October 20, 2020

The Niche

Knoepfler lab stem cell blog

If it walks like a duck and quacks like a duck…how do we tell different cells apart?

The stem cell field is faced with a dilemma.

Stem cells and some non-stem cells are sometimes too similar to tell apart.

Even worse, stem cells and cancer cells are especially similar. If one focuses specifically on cancer stem cells (aka tumor initiating cells), the similarity between cancer stem cells and normal stem cells is even more pronounced.

From the point of view of the old expression “if it walks like a duck and quacks like a duck, it must be a duck”, many very different cell types would all be classified as one type: ducks. After 20 years looking at cells under the microscope, as a cell biologist I can tell many cells apart that look very similar. However, there are many cell types that are indistinguishable by microscopy. In fact, there are many cell types that by more precise, cutting edge assays, such as looking at gene expression patterns, are also indistinguishable or very nearly so.

Complicating life further, the populations of what we call pure cultures of cells, such as an embryonic stem or iPS cell line for example, actually exhibit substantial internal heterogeneity. Thus, if you looked at 1 million stem cells from a single dish, all 1 million are actually different from each other in some ways, some very subtle and some dramatic. And every day that you culture cells in a dish they can and do change. Once transplanted into a patient cells may change their properties as well.

Telling cells apart is important for many reasons. One important reason is that certain cells might be endowed with more positive properties, while other cells may possess very negative properties. However, these “good” and “bad” cells might not be easily distinguished.

A prime example would be comparing stem cells and cancer stem cells, which have striking similarities.

One main difference between “normal” stem cells and cancer stem cells would appear to be that normal stem cells behave according to rules and differentiate when their environment tells them that that is their fate. In contrast, cancer stem cells have the ability to break the rules and escape differentiation a certain percentage of the time. The same kind of difference applies to cell death. At certain times, normal stem cells trigger their own death based upon external or internal signals, but cancer stem cells often fail to die under these circumstances. However, these differences in behavior might not manifest clearly.

What makes cancer stem cells behave differently? At this point, the molecular differences between normal and cancer stem cells remain fairly obscure. In fact, in many ways at the molecular level normal and cancer stem cells are indistinguishable. For example, in terms of gene expression normal and cancer stem cells exhibit similar patterns. Cancer stem cells also express many core pluripotency factors such as Nanog and Oct4. Many pluripotency factors, such as Myc and Klf4, are outright oncogenes. Cancer stem cells also express some of the cell surface markers that scientists use to purify by cell sorting or to identify “true” stem cells.

What this all means is that determining cell identity remains an ongoing challenge in the stem cell field and as a field we need to get far better at it.