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CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

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Purpose A subpopulation of pancreatic adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabine resistant tumors. Experimental Design RT-PCR, Western blotting and DNA sequencing was used to determine CD44 isoform and expression levels. Flow cytometry was used to sort cells on the basis of their CD44 expression level. CD44 expression was knocked down using shRNA. Tumorigenic properties were determined by clonogenic and Matrigel assays, immunohistochemistry, tumor growth in vivo using luciferase imaging and by tumor weight. Results We identified an invasive cell population that gives rise to gemcitabine resistant tumors. These cancer cells express a high level of CD44 standard isoform and have an EMT phenotype (CD44s/EMT). In vivo, CD44s/EMT engraft and expand rapidly and give rise to tumors that express high levels of CD44 isoforms that contain multiple exon variants. CD44 low expressing cells show continued sensitivity to gemcitabine in vivo and knockdown of CD44 in CD44s/EMT cells increases sensitivity to gemcitabine and decreases invasiveness. Conclusion PDAC cells expressing high levels of CD44s with a mesenchymal-like phenotype were highly invasive and developed gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response.

Background Patient navigation (PN) is an emerging strategy to overcome barriers to cancer care. We evaluated the efficacy of PN in improving time of key events in cancer care, including positive screening tests, definitive diagnosis, initiation of therapy, and completion of initial therapy. Methods We evaluated PN in a prospective observational study of predominantly poor Hispanic women with an abnormal breast cancer screening or untreated biopsy proven breast cancer (control = 200, intervention = 260). Controls were contemporary records-based patients with positive screening. Analyses were conducted for the entire cohort and separately by ethnic strata. We used Chi-Square tests to compare differences in proportions and Kaplan-Meier followed by Cox Regression to compare time-to-event curves of the intervention and control groups. Results The average days from definitive diagnosis to initiation of therapy was significantly reduced overall with PN (PN vs control, 57d vs 74d, p=.04). This effect was more pronounced in the Hispanic strata (56 vs 81 days, p=.02). More navigated Hispanic women were diagnosed within 60 days of abnormal screening (62.6% vs 47.5%, p< .01) and more began treatment within 60 days of diagnosis (80% vs 56.3%, p<.01). Navigated Hispanic and other ethnic minority women had a shorter time from positive screening test to definitive diagnosis (16 and 32 days, respectively). Conclusions Minority women may have benefitted from navigation with shorter times from definitive diagnosis to initiation of therapy.. Impact PN intervention may show promise in decreasing some delays that contribute to health disparities among minority women with breast cancer.