CD44 Variant Exon 6 Isoform Expression as a Potential Predictor of Lymph Node Metastasis in Invasive Breast Carcinoma of No Special Type

Background. Invasive breast carcinoma of no special type (IBC-NST) is the most widespread invasive carcinoma subtype causing primarily regional metastases of the lymphatic node (LNM). The capacity of CD44 variant exon 6 (CD44v6) expression as an LNM predictor biomarker in IBC-NST was explored. Methods. We conducted a cross-sectional research with 48 paraffin blocks containing IBC-NST primary tumors that were divided into two groups by LNM. The assessment has been carried out in terms of age, tumor size, tumor grade, lymphovascular invasion (LVI), and CD44v6 expression. The expression of CD44v6 was analyzed on the grounds of immunohistochemical (IHC) staining, while other data were taken from archives. Statistical analysis is carried out by univariate, multivariate, and AUROC. Results. CD44v6 exhibits a dominant expression in IBC-NST tumor cells. Univariate analysis revealed a significant association between CD44v6 and LNM status ( p = 0.001 ). Multiple logistic regression results showed that CD44v6 expression and LVI were significantly associated with LNM with OR 10.7 (95% CI: 2.43 to 47.08) and 6.22 (95% CI: 1.4 to 27.88), respectively. CD44v6 expression was able to discriminate against LNM with AUROC 0.863 ± 0.053 (95% CI: 0.759 to 0.967) at the H-score cut-off 133.889 (75% sensitivity and 83.3% specificity). Conclusion. CD44v6 expression and LVI are potential predictors of LNM in IBC-NST. The H-score cut-off of the CD44v6 expression can also be used as a threshold for classification in further investigation.

CD44v6 High Membranous Expression Is a Predictive Marker of Therapy Response in Gastric Cancer Patients

In gastric cancer (GC), biomarkers that define prognosis and predict treatment response remain scarce. We hypothesized that the extent of CD44v6 membranous tumor expression could predict prognosis and therapy response in GC patients. Two GC surgical cohorts, from Portugal and South Korea (n = 964), were characterized for the extension of CD44v6 membranous immuno-expression, clinicopathological features, patient survival, and therapy response. The value of CD44v6 expression in predicting response to treatment and its impact on prognosis was determined. High CD44v6 expression was associated with invasive features (perineural invasion and depth of invasion) in both cohorts and with worse survival in the Portuguese GC cohort (HR 1.461; 95% confidence interval 1.002–2.131). Patients with high CD44v6 tumor expression benefited from conventional chemotherapy in addition to surgery (p < 0.05), particularly those with heterogeneous CD44v6-positive and -negative populations (CD44v6_3+) (p < 0.007 and p < 0.009). Our study is the first to identify CD44v6 high membranous expression as a potential predictive marker of response to conventional treatment, but it does not clarify CD44v6 prognostic value in GC. Importantly, our data support selection of GC patients with high CD44v6-expressing tumors for conventional chemotherapy in addition to surgery. These findings will allow better stratification of GC patients for treatment, potentially improving their overall survival.

Clinicopathological and Prognostic Significance of CD44s and CD44v6 Expression in Patients with Glioma: A Systematic Review and Meta-analysis

Background: Cancer stem cell surface marker CD44 has been revealed to promote tumor growth, progression, and metastasis in gliomas. Although the prognostic and clinicopathological value of CD44 standard form (CD44s) and its variant isoform CD44v6 expression in glioma patients has been evaluated in several independent studies, their results remained controversial. Therefore, we performed this meta-analysis to investigate the prognostic and clinicopathological association of CD44s/CD44v6 expression with glioma patients.Methods: A comprehensive literature search was performed in the electronic databases PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wangfang Data. The statistical analysis was conducted using Stata 15.0 and Review Manager 5.3.Results: A total of 43 studies with 2817 glioma patients were included in this meta-analysis. Pooled results indicated that positive expression of CD44s was significantly associated with poorer overall survival (OS, univariate analysis, HR =1.63, 95% CI= [1.16–2.29], P=0.005; multivariate analysis, HR=2.14, 95%CI= [1.21, 3.78], P=0.009), and reduced progression-free survival (PFS) in the univariate analysis (HR=2.09, 95% CI= [1.59, 2.75], P<0.00001), but not with PFS in the multivariate analysis (P>0.05) or tumor recurrence (P>0.05). CD44 expression was significantly upregulated in glioma tissues when compared with non-tumorous brain tissues (CD44s, OR=31.31, 95% CI= [15.22, 64.43], P<0.00001; CD44v6, OR=13.18, 95% CI= [5.51, 31.51], P<0.00001). In particular, CD44 expression was preferentially expressed in high-grade gliomas (grade III-IV vs. grade I-II, CD44s, OR=4.67, 95% CI= [3.18, 6.87], P<0.00001; CD44v6, OR=2.06, 95% CI= [1.21, 3.51], P=0.008). CD44s expression was lower in brain metastases than that in primary gliomas (OR=0.25, 95% CI= [0.10, 0.60], P=0.002), however, higher expression of CD44v6 was detected in brain metastases when compared with primary gliomas (OR=49.44, 95% CI= [13.06, 187.22], P<0.00001).Conclusions:This meta-analysis revealed the prognostic value of CD44s expression and clinicopathological significance of CD44s/CD44v6 expression in gliomas. Increased CD44s expression can predict worse prognosis of glioma patients. Particularly, CD44s is an independent prognostic factor for poor OS of glioma patients. Both CD44s and CD44v6 were glioma patients predominantly expressed in glioma tissues, especially in high-grade gliomas. Additionally, CD44v6 is a potential diagnostic biomarker for differentiating brain metastases from primary gliomas in individual cases. Therapeutic strategies targeting CD44 in gliomas should be further explored in the future.

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

CD44v6-containing isoforms are frequently de novo expressed in gastric cancer (GC). Whether CD44v6 has a central role in GC transformation and/or progression, whether it conditions response to therapy or whether it is only a bystander marker is still not known. Therefore, we aimed to clarify the role of CD44v6 in GC. We generated GC isogenic cell lines stably expressing CD44s or CD44v6 and tested them for different cancer hallmarks and response to cisplatin, and we further confirmed our findings in cells that endogenously express CD44v6. No correlation between overexpression of CD44v6 and the tested cancer hallmarks was observed, suggesting CD44v6 is not a driver of GC progression. Upon cisplatin treatment, CD44v6+ cells survive better and have lower apoptosis levels than CD44v6− cells, possibly due to concomitant activation of STAT3 and P38. In co-culture experiments, we discovered that CD44v6+ cells are involved in GC cell overgrowth after cisplatin treatment. In conclusion, we show that CD44v6 expression increases cell survival in response to cisplatin treatment in GC cells and that these cells override CD44v6-negative cells after cisplatin-treatment. This suggests that tumor expression of CD44v6-containing variants may condition the outcome of GC patients treated with chemotherapy.

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

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 CD44_high tumors presented worse OS than those bearing CD44_absent/low tumors, consolidating the role of CD44v6 expression as an independent factor of poor prognosis in this disease. Finally, ourin vitroand 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 supports selection of patients with high CD44v6 expressing tumors for conventional chemotherapy with or without surgery, regardless of the TNM stage.

Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia

Key PointsThe spleen but not bone marrow microenvironment induces CD44v6 variants in CLL, which promote early engraftment. CD44v6 expression is linked to NF-κB and MAPK signaling in murine and human B-cell leukemia and contributes to proliferation.

CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling

Biomimetic ECM models suggest that CD44v6 expression promotes fibrotic ECM remodeling and gastric cancer aggressiveness through a positive feedback mechanism.