The Role Of Cancer Stem Cells In Tumour Progressions Biology Essay

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Lung cancer was once thought to be an incurable disease, causing widespread deaths among global communities and has thus come to the forefront of scientific research predominantly after the finding of cancer stem cells.

Cancer stem cell's share similar properties to normal stem cells in that both have the ability to self-renew, differentiate and proliferate. These cells have been described to be the driving force behind many cancers and thus targeting these cells has become first priority in terms of finding a cure for cancer.

CD133 is an antigen marker which has been linked to target lung cancer stem cells. Evidence suggests that CD133 expression rises during tumorous activity in the lungs. Recent breakthroughs in the treatment of non small-cell lung cancer have been found by inhibiting the epidermal growth factor pathway using gefitinib. It has shown to improve survival rate and standard of living for lung cancer patients.

Thus, there are major improvements in the understanding of cancer stem cells and their ability to be influential in lung cancer, nevertheless there seems to be a lack of specific tumour markers which can be used to target cancer stem cells which should be exploited for further research.

Keywords: cancer stem cells; lung cancer; stem cell markers; CD133; ALDH; gefitinib

Introduction:

Lung cancer is an exceptional case of cancer, being the number one cause of cancer deaths in the United Kingdom and the United States (Ries et al. 2005), which is why the pathogenesis and treatments of lung cancer has become a hotspot for researchers.

Lung cancer is proven to be the world's commonest cancer (Cancer Research UK 2008); approximately 1,300,000 people are diagnosed with lung cancer per annum (Cancer Research 2008). There seems to be a trend between gender, age, geographical location and cigarette smoking to the incidence of lung cancer (Cancer Research UK 2008).

Lung cancer is the second most common cancer in the U.K, in men over the age of 40, whereas it is the third most common cancer in women (Cancer Research UK 2008). However, recent data suggests that the incidence of lung cancer in women is increasing (Cancer Research UK 2008), which may be due to the onset of smoking cigarettes, or as a result of passive cigarette smoke.

The survival rate for lung cancer patients is exceptionally low; for example, between the years 1996-1999, the five year survival rate for lung cancer patients was only 6% (Wood et al. 2000). This may be because so little is known about lung cancer biology and usually when a patient begins to feel symptoms of the cancer and feels a second opinion from a GP is needed, the cancer is already in motion and difficult to inhibit (Wood et al. 2000). Logically, this should make us think what the mortality rates of lung cancer are. According to Cancer Research UK statistics, approximately 7% of UK deaths are due to lung cancer (Cancer Research UK 2009).

Fig. 1: The mortality rates of lung cancer in the UK, taking into account age and gender.

Image taken from Cancer Research UK (Cancer Research UK 2009)Figure 1, shows the lung cancer mortality rates of the UK population in 2007 (Cancer Research UK 2009). It can be seen that it is rare for lung cancer to be fatal up to the 35 to 39 age group. The rate of lung cancer deaths increases progressively for both men and women; the greatest mortality of lung cancer is present in the 75 to 79 group; with 3800 male deaths and 2750 female deaths. This chart shows once again how common lung cancer is in men than women. In the 75 to 79 age group, the rate of male deaths due to lung cancer is almost double that of the female rate.

Lung cancer is caused by a number of factors such as exposure to radiation and chemicals such as asbestos; however it is believed that carcinogens present in cigarette smoke and the age that the individual began smoking is the leading cause of lung cancer with smoking cessation improving an individual's health (Taylor et al. 2002).

Once an individual is predisposed to an environmental factor such as cigarette smoke or through genetic mutations; the control of cells that the body once had becomes reduced, resulting in tumorous cells which evade the immune system. This may occur as a result of changes in the first line of cells affected, known as stem cells. The focus of this project is to critically analyse if there is a relationship between normal stem cells and cancerous stem cells and whether they share similar properties albeit in an uncontrolled manner (Kim et al. 2008).

Current treatments for lung cancer include radiotherapy (Grills et al. 2003), chemotherapy (Eberhard et al. 2005) and surgical removal of the tumour or part of the lung (Rami-Porta et al. 2005). These forms of therapy have reached a plateau for treating lung cancer, because they target only the bulk of the tumour cells. Figure 2 shows that if we aim to treat only the tumorous cells then a relapse of the cancer may occur, especially with the growing feeling among researchers that there may be a small population of cells that are the driving force behind the cancer. Therefore, this project will try to find if these cancer stem cells exist as a small population of cells, and whether they can be targeted to potentially cure lung cancer.

There has been great interest from researchers concerning cancer stem cells. CSC's have elicited a response from many researchers into finding novel markers and therapies which are specifically expressed on the cancerous stem cells in the lungs. This project will refer to the specific markers which will be used to target lung CSC's and potential new therapies that are being looked into, such as anti-angionesis therapy (Shepherd and Sridhar 2003); tyrosine kinase inhibitors (Rosell and Felip 2000); epidermal growth factor inhibitors (Mok et al. 2009) and vascular endothelial growth factor inhibitors (Sandler et al. 2006).

Even though there are numerous therapies being used, conventional chemotherapeutic therapies are becoming less effective due to increased drug resistance (Stewart et al. 2007). Therefore, it is imperative that new drugs which target lung cancer stem cells are developed which as a result will be more effective.

Fig.2: The flaws of current conventional cancer therapies and proposing therapy that targets cancer stem cells (Frank 2008)

Aims:

The aims of my project are firstly to critically analyse the existence of cancer stem cells and their roles in the progression of lung cancer.

In addition to this I will focus on whether there are specific molecular markers for cancer stem cells which can be targeted through various methods as a means of potential treatment of lung cancer.

Stem Cells:

Stem cells are extremely important in the intricate workings of the human body. Their function is to maintain correct functioning of cells (i.e. to help with tissue damage). Stem cells are the ancestral cells for all neural (Clarke, 2003), lung (Eramo et al. 2008), skeletal muscle (Seale et al. 2002) and breast cells (Dontu et al. 2003) as well as numerous other cells.

They have the ability to self-renew, differentiate into different cell lineages and also to proliferate in greater numbers (Jordan et al. 2006). This notion can be described by imagining a tree (Figure 3) where the stem cell being the root/trunk with the ability to self-renew and differentiate to multiple progenitor cells; the branches of the tree are the multiple progenitor cells which are the progeny of cells that have almost differentiated; the leaves of the tree are numerous, symbolising the different blood, brain, lung, breast, prostate and colon cells etc (Sell 2004). The falling leaves may signify the death of mature cells and by means of specific regulators, the stem cells receive signals to self-renew, differentiate and proliferate into the desired cell lineage (Sell 2004).

Stem cells reside in a niche that manipulates the self-renewal, differentiation and proliferation ability that stem cells possess (Li and Neaves 2006). For example, hematopoietic stem cells reside in the bone marrow microenvironment which controls the differentiation and proliferation of these stem cells (Li and Neaves 2006). The bone marrow microenvironment consists of stromal cells which secrete growth factors such as granulocyte colony-stimulating factor, IL-3 and erythropoietin (secreted by the kidney) which regulate self-renewal, differentiation and proliferation of specific cell lines (Bociek and Armitage 1996). Lung stem cells may also have a specific niche in the epithelial lining of the airways (Kim et al. 2005).

Fig. 3: Shows the functions of stem cells and their similarities with a tree (Sell 2004).

4. Falling Leaves

APOPTOSIS

3. Leaves

DIFFERENTIATED TISSUE CELLS

2. Branches

PROGENITOR CELLS

Roots and Trunk

STEM CELLS

Many cells

Few Cells

According to Sell (2004), if cell proliferation increases and the number of cell loss decreases this could explain why cancer arises.

Cancer Stem Cells:

The idea of cancer stem cells existing as a small subunit of cells that are the underlying source of tumour initiation is a controversial topic for scientists. The confusion of whether cancer stem cells (CSC's) exist is present because there are similarities with normal stem cells and CSC's; such as both share the ability of self-renewal, proliferation and differentiation (Jordan et al. 2006). However, normal stem cells are multi-potential (Gupta et al. 2009) in that they are able to produce different cell lineages, but it is still undecided if CSC's also have the ability to produce cells of different lineages (Kitamura et al. 2005). Therefore, how is it possible that these CSC's initiate tumours for example, in the lungs, breast or brain? Even so, recent studies have been able to separate single CSC's from solid tumours with differing tumour marker properties (Kitamura et al. 2009).

For example, CD44+ and CD24- are markers which can be used to identify breast cancer, and CD133+, CD44+ and CD24+ are markers which are expressed on cancer stem cells present during pancreatic cancer (Kitamura et al. 2009).

It has been touched upon that cancer may arise as a result of increased rate of cell proliferation and reduced rate of apoptosis (Sell 2004). The question to be asked is why does the rate of cell proliferation increase? It is thought that this may arise due to one of many risk factors that may cause cancer, such as genetic mutations, radiation and chemicals such as asbestos can predispose an individual to cancer. Although recent studies have found that carcinogens present in cigarette smoke are the main cause of cancer in the lungs (Taylor et al. 2002).

Many researchers have argued that mutations result in the rise of 'mutated progenitor cells' rather than initial mutations in the stem cell (Jordan et al. 2006), (Kitamura et al. 2009). These progenitor cells have the ability to proliferate and produce tumorous cells, but do not have the ability to self-renew unlike CSC's (Jordan et al. 2006). It is thought that mutations within the progenitor cell allow it to obtain self-renewing properties, becoming CSC's (Jordan et al. 2006) as shown in figure 4.

Fig 4. The different ways that a cancer stem cell can arise and ultimately cause cancer (Jiang 2008).

Before lung cancer stem cells are discussed, it will be useful to mention several of the cancer stem cells that may be present in some solid tumours.

There seems to be small population of stem cells located in the colonic mucosa which can undergo mutation, resulting in the formation of CSC's and thus colorectal cancer. These CSC's show customary self-renewal and differentiation capability (Klonisch et al. 2008). In addition, the underlying cause of tumorigenesis in pancreatic cancer may also be cancer stem cells present in the pancreatic stem cell niche, which express high levels of CD133+ (Kitamura et al. 2009).

Lung Cancer Stem Cells:

It has been discussed that there may be a sub population of cells that initiate cancer, known as cancer stem cells. Regarding lung cancer, researchers have provided evidence that there are small populations of cells present in the anatomy of normal lungs that can mutate into CSC's and induce cancer (Kim et al. 2005).

Kim et al. (2005) identified specific stem cells in the lungs which they termed as 'Bronchioalveolar Stem Cells' (BASC's), which they found to have similar properties to normal stem cells such as; the ability to self-renew and differentiate. These stem cells are located in close proximity to non-ciliated cells known as Clara cells and aim to maintain their cellularity in the lining of the bronchi (Kim et al. 2005). The Clara cells have the ability to defend and repair the epithelial cells that line the airways of the lungs (Atkinson et al. 2008). This could suggest that a mutation in BASC's can result in the progression of cancer with an increase in the number of tumor cells, which inadvertently reduces the number of Clara cells and a build up of injured cells in the airways.

One issue with Kim et al. (2005) research is that some of the results that they found on the existence of BASC's in the lungs and their role in cancer (after activation of K-ras) were based on culture techniques in vitro and not in vivo, thus the microenvironment that a stem cell is usually present in, cannot be reproduced with certainty in an in vitro study.

A strength of their research however, is that they were the first researchers that provided solid evidence that progression of lung adenocarcinoma can occur due to BASC's becoming cancerous (Kim et al. 2005), which could counter the issue of having results based on in vitro studies because they were still able to provide proof of cancerous BASC's present in the airway niche.

Targeting cancer stem cells in the lungs:

Thus far, it has been discussed the role cancer stem cells play in the progression of lung cancer. Lung cancer biology is poorly understood and as a result conventional therapies such as chemotherapy have not been as successful in treating lung cancer compared to other cancers, proven by the mortality rates of lung cancer (Cancer Research UK 2009). It is imperative that research is carried out to improve the poor prognosis that lung cancer patients witness, which is what the rest of this project will focus on.

Firstly we need to ask the question; can we target cancer stem cells present in the lungs? This may lead to a breakthrough in new treatments which may alleviate the pain that lung cancer patients suffer from, or even potentially cure the cancer.

The importance of specifically targeting cancer stem cells as a form of treatment is shown in figure 2. At the present time chemotherapy and radiotherapy are the standard methods of treatment; these aim to treat the majority of tumorous cells which can eventually reduce the tumour bulk. However in figure 4b, it can be seen that if a small population of cancer stem cells are the driving force behind a tumour, there will always be a production of tumorous cells. This may be corrected by targeting cancer stem cells directly through specific markers associated with the Bronchioalveolar stem cells present in the lung epithelium (Kim et al. 2005).

The idea of cancer stem cells can be simplified if we try to imagine cancer as a war. The opposing army is the cancer and our army is trying to fight the cancer. During the war the enemy army have; 10,000 soldiers which are the tumour cells and 100 hidden snipers which are the cancer stem cells. If we kill the 10,000 soldiers of the enemy army we have not won the war because the snipers will still be present and leave an opportunity for more soldiers to join the fight. Therefore, the only way to win would be to employ a similar tactic to specifically target the snipers and kill them also, so when we eliminate the 10,000 soldiers we win the war.

This should be the basis of cancer treatment and there are numerous researchers who have found specific markers for bronchioalveolar stem cells in the lung epithelium which will be explained in further detail. Table 1 notes the various markers which can be expressed on CSC's in different cancers.

Specific Markers for Lung Cancer Stem Cells:

There are a number of potential markers that have been found for different cancers which scientists are aiming to target to form a treatment against cancer. Table 1 shows us these various markers. From this point on, the possible markers for lung cancer will be explained and analysed.

Type of Cancer

Possible Markers expressed on CSC's

Breast

CD44+, CD24-.

Colon

CD133+, CD44+, CD166+.

Lung

CD133+, ALDH, PODXL-1, uPAR.

Pancreatic

CD133+, CD44+, CD24+.

Table 1: Various markers which can be expressed on CSC's in a number of solid tumours.

CD133:

CD133 is a glycoprotein antigen (Meng et al. 2009) which is expressed on a number of cells such as hematopoietic stem cells and neural stem cells among others (Eramo et al. 2008). CD133 has been found in brain, prostrate and colon cancer (Eramo et al. 2008). However, it is still being researched as a marker for lung cancer. Eramo et al. (2008) analysed if lung cancer stem cells express CD133 through immunohistochemical, immunofluorescence and microbiological culture techniques and if they have the ability to induce a tumor.

Eramo et al. (2008) concluded that in the normal lung cell niche it is very rare for CD133+ to be found. However in lung cancer the level of CD133+ increased as they found that when they isolated and introduced tumorous CD133+ into immunocompromised mice models; tumorous growth appeared in the lungs of the mice (Eramo et al. 2008).

A downside to this however, is that mice models are not the same as human models and trying to justify results based on mice models can lower the strength and integrity of the result. On the other hand, this study has the strength of paving the way for further research of CD133 expression in lung cancer stem cells and providing a potential to target this marker and remove the cancerous bronchioalveolar stem cell.

Meng et al. (2009) found that both CD133+ and CD133- are expressed equally in bronchioalveolar stem cells (Eramo et al. 2008), which is incoherent with the Eramo et al (2008) study and previous research, and thus concluded that CD133 cannot be used as a clear-cut marker for lung cancer.

However, using both the Eramo et al (2008) and Tirino et al. (2009) studies as a basis of proof for CD133+, it can be argued that Meng et al. (2009) may be incorrect. Tirino et al. (2009) found that levels of cells expressing CD133+ in non-small-cell lung cancer cells increased. Approximately 72% of patients expressed CD133+ in all of the specimens that were tested with non-small-cell lung cancer, and the mean percentage of CD133+ cells was 6% (Tirino et al. 2009). This again could suggest that a small population of cells (CSC's) exist which express the CD133+ marker, which can be used as a future form of treatment.

Aldehyde Dehydrogenase:

Aldehyde dehydrogenase (ALDH) is an enzyme which catalyses the oxidation of aldehydes into carboxylic acids (Ucar et al. 2009). ALDH has many roles, but it has been researched that certain isotopes of the ALDH enzyme increase during lung cancer (Ucar et al. 2009), and can perhaps be used as a marker for lung cancer. Ucar et al. (2009) hypothesised that the activity of ALDH biochemically can be a potential lung cancer stem cell marker. Research by Moreb et al. (2007) wanted to study the role of ALDH in specific lung cancer cell lines and provided evidence that Aldefluor staining can be used to detect ALDH in lung cancer stem cells and was also able to detect the heterogeneity of ALDH in certain lung cancer cell lines (Moreb et al. 2007). This is important in terms of research for lung cancer and cancer stem cells, because if more accurate techniques of analysing potential markers such as ALDH is used; and if we do find a correlation between increased ALDH and BASC's then a potential therapeutic target may be found.

Podocalyxin-like protein 1 (Podxl-1):

PODXL-1 is a marker found on hematopoietic stem cells, although not directly specific for lung cells; Koch et al. (2008) did find that PODXL-1 is positively expressed on epithelial cells in the lung airways and can thus be used as a possible marker for targeting cancer stem cells in the lungs.

Urokinase Plasminogen Activator Receptor (uPAR):

uPAR has been found to increase during certain tumours, usually affecting cell migration and ultimately metastatic potential of the tumour (Gutova et al. 2007). Gutova et al. (2007) found in their study that there are a small population of cells in SCLC, which express uPAR. This can be further researched into as a possible target for treating lung cancer.

Novel Therapies for Lung Cancer:

Phosphatidylinositol 3-kinase (PI3K) and mTOR Inhibition:

Yang et al. (2008) found that the oncogenic K-Ras (permanently activated Ras due to Ras gene mutation) activates PI3K, which they showed caused the proliferation of bronchioalveolar stem cells (Yang et al. 2008). PI3K activation has been shown to increase resistance to conventional chemotherapy and radiation (Yang et al. 2008).

mTOR is known as 'mammalian target of rapamycin,' it is a serine/threonine kinase which commands cell growth, differentiation and proliferation (Marinov et al. 2007). Activation of mTOR and P13K will activate Akt which then sets off a cascade that allows for cell survival and cell proliferation (Marinov et al. 2007). Figure 5 shows the role PI3 and mTOR play in the growth (expansion) and proliferation of cells and in this case, BASC's (Yang et al. 2008). The BASC's can survive because Akt activates NF-kB which can help the cells to evade apoptosis.

Therefore, it could be possible to inhibit PI3K and mTOR to prevent BASC proliferation, limiting the growth of the cancer. A drug currently being used in transplantation to inhibit P13K is LY294002, which has shown to increase apoptosis and reduce cell growth (Marinov et al. 2007). This is a great finding and may help to limit the growth of the cancer and improve prognosis.

There is also a question to be asked. How does PI3K and mTOR inhibitor affect normal cells? The treatment of lung tumours via the PI3K or mTOR pathways may reduce the proliferative ability of the BASC's, but it may also affect normal cells because both PI3K and mTOR play a crucial role in preventing cell death via injury which may occur as a result of hypoxia, physical injury or infections. Therefore, if PI3K/mTOR is inhibited there is increased predisposition to a diseased state or vulnerability to infection.

Fig. 5: PI3 & mTOR pathway to visualise what could happen during cancer if PI3 or mTOR is increased (Marinov et al. 2007).

Anti - Angiogenesis Therapy:

Angiogenesis is a process which occurs normally in a human body to allow for growth of cells (Shepherd and Sridhar 2003), through specific angiogenic factors which increase blood vessel vascularity and vascular permeability (Gazdar 2000). Normally angiogenesis is not an issue, as it will almost always be in homeostasis. However, during lung cancer the rate of angiogenesis will increase which will encourage new blood vessels to appear, also known as neo-angiogenesis (Shepherd and Sridhar 2003). This is a problem when the tumour is on the verge of metastasis, because the new vessels allow some of the tumorous cells to escape into the bloodstream (Shepherd and Sridhar 2003).

Table 2, shows the various anti-angiogenic therapeutic tactics which are being researched or are in clinical trial.

The targets described in this table can provide a possible treatment if clinical trials are published with positive results. It may provide a breakthrough in treating and limiting the growth of the cancer, which in terms of lung cancer is surely a great step in science.

Vascular endothelial growth factor (VEGF) receptors have been found to play a fundamental role in neo-angiogenesis, resulting in the formation of tumours (Reck and Crino 2009).

There has been success in inhibiting VEGF receptors by means of isolating monoclonal antibodies which are directed against VEGF, thus inhibiting their binding to blood vessels and reducing the creation of further blood vessels which assisst the tumour bulk. An approved VEGF inhibitor is bevacizumab (Avastin), which acts as an antibody against VEGF receptors (Reck and Crino 2009) starving the tumours from nutrients restraining their growth.

Bevacizumab treatment for NSCLC has undergone a number of clinical trials before being approved for first line treatment. The phase III study performed by Sandler et al. (2006) found that when bevacizumab was administered along with paclitaxel and carboplatin the patient responded well, compared to the control group (without bevacizumab). The average survival rate for advanced NSCLC with bevacizumab treatment was found to be greater than 1 year, whereas without bevacizumab it was found to be less than a year. This suggests that bevacizumab instigates an effect on the angiogenesis pathway because a large number of patients general survival improved in Sandler et al. (2006) clinical trial.

It can be argued that Sandler et al. (2006) study was gender and culture biased in that more males than females, and more participants of white ethnicity were selected to participate. This could be an issue because the effect of bevacizumab may be different in males and females and between different culture groups.

Avastin treatment is a major finding in lung cancer treatment, yet the impact of this drug on the normal processes within the body are drastic. Fatal side effects produced by bevacizumab are numerous and include; severe bleeding, hypertension, febrile neutropenia, hemoptysis and proteinuria, approximately 14 patients died as a result of toxic effects due to bevacizumab (Sandler et al. 2006) .

Angiogenic Inhibitor

Function

Lung cancer population

Marimastat BB2516 Inhibitor (MMPI)*

Marimastat causes the breakdown of basement membranes and allows for growth of tumour and survival of BASC's (Shepherd and Sridhar 2003). Important to inhibit.

Small Cell Lung Cancer (Shepherd and Sridhar 2003)

VEGF

Binds to VEGF receptors present on endothelial cells to reduce angiogenesis (Reck and Crino 2009). Avastin anti-VEGF antibody is an approved drug against angiogenesis (Sandler et al. 2006).

Non Small Cell Lung Cancer (Sandler et al. 2006)

Interferon Administration

Prevents endothelial cell migration and prevents and hence, inhibits tumour growth and proliferation (Shepherd and Sridhar 2003). Administer into patient to inhibit angiogenesis.

In clinical trial for Small Cell Lung Cancer (Shepherd and Sridhar 2003).

Table 2 - suggesting the inhibition of Marimastat, VEGF and administration of interferon may reduce angiogenesis and thus cancer inhibition.

*MMPI = Matrix metalloproteinase inhibitors (Shepherd and Sridhar 2003)

Epidermal Growth Factor Receptor (EGFR) Inhibitors:

Fig. 6: The numerous effects that the EGFR pathway can elicit, aiding the progression of cancer (Gazdar 2010).Epidermal growth factor pathway has been proven to be involved in cancer via its role in cell proliferation, anti-apoptosis and the spread of tumorous cells (Rocha-Lima and Raez 2009). This is shown in figure 6. It is thus important to see treatments which have focused on EGFR inhibition.

There has been great success in the use of EGFR inhibitors for the treatment of advanced lung cancer (Mok et al. 2009). Although this treatment does not specifically target cancer stem cells it is still successful and a great finding for lung cancer treatment in its own right. Gefitinib (also known as Iressa) is an EGFR inhibitor which has been approved for the treatment of advanced non-small cell lung cancer (Mok et al. 2009). Mok et al. conducted a study on 1,217 patients originating from Asia, showing that gefitinib treatment provided a 12 month survival rate of 24.9% compared those who were on conventional chemotherapy with a survival rate of 6.7%, also finding that those under gefitinib treatment had a better quality of life due to lesser symptoms.

A limitation of the Mok et al. (2009) study is that their patient sample size decreased because the patients either died (due to lung cancer) or they refused to participate after consent, resulting in reduced validity of the study. In addition, 112 patients were excluded from their study due to having excessive/reduced levels of numerous constituents of blood serum, which may again reduce validity due to not finding the true effect of gefitinib; however this may not be a flaw as the researchers may aim to exclude anomalous results.

A further EGFR inhibitor which has been approved for the treatment of advanced non-small cell lung cancer is erlotinib, also known as Tarceva (Tsao et al. 2005). The study conducted by Tsao et al. (2005) used tissue biopsies from lung cancer patients and aimed to see whether erlotonib has any prognostic value and if the tumours contained EGFR. They found that the samples of certain patients were sensitive to erlotonib if patients showed increased expression of EGFR; however they concluded that it did not make a difference to the patient's survival (Tsao et al. 2005).

A study conducted by Shepherd et al. (2005) also found that after 24 months of being treated with erlotonib, the overall response rate to erlotonib was approximately 8.9% compared to the placebo group which was less than 1% (Shepherd et al. 2005). This shows that patients responded to erlotonib treatment and the general surival rate of those treated with erlotonib is prolonged.

Conclusion:

Lung cancer is a grave issue in our lifetime and there are many factors around us which could predispose us to this dangerous disease, especially in the elderly. Therefore, it is important to understand and research the biology behind this cancer.

The first aim of this project was to analyse the existence of cancer stem cells (CSC's) and if so, to further uncover if there were a sub-population of cancerous stem cells that could be found in the lung niche. All in all, the studies which have tried to prove/disprove the existence of CSC's, has allowed myself to come to the conclusion that there are a rare population of stem cells that have self-renewal ability which can instigate the progression of cancer and if administered into a animal model; will have carcinogenic effects.

It has been found and proven that bronchioalveolar stem cells (BASC's) are present in the epithelium of the airways, which have self-renewal and differential properties and together with Clara cells aim to maintain the cellularity of epithelia surrounding the lungs. A mutation in the BASC's may cause this homeostasis to shift towards over-populating the area with tumorous cells and as a result, a reduction in Clara cell function. This can ultimately lead to lung cancer pathology.

Lung cancer is an international problem, being the number one cause of cancer death around many countries in the world. If we imagine 1,300,000 people around the world being diagnosed with lung cancer (Cancer Research UK 2008), and told that there is no cure for this disease and even the steps taken to alleviate the pain is still not enough, should raise questions into the success of cancer science. Taking these figures into account, researchers have aimed to find novel therapies and methods of targeting the BASC's for future therapy.

At this present in time, it is virtually impossible to say that there is one clear cut cure for lung cancer, but what can be said is that it is promising to learn that BASC's have been shown to express specific antigen expression of CD133, PODXL-1 and uPAR. In addition to this, we are beginning to understand certain biological processes such as ALDH, PI3K/mTOR and angiogenesis which in the future may allow us to specifically target CSC's in the lung via antigen expression in conjunction with the inhibition of cancer promoting pathways.

CD133 has been backed up by various research studies and refuted by some. Even though CD133 expression can be found in other cancers; it could be used for lung cancer successfully if combined together with conventional radiotherapy and chemotherapy, taking into account drug resistance CD133+ BASC's could exhibit.

Furthermore ALDH and PI3K/mTOR understanding has been beneficial in the study of cancer stem cell targeting and inhibiting specific parts of the pathways may consequently have the potential to be a remarkable discovery for the treatment of lung cancer, however careful consideration should be taken to account for normal cell homeostasis.

Iressa, Tarceva and Avastin have all gained success in terms of prolonging a patient's life expectancy, but this is not a total cure for lung cancer. This suggests that even with novel therapies being produced, there is a plateau of current lung cancer treatments and the only way to possibly correct this would be to find a definite CSC marker and target it for treatment. This project has researched some of the CSC markers related to lung cancer and a fair conclusion would be to say that there is a lack of specific markers to target the cancer stem cells which trigger tumorigenesis.

To conclude, the direction that researchers should follow is to find more specific markers for lung cancer stem cells, as this would allow for the invention of a drug that can in due course cure lung cancer.

Finally, lung cancer is thus a pressing disease but our world is full of scientific enthusiasts who share the same dream of curing lung cancer. Working as a team using methods of trial and error and understanding the intricate processes causing lung cancer we may come to a point in time and say that we are a part of cancer treatment history.

Acknowledgements:

I would like to thank Dr H. Modjtahedi for providing moral support and pushing me in the right direction to complete this project. I would also like to thank my mother and father for giving me the opportunity to get this far in life.

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