Evidence for the stem cell theory of cancer development

Evidence has been found for the stem cell theory of cancer development. For those of you not aware of this theory, it holds that cancers originate from cells that have inadequately differentiated from their stem cell origins. This would contrast with more standard theories of cancer development that have cells de-differentiating from a more mature state.

Evidence for this theory has been fleeting, but researchers at USC may be on to something. Laird and colleagues, publishing in Nature Genetics, look at the DNA methylation state of certain genes in colorectal tumors in comparison to normal mucosa.

DNA methylation is a means of long-term repression of genes. DNA in cells is not free-floating. It is associated with proteins called histones that keep it coiled up so that it can fit inside the nucleus. The modification of these histones with methyl or acetyl or other groups can affect how much the genes in the associated DNA are expressed. Generally, methylation is a way of turning off genes.

This paper looks at the methylation state of specific genes to infer how active those genes are in the cancer cells. Specifically, they looked at genes that are the targets of what are called Polycomb proteins. Polycomb proteins are methylators and repressors of genes that are involved in development. Specifically, they inactivate genes that allow the cells to differentiate from stem cells to whatever they are going to become. Thus, the activity of Polycomb proteins serves to keep cells more stem cell-like, and the activity of Polycomb target genes is to make the cells differentiate. More information on Polycomb proteins can be found in this review.

Which brings us to the result of this paper. When the researchers looked at the targets of Polycomb proteins in colorectal cancers they found that they were on average much more methylated than randomly selected genes.

What does this mean? It means that polycomb proteins were probably more active in the tumors and that the tumors are more stem cell-like than the normal mucosa. Since DNA methylation is generally is heritable as the cell divides -- all the progeny of the cell are likely to have similarly methylated genes -- it is likely that the origin cell of the tumor was also more stem cell-like. This is evidence that cancer comes from stem cells.

Interestingly, the authors speculate that this result may also suggest that epigenetic changes precede genetic changes in cancer. Epigenetic changes are things like DNA methylation. Whereas genetic changes -- like mutation -- were always assumed to take a primary role in tumor development, epigenetic changes may be far more important. In the press release:

Laird and his colleagues discovered that some genes repressed by Polycomb in embryonic stem cells are essentially pre-marked to become permanently silenced by DNA methylation. "This permanent silencing," Laird explains, "prevents embryonic stem cells from differentiating, and they thus become the seeds of cancer development later in life." USC researchers made these observations in relation to breast, colorectal, lung, and ovarian cancer.

Not only does the USC study provide empirical evidence for a stem cell origin of cancer, but, according to Laird, "It also supports a very early involvement of epigenetics in cancer. We found that cancer arises in cells that have already undergone epigenetic alterations," he adds, "which points to epigenetic events preceding genetic events in cancer development." Laird notes that this theory, while relatively new, is gaining support among scientists.

Hat-tip: Eurekalert.