by Monya Baker
Two papers point to how cancer cells go astray
A growing body of research in breast cancer, leukaemia and brain cancer shows that cancer stem cells co-opt the pathways of regular stem cells to maintain themselves and resist treatments. Two recent studies in acute myeloid leukaemia have used very different techniques that each point to the likelihood of uncovering strategies to target cancer stem cells while sparing healthy stem cells.
A genomewide expression analysis led by Irving Weissman at Stanford University in Palo Alto, California, used samples from acute myeloid leukaemia (AML) patients to identify thousands of genes that are expressed differently between haematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). Comparing the two types of cells implicates both the usual suspects and some unexpected pathways as contributing to disease1. It also points to an analytic technique that can ferret out critical pathways regulating cancer stem cells.
This analysis is the first to use independently derived datasets to compare LSCs with normal HSCs from the bone marrow. Microarray gene-expression profiles were collected on different microarray platforms and at two universities, with both cell types studied at both universities. A combined analysis of the samples (7 for normal bone marrow HSCs and 16 for AML stem cells) revealed just over 3,000 differentially expressed genes, and these genes were then fed into separate pathway-analysis tools. Results from the different datasets and analyses were similar. The top dysregulated pathways are involved in adherens junctions, regulation of the actin cytoskeleton, apoptosis, MAPK signalling, and Wnt signalling. Also implicated were some pathways that had not previously been thought to regulate LSC function: these related to sex hormones, fatty acid synthase, angiotensin, and others. Though these differences will need to be functionally assessed, they may offer new targets for therapeutic intervention.
Unrelated work, also at Stanford, indicates that leukaemia does indeed activate a stem cell program to maintain itself, but when it does so, it activates an embryonic rather than an HSC program2. Researchers led by Michael Cleary worked in a mouse model of AML in which the disease was initiated by the oncogene MLL. They found that, for certain subtypes of the gene MLL, some leukaemic cells were more proliferative than others. They also discovered that the gene transcription and chromatin regulatory elements that help maintain the LSCs resemble those found in embryonic stem cells more than those seen in stem cell programs found in adult tissues.
The first step to identifying targeted cancer drugs is finding differences between healthy and cancerous cells. Though these papers do not go on to identify actual therapies, they go a long way toward making the first steps of identifying those differences.
Sourc: Nature