March 2009 Molecular Cancer Research Highlights

The endothelial cell Tie2 receptor plays important roles in vessel development and maintenance. To study its effect on tumor vessels, Tsai and Lee engineered melanoma cells to inducibly express a soluble Tie2 receptor (Tie2Ex). This inhibitor reduced endothelial cell AKT but not ERK activation, induced their death, and im-paired vascular function. Tie2Ex induction controlled growth of smaller melanoma tumors. Larger tumors, however, were controlled only after combination therapy with sorafenib, a kinase inhibitor that inhibits endothelial cell ERK activation and proliferation. These results show the enhanced potential of antiangiogenic therapy using combinations of agents that target complementary vascular signaling pathways.

Using Aldefluor assay and FACS analysis, Jiang and colleagues isolated ALDH1-positive cells from lung cancer cells. These ALDH1-positive cells are endowed with extensive proliferation and self-renewal potential, being able to generate tumors that recapitulate the heterogeneity of the parental lung tumor cells, and therefore, having stem cell properties. ALDH1 overexpression is associated with a poor prognosis for lung cancer patients. This assay for ALDH1 could be added to the currently available panel of diagnostic markers used to improve the accuracy of clinical outcome predictions. ALDH1 would also facilitate the development of an effective therapeutic target for lung cancer treatment.

p53 and p16^INK4a are two most important tumor suppressors. To study a possible interplay between these two proteins, Leong and colleagues investigated the expression of p16^INK4a in p53 deficient mouse primary cells and various organs and found a transcriptional up-regulation of p16INK4a in the absence of p53, which is mediated by an increase in Ets1, a known positive regulator of p16^INK4a. Ets1 elevation is a result of protein stabilization due to p53 deficiency. This study uncovers a compensatory mechanism for loss of p53 and provides the basis for targeting both p53 and p16^INK4a in cancer therapy.