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Explain the main differences between the stochastic model of cancer and the cancer stem cell hypothesis. The stochastic model assumes that every cell within a tumor has the same potential to act as cancer stem cell. Within this model it is possible that every cell is capable of initiation and tumor propagation. These cells then can further undergo transformation by the accumulation of mutations. The heterogeneity observed in these tumors is probably due to the random genetic changes or environmental effects. It can be summarized as "transformations resulting from random mutations followed by clonal selection".
This cancer stem cell model believes that only small populations of cells in the tumor are actual cancer stem cells. The cells in the tumor are hierarchically organized. This model suggests that the cancer originate through the dysregulation of self-renewal pathways in the progenitor or tissue stem cells. The tumor heterogeneity observed is due to the production by the multipotent cancer stem cells of a wide variety of progenitor and differentiated cells. This means that as there was an expansion of the cell population, they underwent multiple genetic and epigenetic changes to finally get transformed.
Wicha MS, Liu S, Dontu G. Cancer Stem Cells: an old idea---a paradigm shift. Cancer Res February 15, 2006 66:1883-1890
Vaiopoulos, A. G., Kostakis, I. D., Koutsilieris, M. and Papavassiliou, A. G. (2012), Colorectal Cancer Stem Cells. STEM CELLS, 30:Â 363-371
Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nature Reviews Cancer 12, 133-143 (February 2012)
Explain briefly, in your own words, the clonal tumor evolution model proposed by Peter Nowell in 1976. Also, briefly explain how this model has been updated.
Peter Nowell proposed that initiation of a tumor begins with a change in a single cell followed by sequential and linear accumulation of cooperating mutations. He further argued that through selection, there is an expansion of specific subclones that acquire abnormal proliferative capacity. This can be compared to Darwin's natural selection or survival of the fittest.
However, recent studies show that the accumulation of genetic changes can occur in branching as well as in a linear fashion. This was studied in acute lymphoblastic leukemia, where a comparison was drawn between the genetic changes in the major subclone (at diagnosis) and the minor subclone (at relapse). It was observed that in some cases the genetic changes in the major subclone continued to exhibit in the minor subclone while in some cases not. This further confirmed that there unlike the sequential and linear pattern suggested by Nowell, the branching and the progression of the minor subclone cannot be disregarded.
Briefly explain some of the important problems posed by dormant (quiescent) tumor-initiating cells when developing treatments that cure cancer as opposed to managing the cancer, such as the successful management of CML with the drug Gleevac?
The hallmark mutation in CML is the Philidelphia chromosome and its fusion protein BCR-ABL. Imatinib (Gleevec) was developed to inhibit BCR-ABL and thus effectively target progenitor-like CML cells. However this drug is not able to target the tumor-initiating population of cells. This brings in the concept of the niche and the stems cells that reside in them that serve as the tumor initiating cells. In CML, the genetically modified stem cells could stay quiescent in one niche but then can be released in a more active niche thus providing a constant supply of genetically modified cells in CML. Treating with Gleevec will only target the bulk of the tumor burden and will not target these quiescent tumor initiating cells. Hence we can manage CML by keeping the tumor burden low, but there will always be a relapse since we haven't gotten rid of the source of the problem - the genetically modified tumor initiating cells.
Concerns have been raised about the animal models used to test the cancer stem cell hypothesis, especially in regards to the frequency of tumor-initiating cells in human tumors. What was the main concern raised by the study of Quintana et al. (Nature 456:593-598, 2008)? Also, explain briefly whether the study by Ishizawa et al. (Cell Stem Cell 7:279-282, 2010) agreed with Quintana et al., or reached a different conclusion about the frequency of tumor-initiating cells in the four types of human tumors examined by Ishizawa and co-workers?
Though using animals like mice in science has made it extremely easy to observe of things function in-vivo, it comes with its share of limitations. And one such concern is the use of the xenograft mouse models to understand the cancer stem cell hypothesis.
Quintana in his paper states that the use of non-obese diabetic/severe combined immunodeficient (NOC/SCID) severely underestimates the number of tumor initiating cells in the tunor. The other caveat with using animal models (mouse) is the differences in the microenvironment of the mouse versus a human. He demonstrated that the percentage of unselected melanoma cells capable of forming a tumor by performing single-cell transplantations increased significantly to approximately 25% when the NOD/SCID interleukin 2 receptor gamma chain null mice were used. Unlike their NOD/SCID counterparts who still retain the natural killer cells, the NOD/SCID interleukin 2 receptor gamma chain null (NSG) mice were more highly immunocompromised because they lacked the B, T and natural killer cells.
Ishizawa concluded that the percentage of TIC was relatively smaller than claimed by Quintana and that they vary between the different types of cancer under study. He disagreed with Quintana stating that difference between the NOD/SCID and NSG mice wasn't the only reason to see increase in TIC in the NSG mice. Certain immune based therapies have been used to treat melanoma (the cancer studied by Quintana) and therefore maybe that could be the reason why the presence of NK cells decreased the TIC in melanoma. However, this wasn't observed with Ishizawa in the 4 types of tumors examined. Another factor that could cause this variation is the grade or stage of the cancer. Metastatic melanoma was found to have more TIC's than primary tumor.
Since birth, humans ingest a variety of food articles into their body with an intention to gain nutrition. However, with this nutrition aspect of food also comes the production of toxins, either as by-products of metabolism or actual ingestion of exotoxins.
The body has set up a wonderful mechanism of detoxification divided into 3 phases. Phase I is composed of the cytochrome P450 family of enzymes. The CYP450s only alter toxic compounds slightly, adding a molecule that makes the toxin even more reactive and dangerous, but also serves as a chemoattractant to Phase II enzymes. Phase II enzymes take the toxin and connect it to other compounds that make it allow for its elimination by making it water-soluble. Phase III proteins work in getting rid of these water-soluble toxins and cell wastes into urine and feces. Healthy detoxification requires balance among Phases I, II and III. Imbalanced detoxification which includes an upregulated Phase I and downregulated or overloaded Phase II or Phase III-results in the accumulation of highly reactive toxins and garbage inside our cells which is a pre-event for the initiation of cancer.
Phytonutrients naturally found in the cruciferous vegetables (broccoli, cauliflower or brussel sprouts etc.) both increase and balance the activity of Phase I, II and III enzymes. Sulforaphane (SF) is a phytonutrient produced when broccoli is cut or chewed through the action of the myrosinase and ESP-like factor on glucoraphanin and if that doesn't happen; the gut bacteria perform the same function. Sulforaphane targets a transcription factor called nrf2 which is tightly bound to a protein called Keap1. Sulforaphane breaks the bond thus freeing nrf2, which then makes its way into the cell's nucleus and binds to a gene response element called the antioxidant response element (ARE). The antioxidant response element turns on a whole team of genes that produce proteins with antioxidant and balanced cleansing activities. Sulforaphane was isolated and identified in 1992. SF maintains the balance between Phase I and II enzymes thus helping in the detoxification process.
Carcinogenic catechol estrogen quinones are formed as the by-product of endogenous estrogen metabolism which react with DNA to form specific depurinating estrogen-DNA adducts leading to cell transformation and the initiation of breast cancer. Sulforaphane stimulates glutathione S-transferase and quinine reductase which transform estrogen quinones into safer metabolites, which can be eliminated easily. Glutathione-S-transferases (GSTs) conjugate toxins with the antioxidant glutathione; they can also directly detoxify free radicals. Glutathione transferases (GSTs) are dimeric enzymes that catalyze the conjugation of glutathione (GSH) with both xenobiotics, including isothiocyanates (ITCs), and endogenous compounds, thereby facilitating their metabolism and excretion. If this didn't happen then we would have depurinating adducts that causes cancer but causing DNA damage.
SF suppresses the phase 1 enzymes responsible for activation of carcinogens and activates phase 2 enzymes through
the Nrf2 transcription factor that is responsible for multiple detoxification processes. 4
Production of antioxidant and detoxification enzymes thought the Keap-1/Nrf2 pathway which helps in keeping the purinating adducts of estrogen metabolism at bay and thus being chemoprotective. 3
Hwang. J Med Food. 2005 Summer;8(2):198-203.
Sulforaphane inhibits breast cancer growth and induces Quinone Reductase
Shapiro, T. A., J. W. Fahey, K. L. Wade, K. K. Stephenson, and P. Talalay. 2001. Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol. Biomark. Prev. 10:501-508.
Boddupalli S, Mein JR, Lakkanna S and James DR (2012) Induction of phase 2 antioxidant enzymes by broccoli sulforaphane: perspectives in maintaining the antioxidant activity of vitamins A, C, and E. Front. Gene. 3:7. doi: 10.3389/fgene.2012.00007
Juge, N., Mithen, R., Traka, M. 2007. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cellular and Molecular Life Science. 64(9):1105-1127.
Briefly describe mechanisms by which oncogenes are activated and tumor suppressors are lost in tumors.
There are 3 mechanisms by which oncogenes are activated:
These mutations occur at specific sites and regions of a protein and cause an increased
activity of these molecules. For example- EGFR, PIK3CA and B-Raf.
There is also the aspect of qualitative change where a mutation activates an oncogene that causes a different function but the function differs when it is the same mutation in another oncogene. We see a reduced negative regulation of v-src because it lacks the C-terminal inhibitory phosphorylation site (tyrosine 537) therefore leaving it constitutively active. Certain mutations cause increased stability of proteins like in the case of Î²-catenin. Reduced enzyme activity in the case of Ras and its altered interaction with regulators are some of the other examples of activating mutations.
One of the mechanism by which we see overexpression of oncogenes is due to gene amplification (expansion of copy number of a gene within its genome). Breast Cancer (ERB-2), Gliobastoma (ERB-1) and Esophageal Cancer (Myc) are some of the examples where oncogene amplification is observed. mRNA instability is another mechanism of overexpression (such as loss of 3'UTR, miRNA targeting and alterations in miRNA expression (ocnomirs).
Fusions proteins are another way oncogenes are activated. They are generated due to chromosomal rearrangement leading to effects such as increased expression, altered protein and even new deleterious protein activity. Bcr-Abl is one such example, where the fusion of c-Abl protooncogene and the B-cell receptor leads to an increased expression of Abl thus leading to its increased activity and altered location.
Tumor Supressor Genes:
Loss of heterozygosity is one of the mechanisms of inactivation of tumor suppressor genes. This could be possible because of the normal chromosome loss, deletion, unbalanced translocation, loss and reduplication, mitotic recombination and point mutation.
The other mechanism is promoter hypermethylation. This is observed in genes like E-cadherin, Rb, BRCA1, caspase 8 etc. affecting pathways such as tumor-cell invasion, altered cell cycle control, repair of DNA damage and apoptosis respectively. We see that tumor suppressor gene TGFÎ²RII is silenced because of deacetylation and therefore bringing in the epigenetic aspect into the silencing of tumor suppressor genes.
Using Wnt signaling as an example, detail how mutations in a tumor suppressor and an oncogene can have the same effect.
We know that, APC is a tumor suppressor gene and that it is frequently mutated (frame shift or point mutations) in colorectal cancer. APC mutations most usually occur in the Î²-catenin binding (15 amino acid repeat) and Î²-catenin downregulation (20 amino acid repeat) thus preventing that interaction between Axin complex (containing APC) with Î²-catenin. This in turn causes an accumulation of Î²-catenin in the cytoplasm and therefore its entry into the nucleus causing the Wnt signaling pathway to be permanently on.
Î²-catenin is an oncogene and increases in number when APC is mutated indicating the relationship because APC negatively Î²-catenin. Î²-catenin is also mutated at its N-terminal and this prevents its phosphorylation by the APC-complex (GSK-3 Î²) leading it's to accumulation and consequent oncogenic behavior. Some of the Î²-catenin targets include oncogenic cyclin D1, E-cadherin, c-myc etc.