Regulation of cancer cell stemness by hypoxia: a role of delta-like 1 homolog (Drosophila) DLK1

Assoc Prof Ther Radiology
15 York St, New Haven, CT 06510-3221

The stem cell-like characteristics, especially the self-renewal capacity, of tumor cells, is essential for both tumorigenesis and malignant progression. Like normal stem cells, cancer cells can lose their stemness or self-renewal potential in response to environmental stresses.  Therefore, tumor cell stemness needs to be actively maintained.  However, the underlying mechanisms remain to be clearly understood.  Our previous studies and others have suggested that the tumor microenvironment, including hypoxia, plays a significant role in the regulation of cancer stem cell characteristics.  We have identified a previously uncharacterized stem cell pathway mediated by /DLK1/ or delta-like 1 homolog (Drosophila) that is upregulated by hypoxia and enhances cancer cell stemness and tumorigenicity in neuronal tumors.  We found that overexpression of DLK1 promotes tumor growth by increasing the number of mitotic or proliferative cells and inducing angiogenesis /in vivo/using neuroblastoma (NB) xenografts as a model.  On the other hand, tumors
derived from NB cells with down-regulation of DLK1 expression by RNA interference or with overexpression of dominant negative mutants of DLK1 sensitize NB cells to undergo differentiation, as shown by increased
expression of neuronal and glial differentiation markers.  Our data further revealed that DLK1 regulates the activation of ERK1/ERK2.  These results demonstrate that /DLK1/ plays an important role in the maintenance of undifferentiated, stem cell-like phenotype of NB cells /in vivo/.  Our findings also indicate that the tumor microenvironment, especially hypoxia, can exert a profound impact on the tumor cell fate /in vivo/ by regulating specific stem cell pathways.