Anti-DLL4, a cancer therapeutic with multiple mechanisms of action

Cancer can be considered as an aberrant and mutant recapitulation of normal tissue development and homeostasis. Tumors are typically highly heterogeneous at the cellular level, and this heterogeneity frequently mirrors the cellular heterogeneity of the normal tissue. Normal tissue development and homeostasis is driven by an organized hierarchy of stem and progenitor populations which give rise to various differentiated cell types with specialized functions. Long term tissue maintenance is enabled by the unique ability of the stem cell to exhibit self-renewal, which is defined as the ability to proliferate while maintaining pluripotency. Similarly, cancer cells inappropriately activate self-renewal pathways and this enables their ability to grow indefinitely. Thus, the potential connections between normal stem cells and cancer have great importance for understanding tumor biology and also for developing new therapeutic strategies. In the past decade it has become increasingly clear that this self-renewal property is not possessed by all cells within a tumor, but that there exists a subpopulation of cells, often referred to as "cancer stem cells" or "tumor initiating cells" which possesses the ability to undergo self-renewal and thereby drive the growth of the tumor [1-3]. These cells also possess the ability to initiate the growth of new tumors that recapitulate the heterogeneity of the parent tumor. Thus, these cells have hallmark capabilities analogous to normal stem cells. This relationship has been strengthened by genetic studies which have shown that normal stem cells can be the cell of origin for tumors [4]. Additionally, cancer initiating mutations can originate in more differentiated cells and confer stem-like properties on the tumor cells. These connections have led to a careful examination of stem cell signaling pathways and their role in cancer. Intriguingly, several of these pathways, including the Notch and Wnt pathways, have long been recognized to be a