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Metastatic Cancer: Types and Causes

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Introduction

Cancer is something that many people face or is affected by in some way. Cancer is a problem that is global and always growing affecting more people as the world’s population increases. The 2012 statistics show that were about 3.45 million new cases of cancer and 1.75 million deaths as a result of cancer worldwide in the year 2012. The main cancer site being breast contributing 464,000 cases [Ferlay, Foucher, Tieulent, Et.al, 2013]. Thanks to a better understanding and better treatment of cancer like chemotherapy and cancer based drugs, there has been a decrease in death from cancer and so better survival rates for both males and females affect by cancer [Jemal, Simard, Dorell, Et.al, 2012]. The fact cancer is so prevalent worldwide is due to the many features and ways that cancer affects people. One of these features is that some cancer cells are not static. The cancer cells are able to alter and change in order to form into another cancer that is in another part of the body therefore affecting a different organ site. This ability for cancer cells to move or migrate to different parts of the body is known as Metastasis [Yachida, Jones, Bozic, Et.al, 2010] [Fokas, Cabillic, Et.al, 2007]. The fact that cancer cells are able to migrate to other sites of the body is not just random. Where the cells migrate to, is dependent on where the cancer cells was originally was before the migration. What dictates where the cancer cells go, are specific stimuli or environment within the body so that the cells are able to grow into tumours. The stimuli or environment may consist of specific receptors or chemokines that are shared or common between the two sites [Baruch, 2009]. When cancer has metastasised to a different area the site that the cancer had originated in is known as the primary cancer and the site at which the cancer cells moved to is known as metastatic cancer. A common type of metastasis is from breast to brain, with breast being the primary cancer and brain being the metastatic cancer. Breast cancer is often found to metastase to the brain, the chances of this occurring are increased when patients have HER2 over expression [Gupta, Adkins, Et.al, 2013]. HER2 comes from the human epidermal growth factor receptor family that controls response such as cell growth and cell differentiation, therefore it can be easily predicted that over expression of HER2 leads to uncontrollable cell growth a feature that is in all cancers [Rubin & Yarden, 2001]. The metastasises of cancer within patients does not affect them straight away, as it often takes years for the metastatic cancer to be detected and to affect the person. When the primary tumour has grown, only then will the tumour cells migrate and invade to another part of the body and grow at the site. When the tumour cells are at the new site then they the process of cell growth occurs at the site. But it has been shown that the tumour cells at the new site have been dormant which accounts for the time between the detection of the primary cancer and the metastatic cancer [Röcken, 2010]. The way the metastatic cancer cells move from their primary site to their metastatic site can be many ways depending on ultimately were the tumour formation will be formed in. Examples of the movement or migration are 1) local tissue invasion which is movement of the tumour cells through the tissue, 2) hematogenous spread which is the movement through the blood; 3) lymphatic spread which similar to the blood by uses the lymph nodes and finally 4) spreading through surfaces and cavities [Pepper, 2001]. There are many sites of metastatasis, below is a summary table of the sites and where they originated from [Nguyen, Bos, Massagué, 2009].

Type of Tumour

Principal sites of metastasis

Breast

Bone, lungs, liver and brain

Lung adenocarcinoma

Brain, bones, adrenal gland and liver

Skin melanoma

Lungs, brain, skin and liver

Colorectal

Liver and lungs

Pancreatic

Liver and lungs

Prostate

Bones

Sarcoma

Lungs

Uveal melanoma

Liver

Table 1: A brief summary list that shows the sites of metastasis from primary tumours [Nguyen, Bos, Massagué, 2009].

A metastatic cancer that is particularly important and of interest is metastatic cancer that is able to migrate to the brain. From the table above it can be seen that sites of metastasis for the brain is only in 3 types of tumours, these being breast, lung adenocarcinoma and skin melanoma. Out of these three types’ lung and breast tumours usually metastases to the brain making up 60% of brain metastasises [Nguyen, DeAngelis, 2004]. The reason why brain metastasis is of particular interest is because of how the metastatic cancer is able to pass through the blood brain barrier (BBB). In order to understand the movement of the blood brain barrier it structure must first be looked at. The blood brain barrier is made up of 4 main sections or parts that are of important to it function. These 4 parts are 1) tight junctions, 2) adherens junctions, 3) astrocytes, and 4) pericytes, each section has its own function as well. The tight junctions are made up of claudin, occludin, and junction adhesion molecules these are transmembrane proteins which are involved in cell-to-cell adhesion. Adheren junctions are responsible for paracellular permeability. Astrocytes are for structural supports and also for guiding of neurons and finally the pericytes are for mechanical support for cell attachment. [Lawther, Kumar, Krovvidi, 2011] [Hawkins, O'Kane, Simpson, Et.al 2006].

Parts of the BBB and the overall structure of the BBB

Figure 1: Image showing the main parts of the BBB and the overall structure of the BBB. Image was extracted from [Lawther, Kumar, Krovvidi, 2011].

Now that the structure of the blood brain barrier can be seen more clearly, a better understanding of how metastatic brain tumours form and how the cells pass through the blood brain barrier. More specifically primary breast cancer that produces metastatic brain tumour can be looked at. The tumour cells that are being metastasised are able to express vascular endothelial growth factor (VGEF). The expression of the vascular endothelial growth factor by the tumour cells is able to disrupt the blood brain barriers permeability which allows the cells to pass through and into the brain [Gerstner, Fine, 2007]. Another way to metastasise to the brain is by the tumour breast cells attaching or invading the brain microvascular endothelial cells and then passes through the blood brain barrier [Arshad, Wang, Sy. Et.al, 2011]. The survival rates of patients that have a metastatic brain tumour in unfortunately not very high. Those patients that have had primary breast cancer and then later gained a metastatic brain tumour have between 30-40% chance of death due to the metastatic brain tumour [Wadasadawala, Gupta, Bagul, 2007] [Jaboin, Ferraro, DeWees, Et.al, 2013]. There are treatments available that help fight against metastatic brain tumours the main one and most effective being radiotherapy. However the effectiveness of radiotherapy is dependent of where the tumour cells had originated from i.e. which primary cancer the patient had first. Those that had primary lung or breast cancer are more sensitive to the radiotherapy treatment. Other types of treatments include Craniotomy, Postoperative radiotherapy, and Stereotactic radiosurgery. The treatment that is craniotomy is not used often as it is stressful for the patients. Postoperative radiotherapy is also an effective treatment that improves the life of the person, however there are side effects or conditions that can occur as well like disorder of the nervous system or dementia. The final treatment stated is Stereotactic radiosurgery which involves using gamma radiation on the site of the tumour [Shibui, 1999]. With the use of radiation is the fear of persevering the nearby cells and tissues. With the advancement of science and technology the treatment of using radiotherapy has become better. The use of radiotherapy is still the main treatment but with better radiotherapy processes and technique the preservation of the cells and tissue from radiation has greatly improved [Owonikoko, Arbiser, Zelnak, Et.al, 2014].

Epithelial–mesenchymal transition (EMT)

Epithelial–mesenchymal transition (EMT) is defined as a biological process that occurs within polarised epithelial cells which interact with the basement membrane. The polarised epithelial cells undergo many biological changes that brings about a mesenchymal cell phenotype, these changes include an increased ability of migration, invasion and develop a resistance to the process of apoptosis [Kalluri & Weinberg, 2009]. There are keys differences between the epithelial cells and the mesenchymal cells. Epithelial cells are cells that form layers, which are tightly packed by membrane structure such as tight junctions, gap junctions’ adherens junctions and desosomes. These cells do possess an ability of motility, however under normal condition they remain they do not move. In comparison the mesenchymal cells are not organised into layers like epithelial cells. The main difference between the two is that mesenchymal cells are very motile whereas epithelial are not normally [Thiery & Sleeman, 2006].The whole process of epithelial–mesenchymal transition plays a role in normal development. These normal developments include gastrulation which is an early phase in embryonic development and heart morphogenesis which need and take advantage of the transition between the epithelial cells into mesenchymal cells. Another key role of the EMT is that it is for the down regulation of E-cadherin [Larue & Bellacosa, 2005]. E-cadherin is a tumour suppressor that is encoded by the Cadherin-1 (CDH1) gene that is key for the suppression of carcinoma progression. It has been found and seen that the loss of the Cadherin-1 at EMT sites are linked to the formation, development of cancer. The reason for this is due to the fact that the loss of the E-cadherin increases the ability of invasion in cells [Wang & Shang, 2013].

As with any biological process there are transcription factors that cause and regulate the transition. The transcription factors that mediate the processes are SNAI1 which down regulates E-cadherin, Zinc finger E-box (ZEB) and also basic helix–loop–helix transcription factors [Lamouille, Xu, Derynck, 2014]. There are features and properties of the mesenchymal cells that can be linked to cancer if not regulated properly. The mesenchymal cells are able to produce and secrete chemokines and growth factors that stimulate cell growth and angiogenesis. Another key feature of the mesenchymal cells is that they have anti apoptotic properties that can stop or save cells from undergoing apoptosis [Murphy, Moncivais, Caplan, 2013]. Just from seeing the features of the mesenchymal cells it can easily be seen that if the regulation of the process, mutation or changes in expression occur the consequences can be predicted and linked to the formation of cancer. The final aspect of epithelial–mesenchymal transition is how it is linked to the formation of cancer and more specifically metastatic cancers. As stated epithelial–mesenchymal transition is regulated by many growth factors and proteins such as Epidermal growth factor, Hepatocyte growth factor and Transforming growth factor beta, all of which if changed by mutation or expression can ultimately contribute to the hallmarks of metastatic cancer like uncontrollable cell growth and invasion into other tissues and organs in the body which is the main feature of metastatic cancer [Gos, MiÅ‚oszewska, Przybyszewska, 2009]. Below is a diagram that summarises and shows the process of how epithelial–mesenchymal transition can promote the formation of metastatic cancer [Kongemail, Liemail, Wangemail, Et.al, 2011].

How epithelial-mesenchymal transition can be linked to metastatic cancer

Figure 2: A summary of how epithelial–mesenchymal transition can be linked to metastatic cancer. EMT is the process of epithelial–mesenchymal transition and MET is the process of Mesenchymal–Epithelial Transition. Image taken from [Kongemail, Liemail, Wangemail, Et.al, 2011].

The image above shows the transition of a primary tumour into a metastatic tumour and reason for this to happen. Red arrows show aspects that may be gone wrong due mutation or change in expression through methylation.

Epigenetics

Epigenetics is the genetic control by using factors that does not include a person’s DNA sequence [Simmons, 2008]. Epigenetic control or regulation is the process whereby genes are activated or deactivated within a cell [Mitsuyoshi Nakao, 2001]. Essentially the concept of epigenetics is the change in gene expression that can be caused by certain mechanisms such as DNA Methylation or Histone modification. These changes in gene expression whereby expression of a gene is switched on or off can be inherited and passed on. The idea of epigenetics and its mechanism is needed for maintenance of genes that are specific to tissues. Changes in the process of epigenetics, like DNA Methylation or Histone modification causes disruptions in a genes function, which alters its expression and is one of the hallmarks of how cancer begins [Sharma, Kelly, Jones, 2010]. As stated there two ways that can causes changes, histone modification and DNA methylation which will be the main focus of this paper. The process of histone modification to a certan extent is reversible depending on the type of modification. The process of DNA methylation is more long term creating long-term repression [Cedar & Bergman, 2009]. DNA methylation is the common mechanism in which genes are activated or deactivated by the addition of a methyl group to cytosine or adenine bases, making it an epigenetic signal tool. Changes in the process of DNA methylation can result in a gene being constantly activated or deactivated which can lead to brain tumours or other tumours in the body [Phillips, 2008]. The process of DNA methylation is catalysed by the family of enzymes known as DNA methyltransferases. DNA methyltransferases is an important enzyme in epigenetic silencing of transcription. As this is a family of enzyme there are many types of DNA methyltransferases which are DNMT 1, DNMT 2, and DNMT 3 each one having their own function [Simmons, 2008] [Fakhr, Hagh, 2013]. There are two types of DNA methylation these are 1) Hypermethylation and 2) Hypomethylation. Hypermethylation stops transcription in the promoter region of suppressor genes which ultimately lead to gene silencing [Das & Singal, 2004]. The location at which hypermethylation occurs at are known as CpG sites, these are sites were cytosine is next to guanine. It is the cytosine in these CpG sites that are usually methylated and therefore switched off [Esteller, 2002]. Hypomethylation is the loss of methylation at regions or sites that are normally heavily methylated, for example satellites like SAT 2. The loss of the methylation at SAT 2 can lead to instability and oncogene activation (Jin, Li & Robertson, 2011). Oncogenes when activated increases protein expression which in turn leads to increase in cell division, decreases in cell differentiation and the inhibition of cell death [Chial, 2008]. It is the mutation of a proto-oncogene by hypomethylation that makes an oncogene which is the cause of increase in cell division and therefore the cause of an abnormal growth of cells that leads to tumours and cancer. A proto-oncogene is the normal, non-mutated gene that regulates cell division making it controllable by balancing cell growth and death. There many types of proto-oncogenes these include WNT, RAS and ERK [Chial, 2008] [Torry, Cooper, 1991]. To summarise the idea of Epigenetics is the control of gene expression using DNA methylation or Histone modification. If any of these two processes are damaged or mutated this then means the control of gene expression can no long be controlled and so this leads to increase in cell growth and therefore tumours and cancer.

Methylation of Promoter Region

The DNA methylation of the promoter region within genes is as stated an epigenetic event that is linked to transcriptional silencing in cancer. This means that DNA methylation in this region is for the control of gene expression [Yang & Park, 2012]. The promoter region of gene is a region that starts or causes the initiation of transcription [Gordon, Chervonenkis, Gammerman, 2003]. The process of methylation in the promoter region causes the expression of genes to reduce or in the in case of cancers cause the silencing of the gene altogether. There are two ways that this happens in the promoter region. One of the ways it can occur is the inhibition of sequence-specific transcription factors which contain CpG sites. The second way is by the use of methyl-CpG binding proteins which can compete for binding sites of methylated DNA [Robertson & Jones, 2000]. E-cadherin was introduced to have a key role in epithelial–mesenchymal transition. If there is methylation more specifically hypermethylation in the promoter region of the E-cadherin then this can cause the silencing of the gene which has been linked to many types of gastric cancer also known as stomach cancer [Tamura, Yin, Wang, 2000]. Another gene that is important and methylation of it has been shown and linked to astrocytic brain tumour is the Methylguanine-DNA methyltransferase (MGMT). Methylguanine-DNA methyltransferase’s function is as a repair protein that can remove promutagenic alkyl groups’ guanine in DNA. DNA methylation in the CpG Island of the Methylguanine-DNA methyltransferase means that its function in order to remove promutagenic alkyl groups is decreased [Nakamura, Watanabe, Yonekawa, Et.al, 2001].


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