Dataset Information

CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance.

ABSTRACT: Tumor progression requires a crosstalk with the tumor surrounding, where the tumor matrix plays an essential role. We recently reported that only the matrix delivered by a CD44v6-competent (ASML(wt)), but not that of a CD44v6-deficient (ASML-CD44v(kd)) rat pancreatic adenocarcinoma line supports metastasis formation. We here describe that this matrix provides an important feedback toward the tumor cell and that CD44v6 accounts for orchestrating signals received from the matrix. ASML(wt) cells contain more hyaluronan synthase-3 and secrete higher amounts of >50 kDa HA than ASML-CD44v(kd) cells, which secrete more hyaluronidase. Only the ASML(wt)-matrix supports migration and apoptosis resistance, which both can be initiated via CD44v6, c-Met, and ?6?4 ligand binding and proceed via FAK, PI3K/Akt, and MAPK activation, respectively. However, c-Met- and ?6?4-initiated signaling are strongly augmented by the association with CD44v6 as only very weak effects are observed in CD44v6-deficient cells. The same CD44v6-dependent convergence of motility- and apoptosis resistance-related signals also accounts for human tumor lines. Thus, CD44v6 promotes motility and apoptosis resistance via its involvement in assembling a matrix that, in turn, triggers activation of signaling cascades, which proceeds, independent of the initiating receptor-ligand interaction, in a concerted action via CD44v6.

SUBMITTER: Jung T

PROVIDER: S-EPMC3091196 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance.

Jung Thorsten T Gross Wolfgang W Zöller Margot M

The Journal of biological chemistry 20110303 18

Tumor progression requires a crosstalk with the tumor surrounding, where the tumor matrix plays an essential role. We recently reported that only the matrix delivered by a CD44v6-competent (ASML(wt)), but not that of a CD44v6-deficient (ASML-CD44v(kd)) rat pancreatic adenocarcinoma line supports metastasis formation. We here describe that this matrix provides an important feedback toward the tumor cell and that CD44v6 accounts for orchestrating signals received from the matrix. ASML(wt) cells co ...[more]

PMID: 21372142

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Project description:Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

Dataset Information

CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance.

Publications

CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance.

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