Cancer therapy is one of the most rapidly advancing fields in medical biology. In mere decades, survival rates have significantly increased and undergoing chemotherapy is a far more pleasant experience than it used to be. While improvements have clearly made, the amount of cancers that remain stubbornly resistant to chemotherapy remains substantial. Patients can appear to respond well to a treatment, only to see the cancer return either in the same location, or even somewhere else, within a few months or years. Figuring out what is behind this resistance – termed chemoresistance – is crucial, as the clinical benefits would be significant for patients whose tumours had previously been seen as incurable.
One model that has been suggested to be responsible for this chemoresistance – and a number of other characteristics of cancers – is the cancer stem cell (CSC) model. CSCs are exactly as the name suggests; a cancer cell that has similar characteristics to stem cells. Stem cells are a form of cell that plays crucial roles throughout our development: embryonic stem cells are the cells from which every cell in the body will eventually derive. As such, they have the ability to go down numerous differentiation pathways (the range of cell types a stem cell can become is referred to as its potency) depending on the external stimuli. Stem cells also play a role in adult tissues. Numerous systems, such as the haematopoietic system and the crypt structures that provide a constant supply of cells to the intestinal epithelium, have stem cells at the ‘top’ of their differentiation hierarchy.
Adult stem cells are often restricted to maintaining certain tissues and as such their potency is less. The two key characteristics of stem cells are their ability to self-renew and their ability to produce differentiated progeny. Essentially, when stem cells divide they can either produce two identical daughter cells, this is called symmetrical division and works to maintain the stem cell population, or they can produce one cell identical to itself and one that has undergone a step of differentiation and is committed to becoming a terminally differentiated cell, this process is referred to as asymmetric division.
Keeping these concepts in mind is important when considering CSCs. These cells are thought to function in the same way as ‘normal’ stem cells, but in the niche of a tumour. They too are thought to be able to perform the two main functions of stem cells: self-renewal and production of more differentiated progeny. In terms of the tumour, that equates to a constantly maintained population of CSCs constantly feeding the tumour with a fresh supply of cancer cells. Of crucial clinical importance, CSCs are thought to be highly resistant to a number of chemotherapeutic strategies. The mechanisms responsible for this are varied and are thought to be a result of the CSCs retaining similar characteristics to normal stem cells. These include an enhanced response to DNA damage, a strategy often employed by cancer therapies to induce death in cancer cells, the production of transporters that remove drugs from a cell before they can have their effect and the expression of proteins that prevent the normal mechanisms of programmed cell death, induced by many chemotherapies, from occurring. As a result of this resistance, current generations of chemotherapy may not clear the CSCs which due to their stem cell-like characteristics, can re-seed the tumour. As such, therapy that specifically targets CSCs would be required to completely cure a cancer.
The issue that arises with targeted therapy is that you need to determine a way of separating the CSCs from the other cancer cells in a tumour. As yet, very few CSC markers have been identified so targeted therapy is some way off. However, for those cancers that have potentially had a CSC marker characterised targeted therapy is beginning to be seen as clinically feasible. One of these is colorectal cancer, one of the most common cancers in both the UK and the world. Both the incidence and mortality of colorectal cancer in this country have remained stubbornly high and it is thought that research into potential CSC markers may allow for a more successful treatment strategy. Recently, a marker called LGR5 has been found to be present in a large number of colorectal samples and it is thought that this may a CSC marker. Furthermore, LGR5 was found to be a product of an enzyme called COX-2, which is overexpressed in a high proportion of colorectal cancers and whose activity has been causally linked to a number of the characteristics of colorectal cancer. As such, it is thought that drugs that inhibit the action of COX-2 may be of use therapeutically, alongside traditional therapies.
While more evidence is required to fully establish the existence of CSCs, this hypothesised model does explain a number of the characteristics of cancers and the way they respond to therapy. Namely, the resistance of many cancers to traditional chemotherapeutics and furthermore the significant heterogeneity that exists both within an individual tumour and between the tumours of different patients. It is thought that targeted therapy that specifically removes cancer stem cells will significantly improve the response to chemotherapy.
