In vitro and in vivo models of cancer

In vitro and in vivo models of cancer

PART ONE
Question 1
In vitro and in vivo models of cancer differ in many ways. Give one example of each type of model. Describe THREE major differences between the two types of models explain the molecular and cellular bases for them. (20 pts)
The in vitro models of cancer have been employed in cases of pancreatic cancers, carcinomas and even breast cancers. It entails utilizing human tissue equivalents to carry out tests that would otherwise have been carried out using animals. A good example of such a model is the use of Alloderm, by Kataoka & Umeda et al 2009. The in vivo model usually involves the use of animals, as well as live tissues, a good example of these models include, mouse models, whereby similar cancers to the ones that affect humans are modeled in mice using methods such as xenografts. A good example of such a model is the study on prostate cancer metastasis by Havens, Pedersen & Shiozawa et al 2008.
The major differences between in vivo and in vitro models include the cellular composition of the tissues being experimented upon. In the case of the former, animal tissues are still used for experimentation, whereas in the case of the latter, one could argue that synthesized tissues, with similar characteristics to the original one, is used.
Secondly, in vivo models widely utilize the process of transplantation of animal tumors, whereas in the case of in vitro models, the mutagens are introduced to the synthesized tissue or cell cultures.
Finally, the measures described above therefore bring about a situation whereby the in vitro models are majorly cell based, whereas the in vivo models are mainly tissue based.
Question 2
Describe the mechanisms in place that ensure that passage through the cell cycle is
unidirectional. Explain the benefit of such mechanisms and describe why they are necessary. (20 pts)
A number of mechanisms usually ensure that the cell cycle is unidirectional, this mechanism include:
The irreversible nature of proteolysis, this is significant due to the fact that in most cell cycles, degradation of various regulatory proteins by kinases usually leads to the regulation of various cellular proteins, thereby ensuring that the process cannot be reversed or be derailed. The ubiquitin mediated proteolysis process however entails a more complex process that essentially involves a number of elements. Amongst them, are a complex consisting of F-box proteins, Skp1 and CDc53, although Cdc34 is also involved in the process, more so when it comes to the targeting of proteins that are supposed to be degraded.
This process of cell cycle regulation is actually quite important, as studies show that errors in the process in most cases usually lead to most cancers. A study by Gao, Inuzuka, Wei and Tseng (2009), found that over-expression of Skp2 was evident in most cancers, with its degradation in cancer cells in which elevated Akt activity was observed being protected. In a nut shell therefore, it is clear that most cancers occur when proteolysis and degradation of such regulatory proteins does not take place as it should. This therefore means that the unidirectional progression through the phase transitions is lost resulting in a mutated cell, thus cancer. This observation is particularly important when it comes to explaining the use of Akt1 inhibitors in anti-cancer treatments, more so for prostate and breast cancers.
Question 3
Describe in detail FOUR distinct mechanisms by which viruses/viral infections can promote tumorigenesis. (20 pts)
An association has long been established, between viruses and cancers, implying that viral infections do indeed play a vital role in the development of cancers. A good proven example of such a relationship is the presence of the human papilloma virus and the development of cervical cancer. This therefore means that viruses through various mechanisms usually contribute towards the development of cancers, some of these include:
Viruses belonging to the poxvirus family, such as Shope fibroma virus (SFV), Yaba monkey tumor virus and Molluscum Contagiosum virus (MCV), usually cause benign cutaneous tumors in rabbits, epidermal tumors in patients suffering from immunosuppression, as histiocytomas in monkeys respectively. Research shows that this causation can be linked to a homologue of the epidermal growth factor (EGF) known as the transforming growth factor alpha usually produced by these viruses. Thus the production of homologues could be argued to be one mechanism through which viruses promote tumorigenesis, as the homologues may compete with the normal growth factors for receptors but induce totally different cell reactions, leading to the development of tumors (Sabourdy, Casteignau, & Gelfi et al, 2004).
A simple way of describing another set of mechanisms through which viruses promote tumorigenesis, is by arguing that they provide extra growth stimuli resulting in an extension of the proliferative capacities of the cells infected. This means that the viruses essentially mess with the cell cycle control system. The viruses may impair cell cycle control by using its oncoproteins to interfere with the transduction pathways, thus resulting in uncontrolled cell cycles, thus mutated cells. Secondly, the oncoproteins may interfere with the growth suppressive nuclear proteins by inactivating them, resulting in uncontrolled growth. This interference can take place in the form of direct binding. Finally, this can take place by modulation of certain key cell cycle regulatory genes, more so when it comes to their expression (Jansen, 1996).
One could also argue that viruses can indirectly cause tumors, by virtue of contributing towards the development of the tumors but not necessarily through cellular action. A good example would be through immunosuppression, whereby uncontrolled cell growth comes about as a result of lack of normal immune control mechanisms. A good example of such a situation is the relationship between HIV and Karposi’s Sarcoma causing herpes virus.
PART TWO
Question 4
Loss of regulation by p53 is seen to be a key event in oncogenesis. Specifically, activation of p53 can result in two outcomes at the cellular level. What are those outcomes? What is the relationship, if any, between the two outcomes? What determines what the ultimate outcome will be? Provide primary scientific evidence (i.e. at least two papers) to support your answer. Be sure to point out the key experiments, the experimental/model system(s) used, what the data are and what they show, and the interpretations of that data. (50 pts)
Activation of the p53 gene usually results in the arrest of the cell cycle at the G1/S point of regulation, or the initiation of apoptosis in cases where DNA repair is impossible, as well as the activation of various cellular proteins charged with the responsibility of ensuring DNA repair in case of damage. These two outcomes are related by virtue of the fact that the gene actually halts the cell cycle to give the repair proteins time, and failure to repair the DNA results in the same outcome; initiation of apoptosis. This means that the two processes or outcomes are related and linked to each other. The level of activation of the p53 gene usually determines the outcome. The bone of contention is however how these different levels of activation are achieved. Lowe argues that activation by adenovirus E1A results in apoptosis, while activation by oncogenic ras results in senescence (Lowe, 1999). Whereas Brooks and Wei (2010) following various experiments on rats concluded that the type of activation depends on the presence of Mdm2 or Mdmx, with the loss of the former resulting in apoptosis and the loss of the latter resulting in cell repair.
Question 5
The Myc family of transcription factors include the C-Myc, N-Myc and L-Myc transcription factors. The N-Myc in particular could in my view act as a tumor growth suppressor.
In order to test this hypothesis, it would be necessary to investigate the relationship between low levels of the N-Myc and tumor development, as well as create an experiment whereby the levels of N-Myc are increased in an organism already developing tumors. Regression of the tumors would be indicative of the transcription factor’s inhibitory and suppressant characteristics, thus proving that it does indeed have tumor suppressant capabilities
Question 6
The most commonly used approach to cancer treatment is the targeting of rapidly replicating cells. Another approach entails the activation of the p53 gene in tumor cells in order to promote apoptosis in the tumor cells, or senescence. By activating p53, the cell cycle would be stopped and in essence the flawed p53 system be restored, thus ensuring that treatment is specific to only mutated cells. Another recent approach is the use of insulin potentiation therapy. This approach exploits the fact that cancerous cells usually have more insulin receptors than normal cells, thus cell targeting can be achieved by combining the chemotherapy with insulin.
Personally, I believe the approach that targets the p53 gene system, is the best, as it is target specific and quite efficient, more so considering that in some cases the normal cell cycle can be restored.

 

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