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Cancer Stem Cells: a New Approach to Tumor Development

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Cancer Stem Cells: a New Approach to Tumor Development REVIEW ARTICLE KOBAYASHI NCC ET AL. Cancer stem cells: a new approach to tumor development NATÁLIA CRISTINA CIUFA KOBAYASHI1*, SAMUEL MARCOS RIBEIRO DE NORONHA2 1Full Teaching Degree in Biological Sciences – Graduate degree in Molecular Biology, United Metropolitan Colleges (FMU), São Paulo, SP, Brazil 2PhD – Department of Allergy and Immunology, University of São Paulo (USP), São Paulo, SP, Brazil SUMMARY Many theories have been proposed to explain the origins of cancer. Currently, evidences show that not every tumor cell is capable of initiating a tumor. Only a small part of the cancer cells, called cancer stem cells (CSCs), can generate a tumor identical to the original one, when removed from human tumors and transplanted into immunosuppressed mice. The name given to these cells co- mes from the resemblance to normal stem cells, except for the fact that their abi- lity to divide is infinite. These cells are also affected by their microenvironment. Many of the signaling pathways, such as Wnt, Notch and Hedgehog, are altered in this tumoral subpopulation, which also contributes to abnormal prolifera- tion. Researchers have found several markers for CSCs; however, much remains to be studied, or perhaps a universal marker does not even exist, since they vary Study conducted at United among tumor types and even from patient to patient. It was also found that Metropolitan Colleges (FMU) cancer stem cells are resistant to radiotherapy and chemotherapy. This may ex- Article received: 4/24/2014 plain the re-emergence of the disease, since they are not completely eliminated Accepted for publication: 4/24/2014 and minimal amounts of CSCs can repopulate a tumor. Once the diagnosis in *Correspondence the early stages greatly increases the chances of curing cancer, identifying CSCs Address: Rua Padre Pedro Rigo, 310 in tumors is a goal for the development of more effective treatments. The ob- Postal Code: 09895-750 São Bernardo do Campo – SP jective of this article is to discuss the origin of cancer according to the theory of [email protected] stem cell cancer, as well as its markers and therapies used for treatment. http://dx.doi.org/10.1590/1806-9282.61.01.086 Keywords: neoplastic stem cells, biological tumor markers, SCID, mice, local Conflict of interest: none neoplasm recurrence. INTRODUCTION However, this concept was discredited in the twen- Cancer is among the diseases that kill more people in the tieth century with the Theory of Dedifferentiation, which world, and its chance of cure is directly linked to early de- states that tumors are derived from the unlimited growth tection. One example is cervical cancer, which has 85 to of cells regressing from a more differentiated state to a 100% cure chance in stage I, while in level III tumors, this simpler, pluripotent, state.3 estimate drops to 50%.1 The development pattern called stochastic suggests Tumors have the same population of cells seen in the that tumors are homogeneous masses that may be deri- normal tissue: stem cells, cells that are dividing and will ved from any cell that composes them, provided that the differentiate, fully differentiated cells, and dead cells. The- necessary mutations have occurred. New research has se cells that are dividing and about to differentiate have shown that cancer development follows a hierarchy whe- a limited number of divisions until they do so, and die. re only a subset of tumor cells is responsible for its ori- In cancer, however, they continue to divide and do not gin and generate all cell lines forming the tumor.4 die, causing their accumulation.2 The idea that cancer could arise from stem cells emer- DISCUSSION ged in the nineteenth century. According to a theory pro- Origin and characteristics posed at the time, the human body had remnants of em- The division of normal stem cell is asymmetric, origina- bryonic tissue, which after a change in the environment ting a new stem cell (self-renewal) or a cell that will diffe- or surrounding tissues would return to cell division and rentiate. This process is highly controlled by several sig- produce cell masses similar to that tissue.3 naling molecules and growth factors.5 86 REV ASSOC MED BRAS 2015; 61(1):86-93 CANCER STEM CELLS: A NEW APPROACH TO TUMOR DEVELOPMENT Cancer stem cells are named like this because they tion of this pathway in pancreatic cancer cells themsel- present the following properties, very similar to normal ves has not had any effect on the tumor.12 stem cells: The WNT pathway, in turn, controls the proliferation and migration of cells. In patients with colorectal cancer, 1. Self-renewal capacity. however, it is dysregulated. High concentrations of β-catenin 2. Chance to differentiate. are found in the nucleus of tumoral cells that lost expres- 3. Great expression of telomerase. sion of E-cadherin. These cells are associated with metas- 4. Evasion from apoptosis. tasis and a lower chance of survival. Moreover, nuclear 5. Increase in transportation of substances through the β-catenin increases the expression of survivin, which pro- membrane. motes cell proliferation and resistance to apoptosis.13 6. Ability to migrate and, in the case of CSCs, to gene- The Notch pathway, along with WNT, maintains the rate metastases.6 homeostasis of stem and progenitor cells by inhibiting their differentiation. Notch is also responsible for the expansion Due to these similarities, there are two hypotheses for their of neural and mammary stem cells. Disorder in this path- emergence: either a) the stem cells themselves would un- way is connected to self-renewal in medulloblastoma tumors. dergo mutation and become cancer stem cells, or b) dedif- Inhibition of this pathway resulted in CSC apoptosis.13 ferentiation of already differentiated cells, providing them It has also been discovered that specific miRNAs, such pluripotency.7 There is also a third option that proposes a as miR-302a, have an important role in the control of plu- rare fusion between normal stem cells and other cells.8 ripotency by activating genes involved in cell cycle, epige- When dividing, both CSCs and normal stem cells give netic modifications, and epithelial-mesenchymal transi- rise to two different cell types. The first maintains the tions. Researchers have shown that miR-302a expression property of self-renewal.7 These are cells that, when ta- is capable of causing dedifferentiation of skin cancer cells, ken from a human tumor and transplanted into non-obe- proving that miRNAs are also able to reprogram cells into se, diabetic, immunosuppressed mice (NOD-SCID mice), a pluripotent state.11 form a new tumor similar to the original.9 The second type is that of tumor cells which are ca- BIOMARKERS OF CANCER STEM CELLS AND pable of differentiating but unable to initiate a tumor.7 THERAPEUTIC APPROACHES Cancer stem cells have been found in myeloid leukemia, CONTROLLED BY NICHE breast cancer, prostate cancer, ovarian cancer and some Adult stem cells are responsible for tissue maintenance and types of brain tumors.14 homeostasis. If there is any damage, for example, they start Tumor markers such as CA 125 and prostate antigen, to divide in order to regenerate the lesion.10 But they are not for example, are the most commonly used forms to in- constantly in mitosis. The niche, a microenvironment formed vestigate the disease. But they come from differentiated by adjacent cells, must send signals so that these cells can cells in the midst of tumors already formed.6 Neverthe- leave their state of dormancy and enter cell division.6 less, CSCs are the beginning of cancer, and detection Unlike adult stem cells, CSCs have unlimited divisions.10 would allow for earlier diagnosis. Autocrine and paracrine signaling pathways, such as Several biomarkers have been used to identify CSCs WNT, Notch, Hedgehog, TGF-β, and tyrosine kinase re- in many types of cancer: CD34CD38- for acute myeloid ceptors are strongly associated with the control of can- leukemia; CD44-CD24- and ALDH for breast cancer; 11 high cer stem cells. CD133 for the brain; CD44α2β1 CD133 for prostate For example, the Hedgehog signaling pathway plays cancer; CD44 for head and neck; CD133, EpCAMhighCD44, a pivotal role in organogenesis, patterning and mainte- ALDH1 for colon cancer; ESACD44CD24 and CD133 for nance of stem cells. It can act as a morphogen by indu- pancreas; side population (flow cytometry) for mesenchy- cing cell differentiation or as a mitogen, leading to pro- mal cancer; CD133 for lung; CD90 for liver cancer, ABCB5 liferation of precursor cells and mediating the interaction for melanomas, and CD133 for ovarian cancer.12 between mesenchymal and epithelial compartments.4 However, a universal biomarker for these cells may This pathway also plays an important role in the mainte- not exist. Studies have demonstrated that the most wi- nance of tumors associated with stromal cells. Its inhibi- dely used marker for brain tumor, CD133, is not present tion in stromal cells associated with pancreatic cancer in all tumors, and also that CD133- cells are capable of showed suppression of tumor growth. However, inhibi- forming tumors.4 REV ASSOC MED BRAS 2015; 61(1):86-93 87 KOBAYASHI NCC ET AL. Based on the principle that all types of cancer have in bodies against CD123 also avoided grafting of these cells common an excessive proliferation of affected cells, and into mice, and decreased tumor load in those with already that more differentiated cells have a lower rate of division, established disease.16 therapeutic approaches were developed such as induction The origin of the leukemic stem cells is still contro- of differentiation and destruction of these differentiated versial. Since both are capable of self-renewal, it is possi- cells. But none of these approaches can cure cancer com- ble that leukemic stem cells are normal hematopoietic pletely.5 Studies have proven that removing as much as stem cells that have undergone accumulation of muta- possible of the tumor does not mean cure, because mini- tions.
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