CD44: Does CD44v6 Adversely Impact the Prognosis of Cancer Patients?

Colorectal cancer (CRC) is the third leading cause of cancer-related death in the USA. This high level of CRC death is primarily due to chemoresistance and metastasis. The ability of cancers to maintain tumorigenesis for a long term depends on a subpopulation of cancer cells, the self-renewing cancer-initiating cells (CICs) with cancer stem cell-like properties responsible for tumor initiation, progression, and drug resistance. The CICs can be identified and isolated by CIC-specific cell-surface adhesion marker expression, and CD44v6 is the most frequently functional marker on CICs. Knockout and knockdown of CD44v6 in mice accompanied loss of tumor progression but did not fully regress primary tumor growth indicating that CD44/CD44v6 (Variant 6 of CD44) may have an indispensable role in maintaining CIC turnover. We have recently shown that CRC-CIC enrichment markers and CD44v6 support the maintenance of CICs through communication of the CRC-CIC/niche with the cancer-associated stromal microenvironment. These positive CD44v6 activities for CICs depend on CD44v6’s ability to join tissue microenvironmental cues with growth factor/cytokine signals that transduce signals to membrane receptor proteins or to the nucleus to regulate a variety of transcription factors and their target gene expression levels necessary to maintain the stemness of CICs and to convert differentiated tumor cells into CICs. In this perspective we encapsulate the current findings regarding the potential role of CD44/CD44v6 in the regulation of CICs stemness and the current status of therapies that target CD44v6-positive/CIC mechanisms, which will hold great potential to optimize therapeutic targeting of CRC.