CD44v6 expression is a novel predictive marker of therapy response and poor prognosis in gastric cancer patients

Abstract

Late diagnosis, modest treatment options and lack of predictive markers of therapy response dictate the poor overall survival (OS) of ~1 year in most gastric cancer (GC) patients. We hypothesized that the level of CD44v6 expression in tumor cells could predict therapy response and prognosis in GC patients.We analyzed a surgical tumor series of GC patients for the extension of CD44v6 membranous immuno-expression, clinical-pathological features, patient survival, and response to therapy. By integrating this information, we assessed the value of CD44v6 expression to predict benefit from current treatment regimens and prognosis in GC patients. We used GC cell lines and mouse xenografts to assess and/validate the biological impact of CD44v6 expression in GC cells behavior.We demonstrated that GC patients whose tumors present higher levels of CD44v6 membranous expression benefit from adding chemotherapy to surgery as opposed to those without CD44v6 expression. Moreover, patients bearing CD44v6_high tumors presented worse OS than those bearing CD44v6_absent/low tumors, consolidating the role of CD44v6 expression as an independent factor of poor prognosis in this disease. Finally, our in vitro and patients' data pinpoints the CD44v6+ cell population as the driver of tumor recurrence following conventional chemotherapy, in heterogeneous tumors composed by CD44v6-and CD44v6+ cells.Our study pioneers the identification of CD44v6 as a potential predictive marker of response to conventional chemotherapy, and consolidates CD44v6 as an independent marker of poor prognosis in GC. Overall, our data strongly 4 supports selection of patients with high CD44v6 expressing tumors for conventional chemotherapy with or without surgery, regardless of the TNM stage. 5Introduction:

O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

“…CD44 has been implicated in cancer stem cell properties, and cancer cells that overexpress CD44 display an increased metastatic potential and are associated with poor survival of the patients . Particularly the expression of the v6 variant form of CD44 has been associated with distant metastasis, poor prognosis, but also susceptibility to chemotherapy in gastric cancer . Functionally, CD44v6 has been shown to play a crucial role in activation of RTKs, such as MET and RON, and thereby to contribute to oncogenic features .…”

Expression of CD44v6-Containing Isoforms Influences Cisplatin Response in Gastric Cancer Cells

“…Our data also shed light into GC molecular heterogeneity and its relation with therapy, by suggesting that the CD44v6+ population is responsible for tumor overgrowth and may potentially help drive recurrence following conventional chemotherapy, in tumors composed of CD44v6+ and CD44v6− cell populations. Indeed, considering that more than half of GC tumors possess some degree of heterogeneity regarding CD44v6 expression (with CD44v6+ and CD44v6− cell populations co-existing in the same tumor) [29], this may have important consequences in terms of GC patients' clinical outcome.…”

“…As CD44v6-positive (CD44v6+) cells seem to survive better after cisplatin treatment than CD44v6-negative cells (CD44v6−), it is likely that the proportion of CD44v6+ and CD44v6− cells in heterogeneous tumors (often found in GC, as shown in [29]) influences response to chemotherapy. We set out to test this hypothesis in vitro, by mimicking the effects of chemotherapy on a CD44v6 heterogeneous tumor.…”