Cancer stem cell

From Wikipedia, the free encyclopedia

Cancer stem cell theory is the theory that tumors arise from cells termed cancer stem cells that have properties of normal 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.

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. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate a new one. 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.

Contents 1 Evidence for cancer stem cells 1.1 Mechanistic and mathematical models 2 Cancer stem cell pathways 2.1 Bmi-1 2.2 Notch 2.3 Sonic hedgehog and Wnt 3 External links 4 References

[edit] Evidence for cancer stem cells

Opponents of the paradigm do not deny the existence of cancer stem cells as such. Cells with some degree of "stemness", especially with unlimited self-renewal potential, must exist to sustain the growth of a tumor. 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.

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.^[1]

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.^{[citation needed]}

The idea of cancer cells arising from a common origin has been thoroughly explained and published as the Unitarian or Trophoblastic thesis of cancer in the July 1950 issue of the Medical Record. It states that cancer -- differentiated trophoblast proliferation -- is part of the healing process, and the disease only manifests if its control (immune response and nutrition) are impeded.

[edit] Mechanistic and mathematical models

Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models,^[2] 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 be employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.^[3] Considerable work needs to be done, however, before the clinical efficacy of such models is established.

[edit] 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.

[edit] Bmi-1

The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma^[4] and later shown to specifically regulate HSCs^[5]. The role of Bmi-1 has also been illustrated in neural stem cells.^[6] The pathway appears to be active in cancer stem cells of pediatric brain tumors.^[7]

[edit] 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^[8] stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary^[9] and other tumors.

[edit] Sonic hedgehog and Wnt

These developmental pathways are also strongly implicated as stem cell regulators.^[10] 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.^[11] This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.^[12]

[edit] External links

• "Cancer Stem Cell Scientific Literature Review", UMDNJ Stem Cell Research and Regenerative Medicine, June 17, 2006
• "Stem cells may cause some forms of bone cancer", News-Medical.Net, December 7, 2005
• "The Bad Seed: Rare stem cells appear to drive cancers", Science News Online, March 20, 2004
• "The Real Problem in Breast Tumors: Cancer Stem Cells", Genome News Network, March 7, 2003
• [1] Stem Cell and Cord Blood information database

[edit] References

Stem cells
Sources:  Embryonic stem cells | Adult stem cells | Cancer stem cells
Related articles:  Stem cell treatments | Stem cell controversy | Stem cell line | Progenitor cell | Cell differentiation