal breast epithelial cells, upregulation of a cell-surface glycoprotein, CD147, increases EGFR activation leading to invadopodia formation and upregulation of MT1-MMP expression. 68 This effect is mediated by increased hyaluronan-CD44 signaling and interactions between CD147, CD44, and EGFR, which facilitates invadopodia formation and cancer cell migration. 68,69 Here, localization of growth factor receptors, which generate the necessary invadopodia-forming signals, with cell-surface proteins such as CD147 is critical for invadopodia formation.…”

Section: Growth Factorsmentioning

confidence: 99%

“…68 This effect is mediated by increased hyaluronan-CD44 signaling and interactions between CD147, CD44, and EGFR, which facilitates invadopodia formation and cancer cell migration. 68,69 Here, localization of growth factor receptors, which generate the necessary invadopodia-forming signals, with cell-surface proteins such as CD147 is critical for invadopodia formation.…”

Section: Growth Factorsmentioning

confidence: 99%