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.

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis

“…In addition to our data showing upregulation of CD44 by ATDC, it has previously been shown that CD44 is a switch for EMT and that YFP + pancreatic epithelial cells undergoing EMT in vivo in the KPCY model expressed CD44 (Kim et al 2008;Afify et al 2009;Brown et al 2011;Jung et al 2011;Rhim et al 2012). Furthermore, many studies have shown that knockdown of CD44 or the use of CD44-blocking antibodies inhibited EMT and invasion (Kim et al 2008;Afify et al 2009;Craig et al 2009;Bhat-Nakshatri et al 2010;Brown et al 2011;Provenzano et al 2012;Li et al 2014).…”

Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling

“…A drawback of these inhibitors is that they very often induce drug resistance and side effects. CD44v6 and Met-expressing tumor cells are protected against drug-induced apoptosis 10 . Thus, the CD44v6 peptide might protect against drug resistance in combination regimen.…”

“…8 and 9 CD44v6 also collaborates with VEGFR-2, which plays a critical role in angiogenesis. 10 The CD44v6 peptides also can block VEGF-induced VEGFR-2 activation and signaling. 9 Together, these data add to the relevance of CD44v6 signaling in tumor growth and metastasis.…”

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

“…Nowadays, several studies have demonstrated that CD44v6 was correlated with the prognosis of ovarian cancer (Shi et al, 2013), colorectal cancer (Wielenga et al, 1993), gastric carcinoma (Mayer et al, 1993), osteosarcoma (Deng et al, 2013), breast cancer (Kaufmann et al, 1995), bladder cancer (Omran et al, 2012) and liver cancer (Coradini et al, 2004). What's more, it has been reported that CD44v6 can contribute to both PI3K/Akt and MAPK activation, which can regulate the extracellular matrix, promote cell motility, and suppress cancer apoptosis (Marhaba et al, 2005;Jung et al, 2011).…”