The expression of CD44 tags cells with stemness-associated properties (cancer initiating cells or
cancer stem cells - CSC). This membrane glycoprotein with a cytoplasmic domain indirectly associated
with the cellular cytoskeleton, has a crucial role in tumorigenesis. The CD44 receptor enables the cell to respond to
changes in tumor microenvironment, promoting several signaling events related to tumor initiation, progression and
fixation in distant host tissues. Although the contribution of this transmembrane protein in gene regulation remains
unclear, its overexpression in adenocarcinomas, mostly supported by microRNA (miR)-mediated upregulation of target
mRNA, is widely accepted. Herein, we gather the evidence that CD44 is one of the most predominant markers of
malignant cells and may be found in diverse phenotypes associated with tumor progression. Additionally, CD44 tumor
receptors were found to have different roles at a transcriptional level. Thus, innovative therapeutic strategies should rely
heavily on its metastasis-promoting ability. Furthermore, the concept of selectively targeting cell sub-populations may be
used to develop specific therapeutic and/or diagnostic systems. An approach based on targeting CD44+ cells might
provide a strategy to design guided-therapeutic systems against multiple malignant cells including putative CSC.
Keywords: Cancer stem cells, CD44, epithelial-mesenchymal transition, metastasis, tumor progression.
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