Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells

In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44(neg)). Unexpectedly, these sorted CD44(neg) cells rapidly and spontaneously converted to a stable CD44(high) phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44(high) subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10(pos) PC3 cells, resulting from the conversion of the CD44(neg) subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44(high) cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10(pos) cells with stem-like and invasive features, derived from a minoritarian CD44(neg) cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC.