Cancer Stem Cell Marker CD44 Plays Multiple Key Roles in Human Cancers: Immune Suppression/Evasion, Drug Resistance, Epithelial-Mesenchymal Transition, and Metastasis.

One of the most frequently utilized cancer stem cell markers in human cancers, including colorectal cancer and breast cancer, is CD44. A glycoprotein, CD44, traverses the cell membrane and binds to many ligands, including hyaluronan, resulting in activation of signaling cascades. There are conflicting data, however, on expression of CD44 in relationship to subtypes of cancers. Moreover, the associations of CD44 expression with drug resistance, immune infiltration, epithelial-mesenchymal transition (EMT), metastasis, and clinical prognosis in several cancer types are not clear and call for further studies. We report here an original study on CD44 expression in several human cancers and its relationship with tumorigenesis. We harnessed data from the publicly available databases, including The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Oncomine, Genomics of Drug Sensitivity in Cancer, and the Tumor Immune Estimation Resource. Our analysis reveals that CD44 expression varies across cancer types and is significantly associated with cancer patients' survival, in gastric and pancreatic cancers (p < 0.05). In addition, CD44 expression is closely linked with immune infiltration and immune suppressive features in pancreatic, colon adenocarcinoma, and stomach cancer. High CD44 expression was significantly correlated with the expression of drug resistance, EMT, and metastasis associated genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients compared to tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anticancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cell-substrate adhesion, migration, platelet activation, and cellular response to stress. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling, and the response to stimulus. In summary, these findings lend evidence for the multiple key roles played by CD44 in tumorigenesis and suggest that CD44 is considered further in future studies of cancer pathogenesis and the search for novel molecular targets and personalized medicine biomarkers in clinical oncology.