Cancer stem cell

From Molecular Biology Wiki

Cancer stem cell hypothesis states that tumors arise from cells termed cancer stem cells that have properties of adult stem cells, particularly the abilities to self-renew and differentiate into multiple cell types, and that these cells persist in tumors as a distinct population that likely causes disease relapse and metastasis - they are the only cells capable of, by themselves, giving rise to new tumours.

Cancer stem cell specific and conventional cancer therapy

The main question posed by proponents of the theory is "Are we targeting the right kind of cell?" Most existing cancer treatments were developed on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study and was largely neglected by most researchers.

Another problem lies in the fact that the efficacy of cancer treatments are, in the initial stages of testing, often measured by the amount of tumour mass they kill off. As cancer stem cells form a very small proportion of the tumour, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of cancer stem cells, which gave rise to it, remains untouched and may cause a relapse of the disease.

Development of specific therapies targeted at cancer stem cells holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease, where little progress has been made in recent years.

Evidence for cancer stem cells

Opponents of the paradigm do not deny the existence of cancer stem cells as such. Cancer cells must be capable of continuous proliferation and self-renewal in order to sustain the growth of a tumor, as normally, differentiated cells cannot divide indefinitely (constrained by the Hayflick limit). However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties there is no incentive to focusing on a specific subpopulation.

Cancer stem cells were first identified in certain types of leukemia in 1997 by John Dick and colleagues at the University of Toronto. These cancer stem cells were harder to identify in solid tumors because researchers then did not possess the means of recognizing the surface markers of these cells (characteristic proteins on the surface of a cell) that had been developed for a stem cell that makes red and white blood cells. Their findings were published in Nature Medicine in 1997. Bonnet and Dick^[1] isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34⁺/CD38^- subpopulation is capable of initiating tumors in NOD/SCID mice that is histologically similar to the donor.

In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small fraction of the injected cells, the cancer stem cells, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.^[2]

Further evidence comes from histology, the study of tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.^[3]

The existence of leukaemic stem cells prompted further research into other types of cancer. Cancer stem cells have recently been identified in several solid tumours, including breast cancer,^[4] brain cancer^[5] and colon cancers.^[6]

Mechanistic and mathematical models

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models,^[7] e.g., based on the cell compartment method. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.^[8] Considerable work needs to be done, however, before the clinical efficacy of such models is established.

Where do cancer stem cells come from?

This is still an area of ongoing research. Logically, the smallest change (and hence the most likely mutation) to produce a cancer stem cell would be a mutation from a normal stem cell. Also, in tissues with a high rate of cell turnover (such as the skin or GI epithelium, where cancers are common), it can be argued that stem cells are the only cells that live long enough to acquire enough genetic abnormalities to become cancerous. However it is still possible that more differentiated cancer cells (in which the genome is less stable) could acquire properties of 'stemness'.

It is likely that in a tumour there are several lines of stem cells, with new ones being created and others dying off as a tumour grows and adapts to its surroundings.^[9] Hence, tumour stem cells can constitute a 'moving target', making them even harder to treat.

Treatment Difficulties

In addition to the factors mentioned above (that current research methodologies are inadequate and that the stem cell population may change), there are further difficulties.

Normal tissue stem cells are naturally resistant to chemotherapeutic agents - they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells).

Also, there has been a lot of research into finding specific markers which may differentiate cancer stem cells from normal cancer cells, with some success.^[10] This may allow drugs to directly target the stem cells.

Cancer stem cell pathways

A normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it. Scientists working on cancer stem cells hope to design new drugs targeting these cellular mechanisms. The first findings in this area were made using haematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease whose stem cell origin is most strongly established. However, these pathways appear to be shared by stem cells of all organs.

Bmi-1

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma^[11] and later shown to specifically regulate HSCs.^[12] The role of Bmi-1 has also been illustrated in neural stem cells.^[13] The pathway appears to be active in cancer stem cells of pediatric brain tumors.^[14]

Notch

The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary^[15] stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary^[16] and other tumors.

Sonic hedgehog and Wnt

These developmental pathways are also strongly implicated as stem cell regulators.^[17] Both Sonic hedgehog(SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand.^[18] This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.^[19]

References

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