About cancer stem cells

Cancer has been defined in many ways. Starting from Hippocrates' observation of angiogenesis, the word cancer itself refers to the thick blood vessels that feed the tumours and that resemble the claws of a crab.

Research has come forward a long way and different approaches are now being used to look at cancer. Here we hope to answer some of your questions that relate to cancer stem cells:

Types of stem cells - what's the difference?

Stem cells are cells that are required for the maintenance of high cell turnover tissues where cells continually need to be replaced.

They constitute a small population of relatively undifferentiated cells that express no "differentiation" or specialisation markers of the tissue. They are slowly self-renewing with each cell division producing an average of one stem cell and one what is called a transit-amplifying or progenitor cell (Figure 1). This progenitor cell has limited proliferative potential, undergoing terminal differentiation to form the functioning cells of the tissue required.

This differentiation (or potential to become specialised) is guided by internal signals controlled by genes/DNA within the cell and related signals such as chemicals secreted by other cells and physical contact between cells also known as the microenvironment.

Diagram showing how cancer stem cells could arise
This shows how a normal stem cell creates a new stem cell and a progenitor cell. The normal progenitor cell then matures into differentiated (specialised) cell required by the body. An event such as a direct genetic mutation or effect from external factors could make these cells mutate or de-differentiate i.e. lose their specialisation at any stage. These affected cells could then produce a cancer stem cell. (With inspiration from Therese Winslow’s artwork)

The difference between an embryonic stem cell and a non-embryonic "somatic" or "adult" stem cell is really down to the level to which they can change themselves into different cell types, so the therapeutic potential in medical terms of the embryonic stem cell is probably very broad and that of the adult stem cell is much narrower.

An embryonic stem cell has the remarkable capability of changing itself into every one of the several hundred different cell types that make up the human body. It is classed as undifferentiated. These cells, which form the early stage embryo were discovered by Cardiff University President Professor Sir Martin Evans, Mario R. Capecchi, and Oliver Smith in 2007 - they received a Nobel Prize for their endeavours.

An adult stem cell is already committed and has a much more limited range of pathways. In many tissues, they serve as an internal repair system to replenish cells without limit while the person is alive. Cells are lost through wear and tear, injury or disease for example in the gut, blood/bone marrow, skin, muscle and brain. In some cases, stem cells found in organs such as the heart and pancreas only divide under special circumstances.

Embryonic and adult stem cells
This shows very simply how a fertilised egg can develop into a blastocyst (this has an inner mass of cells) which is the source of stem cells. These can produce all the cells of the foetus, whereas the adult has a limited stem cell supply.

Induced Pluripotent Stem Cells (IPSC) are adult stem cells that have been grown in special conditions to reprogramme them, so they are in a more stem cell-like state. This has been done in a laboratory.

Cancer stem cells, like all stem cells, are unspecialised (i.e. they have no tissue-specific structures), they can divide and renew themselves for long periods and they can give rise to specialised cells. They can therefore recapitulate tumour heterogeneity as they can be found in tumours. Research so far has suggested they also have multi drug and radiotherapy resistance

We know there may be more similarities between cancer stem cells and normal stem cells, further research in needed to identify and characterise these cells, efforts are also now being directed towards identifying therapeutic strategies that could target these cells.

Cancer stem cell theory
This shows the initial theory of how cancer stem cells can maintain a tumour. Even with conventional cancer therapy the cancer stem cells survive and the cancer can relapse but if we can identify cancer stem cells and develop specific treatment the patient outcome could be improved as the tumour would regress or enter remission.

Why are scientists excited about cancer stem cell research?

If we are right about cancer stem cells, they offer the possibility of transforming our ability to treat cancer. ie increasing how long and how well patients can live after diagnosis.

There is growing evidence that cancer stem cells are crucial to the formation of tumours. Not only can they renew themselves, they can generate all the other types of cells observed in the tumour. Therefore, it should be possible to treat cancer by eliminating all the cancer stem cells in tumour – rather than attacking all the tumour cells, as has happened in the past.

Cancer stem cells have already been shown to be capable of initiating leukaemia. Work conducted here at Cardiff shows they also play a role in the onset of skin cancer. However, the situation with other types of cancer is much less clear.

Is has been said that cancer stem cells (CSC) are 'rare in number and indefinite in potential'. The Goldie-Coldman hypothesis (1979) suggested that a small percentage of cells in a tumour harbour intrinsic characteristics that make them resistant to treatment. The tumour stem cell theory may support this hypothesis and could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics, including the ability to give rise to a new population of cells with resistant phenotype.

There may also be stages of CSC evolution. For many tumour types, there can be de novo mutations or events leading to primary CSC - which are varied. The biology of primary CSCs may therefore be heterogeneous. Properties such as CSC frequency, cell-surface phenotype, and drug sensitivity may vary as a function of the specific mutations as well as the nature of the normal cell type in which the primary events occur. Then in tumour progression further events may occur either as a consequence of intrinsic tumour pathogenesis and/or challenge with chemotherapy. Selective pressures associated with neoplastic progression may lead to a higher frequency of functionally defined CSC in secondary or metastatic stages as well inter-patient and intra-patient variability of CSC properties (Rosen and Jordan Science 2009; 324:1670-1673). All of which need further investigation.

Cancer stem cell theory 2
This shows another theory of how cancer stem cells can conserve a tumour. There may in fact be more than one type of cancer stem cell so with conventional cancer therapy the tumour mass is maintained. But again if we can identify cancer stem cells treatment could be improved.

Is there a difference between CSC and tumour initiating cells?

No, the terms tend to be referred to interchangeably.

Can you briefly describe a cancer stem cell?

Cancer stem cells may represent a small tumour cell sub-population that can initiate and maintain cancer growth.

What does a cancer stem cell look like?

They look the same under the microscope but they express a unique combination of surface molecules.

Tumour regression
Pictures from Dr Richard Clarkson (Cardiff University) showing how Cancer Stem Cells grown in the laboratory can be killed over time – a model of tumour regression.

Where do we find cancer stem cells?

Within the tumour or very closely linked ie initiating leukaemia.

What are the potential benefits?

We can hopefully beat the mechanisms of drug resistance currently seen in treatment & that contribute to relapse so that cancer therapy can be more directed.

Useful films and posters

Films

Professor Hans Clevers and colleagues at the Hubrecht Institute in the Netherlands have a great film, which shows how stem cells with a genetic mutation in the adenomatous polyposis coli (APC) gene can possibly initiate cancer within the gut.

Poster links

A good cancer stem cell poster has been designed by Nature and Abcam and with Abcam's permission you can download the PDF here.