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

Abstract

One of the most used markers of cancer stem cells in several cancers, including colorectal cancer and breast cancer, is CD44. CD44 is a glycoprotein that traverses the cell membrane and binds to many ligands including hyaluronan resulting in activation of signaling cascades. Several reports have shown conflicting data on the expression of CD44 and that the expression depends on modes of investigations and subtypes of cancers. In addition, the correlation between CD44 expression and drug resistance, immune infiltration, EMT, metastasis and patients prognosis in several cancer types remains unclear. This study investigated CD44 expression in several cancers and explored its relationship with tumorigenesis using various publicly available databases, including The Cancer Genome Atlas, GEPIA, Oncomine, Genomics of Drug Sensitivity in Cancer and Tumor Immune Estimation Resource. Our analysis reveals that CD44 is differentially expressed in different cancers. CD44 expression is significantly associated with cancer patients' survival in gastric, pancreatic and colorectal cancers. 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-linked genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients than tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anti-cancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cellsubstrate adhesion, migration, platelet activation, and cellular response to stress. KEGG pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling and the response to stimulus. Overall, this investigation reveals that CD44 play significant roles in tumorigenesis, can be used as a prognostic biomarker in several cancers and can be therapeutically targeted in cancer therapy.

CD44-Mediated Poor Prognosis in Glioma Is Associated With M2-Polarization of Tumor-Associated Macrophages and Immunosuppression

“…To go a step further, we explored the immunosuppressive role of CD44 in glioma. As reported, CD44 expression level is positively correlated with PD-L1, PD-1, IL10, and TGFB1 expression in some cancers (56,57). Thus, coexpression of CD44 and checkpoint family members were checked in glioma, and we found that CD44 expression positively correlates with the expression level of PD-L1 and PD-1 and correlates with the expression level of PDCD1LG2 (namely PD-L2) as well in the TCGA and CGGA glioma datasets (Supplementary Figure 10).…”

CD44 is a prognostic biomarker and correlated with immune infiltrates in gastric cancer

“…Compared with cells of a gastric cancer cell line, the expression of CD44 mRNA is significantly higher in gastric cancer stem cells (CSC-Gs) [ 15 , 16 ]. Abundant studies have demonstrated that CD44 serves as a marker for several tumour stem cells, including CSC-Gs [ 15 , 17 – 19 ].…”

Mutational Landscape of Cancer-Driver Genes Across Human Cancers

“…Over the last few decades, our understanding of the genes, the pathways within which they function, and their role in oncogenesis have grown significantly and, along with this increased interest, concerted efforts to treat various cancer types [9][10][11][12][13][14] . Furthermore, various genetic aberrations have been identified in human cancers, and several of the proteins encoded by these genes are well-established drug targets, and others are promising drug targets 3,4,15,16 .…”