The hyaluronan (HA) receptor CD44 is a single pass transmembrane glycoprotein involved in cell-cell and cell-matrix adhesion. Alternative splicing in human CD44 pre-mRNA results in expression of different transcript variants (CD44v), leading to variation in the length and function of extracellular domain. CD44, particularly CD44v isoforms, are known to be cancer stem cell (CSC) markers and critical regulators of tumor initiation and metastasis and CD44v are expressed in a broad range of cancers in advanced stages. In addition, the expression of different CD44 variants on endothelial cells may be implicated in tumor angiogenesis affecting HA-binding.
Our main aim is to identify specific CD44 variants expressed by prostate cancer (PCa) and testicular cancer (TGCT) cells with CSC and metastatic traits in different microenvironment by using various cell lines and cultured sample of primary prostate tumors and paraffin-embedded section from testicular tumors. Interestingly, CD44 can function as co-receptor for the receptor tyrosine kinase (RTK) c-MET. Thus, the role of CD44v in c-MET activated cell pathways that promote tumorigenic functions will be investigated in our models.
We have previously identified a scanty CD44-negative cell population isolated from human PCa cell line PC3 that rapidly converts to CD44-highly positive cells expressing specific CD44v8-10 isoform and displaying high clonogenic and invasive potential (Di Stefano C et al Oncotarget 2018). At present, CAR-T technology development is a big challenge for the treatment of malignant solid tumors including prostate cancer. Therefore, we aim to identify CD44v8-10 as a novel marker of aggressiveness to use it as target of CAR-based therapeutic strategy.
We therefore believe that any progress in the knowledge of CD44 variants specifically expressed on CSC-like very aggressive PCa and TGCTs may constitute an important proof-of concept on the potential efficacy of adoptive immunotherapy.
