Overview Of Cancer Stem Cells Biology Essay

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Abstract

The purpose of this project is to review surface markers of CSCs in CRC. CRC is one of the leading causes of death from cancer, in males third most common and in females it is the fourth common cause of death from cancer. CRC is more common in Western Europe, North America and Australia while rare in Asian and African.

The treatments that are available for CRCs are surgery, chemotherapy, radiotherapy and biological therapy. In most cases after therapies relapses do occur, the main cause has revealed by recent studies is the presence of CSCs in those tumours. The transformation of SCs into CSCs is because of increased variation in genes and epigenetic. At lot of work is been done on CSCs and studies found couple of surface markers including CD133, CD44 and CD166 but which marker in case of prognosis has greater impact in not known yet.

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In case of CSCs markers if exacted markers are known for CRC then future therapies can help to cure CRC permanently and also stop relapses. The therapies that are available to cure CRC till date not only cause tumour cell to die but also damage normal cell of the body. One best advantage of therapy against CSCs is it will only target CSCs so very fewer chances for normal cells get affected.

Background:

Epidemiology

Colorectal cancer is one of the leading causes of death from cancer, and incidence varies for CRC all over the world. The cases of CRC have been decreased since 1980's because of better screening and preventions. It is the third common cancer and also the second most common cause of death from cancer in UK and 90% of patients who are suffering from colorectal cancer are over the age of 50 (http://www.medicinenet.com).

Colorectal cancer is more common in Western Europe, North America and Australia while rare in Asian and African. Also there has been an increase in rate in those countries that have start eating western diet (Ajani et al 2004). CRC in males third most common and in females it is the fourth common cause of death from cancer (http://www.medicinenet.com).

CRC generally thought to arises from ADP that is mainly forms hyperproliferation in epithelial cells and crypt dysplasia (Ajani et al 2004). A national polyp study by Winawer (1999) reported that 2/3 of removed polyps were ADP and were able to form malignant transformation, if the size of polyp is larger than 1cm it took five and a half years and in case of smaller polyps it took ten years. Winawer, (1999) also found that removal of polyps decrease the incidence of colorectal cancer. Mettlin et al, (1997) studies shows most colorectal cancer arises in proximal colon.

Tumours in the colon arises from the inner wall of the large intestine, it can be benign or malignant. Benign tumours are called polyps and malignant tumours are called cancerous. Colon polyps develop when chromosome damage occurs within the cells in the inner site of the large intestine, affects the cell growth which then result into an extra massive tissue called polyps (http://www.medicinenet.com).

Risk factors:

The risk factors are mainly aging, high fat and low fibre diet, more consumption of alcohol, smoking, obesity, hereditary colon cancer syndromes mainly FAP and HNPCC and also person with family history of CRC. Also patient with crohn's disease or ulcerative colitis are 20 to 30 times more at risk than the person without those diseases (Ajani et al 2004).

Symptoms:

In case of colorectal cancer patient might be suffering from rectal bleeding, fatigue because of anaemia, changes in bowl habits and also abdominal pain. On the other hand patient could be asymptomatic but results for hemoccult test shows positive on stool specimens (Ajani et al 2004).

Therapies:

The treatments that are available for CRCs are surgery, chemotherapy, radiotherapy and biological therapy. Chemotherapy given after surgery called adjuvant chemotherapy that causes microscopic metastatic cells to die. The results for adjuvant chemotherapy demonstrated by recent studies shows very positive results for therapy within 5 weeks of surgery. Whereas only chemotherapy used to treat tumour shows very poor results. On the other hand results for reoccurrence after radiotherapy either before or after surgery are decreased; chances for reoccurrence without radiotherapy are 50% while with radiotherapy chances are less than 7% (http://www.medicinenet.com). In most cases after therapies relapses do occur, the main cause has revealed by recent studies is the presence of CSCs in those tumours. CSCs are responsible for relapses to occur after some time because they are resistant to therapies.

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The aim of study is to look for CSCs what are they and their role in the progression of colorectal cancer. Also to find out CSCs surface markers for colorectal cancer including what kind of markers are there and do they really exist? If they do exist then how they can be used in novel therapies to treat cancer for better cure and also to stop relapses.

Table 1:

Risk factors that can cause colorectal cancer.

Risk factors

Description.

Age and Diet.

Age is very important factor in case of colorectal cancer and people with higher age are at higher risk. In case of diet food with higher saturated fat and red meat and also low fibre food increased the risk of colorectal cancer. On the other hand more intakes of fruits and vegetables showed a very positive effect in most studies (Ajani et al. 2004).

Smoking and Alcohol consumption.

Those people who start smoking at early age and also higher number of cigarette smoked before age 30 are at higher risk of colorectal cancer (Ajani et al. 2004). Longnecker et al. (1990) studies demonstrated that people who had 2 drinks a day are at higher risk with 10% of colorectal cancer.

Family history of colorectal cancer.

Johns and Houlston. (2001) studies showed that colorectal cancer risk increased if a very close relative of individual developed colorectal cancer. The result of studies showed for 1st degree relative of colorectal cancer patients were 2.25 for 27 studies, the further increased in risk was shown if 2nd degree relative had colorectal cancer that was 4.25. Hereditary condition increased risk that includes FAP, HNPCC and Peutz-jeghers syndrome.

Person with HNPCC (hereditary nonpolyposis colon cancer).

Whereas in case of HNPCC colon polyps also developed and cause cancer if left untreated, but usually in the right colon, at the 30s to 40s of age. The person is also at risk of developing uterine cancer, stomach cancer, ovarian cancer and the biliary tract (website). Peltomaki. (2003) study revealed HNPCC is more common than other hereditary syndromes and most of the cases based on mutation in DNA mismatch repair gene that were identified as Hmsh2, Hmlh1, Hpms2 and Hmsh6. According to Vasen et al. (2002) two most common form of cancer in case of HNPCC family member are colorectal and endometrial cancer.

Person with FAP (familial adenomatous polyposis).

It is a hereditary colon cancer syndrome. In case of FAP mutation in APC gene on chromosome 5q occurs and cause polyps to develop. If those polyps left untreated they will then converted into cancers. Person can usually develop cancer in 40s but there are greater risk of developing cancer of thyroid gland, stomach and ampulla. Burn et al. (1991) studies shows FAP rate is 2 cases per 10000 whereas for peutz-jeghers syndrome is four time rarer.

Table 2:

Therapies used to decrease the risk of colorectal cancer.

Therapies

Description

NSAIDs

According to Thun et al. (2002) studies the results for 5 cohort and 6 control case studies shows protection against CRC by using no steroidal anti inflammatory drugs (NSAIDs). Also the study of Steinbach et al. (2000) demonstrated that in CRC the reoccurrence was successfully prevented in FAP patient by using NSAIDs.

HRT

The use of HRT shows positive results against CRC protection. The control trial was done by women's health initiation and the report shows 38% decrease in CRC after HRT used for five years (Ajani et al. 2004).

Screening

The incidence of CRC can be decreased by doing screening. For example by doing fecal occult test following with endoscopy at 5 to 10 years period. This will help people by decreasing the risk to develop CRC and then dying of it afterwards (Ajani et al. 2004).

Stem cells:

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Stem cells are defined as a special cell type that has the ability to self-renewal and differentiate into specialized cell types. They are rare in most tissues and found mainly in nerves, muscles and the cells lining of digestive system. In most parts of the body they are not very active apart from the gastrointestinal tract where they proliferate and differentiate constantly to replace dead cells. In somatic adult tissues SCs niche play an essential role by maintaining stem cells or preventing from tumorigenesis (Li and Neaves 2006).

Cancer stem cells:

CSCs are distinctive cells in tumours that have the ability to initiate tumour growth and prolonged tumour self-renewal. They thought to arise from normal stem cells or progenitor cells because they have the ability of self-renewal and proliferation. The transformation of SCs into CSCs is because of variations in genes and epigenetic. CSCs are resistant to drugs with the expression of typical surface markers of stem cells (Soltysova et al. 2005). In case of CRC recent studies found some surface markers for CSCs that are CD44, CD133, CD166, and CD24. There is still more work going related to markers mainly which marker exactly cause CRC and how to use those markers to target CSCs directly to treat CRC permanently.

Colorectal cancer stem cells

Normal adult SCs are important for the production of colonic epithelium, which exist at the base of the crypt. If mutation occur in stem cells that lead to neoplastic changes because of that SCs dissociate from epithelium and move towards mesenchyme and as a result invasive cancer formed (Salama and Platell 2009).

Salama and Platell (2009) also mentioned the presence of <1% cells those actually initiate tumours which are resistant to chemotherapies and radiotherapies. So the resistance of CSCs to therapies causes tumour relapses. In colorectal cancer the identification of normal stem cells and cancer stem cells is quite difficult because of presence in lower number. The most frequently used methods to identify surface markers of CSCs are immunohistochemistry, identification of DNA methylation pattern and RNA binding protein method.

The Wnt pathway play important role for SCs proliferation and migration, and mainly controlled by transcription factors and adhesion molecules. In case of CC the normal function of Wnt pathway get disturbed.

Functional importance of CD44

Recent studies have found some markers CD133, CD44, CD166, CD24 and..... for isolating colorectal cancer stem cells (CSC).

Du et al. (2008) studies revealed that CD44 is an important marker in colorectal CSC to initiate cancer. To prove that hypothesis Du et al. (2008) studies used samples from normal colonic tissues and primary colorectal cancer to assess the expression of CD44 and CD133 by immunohistochemistry. They were able to found CD44+ cells clustered growth but not with CD133+ cells in same tumour tissue of colorectal cancer.

Du et al. (2008) studies shows CD44+ cells have greater capacities in both in vivo and in vitro tumours. Results of western blotting and RT-PCR showed different isoforms of CD44. The knocked down of CD44 results demonstrate the downregulation of stemness genes like Bmi, Oct3/4 and β-catenin. Although Du et al. (2008) studies suggested further studies are required to understand the affect of CD44 on stemness genes expression. Du et al. (2008) found antibodies only against CD44 not against CD133.

To see the functional importance of CD44 RNA interference was used to knockdown only CD44 not CD133 in nude mice model and result showed inhibition of tumour in that model. Specific antibodies against CD44 or CD133 were also used for further test. For CD44, DF148 and 2C5 were used and CD44 function was decreased by 2C5, also clonal formation was inhibited with result P < 0.01 (Du et al. 2008).

Bourguignon LY et al, (2004) studies also found knockdown of CD44 inhibit the invasion of prostate cancer. In case of colorectal cancer targeting CD44 and signalling pathways can also play important role towards better cure for colorectal cancer therapy.

Du et al. (2008) performed experiment to see cells ability to grow tumour in xenograft for CD44 cells. According to the results three out of six patients were able to produce tumour within 28 days only from 100 CD44+ cells with average volume 14 ± 5.7 mm³, while CD44- cells were more than 10000 but the tumour volume at the 90th day was 6.4 ± 2.2 mm³. Also found patient with CD44+/CD133+ cancer cells has less tumorigenicity than only CD44+ cancer cells from same patient. The conclusion was CD44+ cancer cells have hundred times grater tumorigenicity than CD44- cells whereas CD133 did not increase tumour growth in xenograft.

Du et al. (2008) studies used sixty sample tissues and also different methods were used to assess these tissues samples for example flow cytometric analysis, tissue microarray construction and histochemistry, clonogenic and tumorigenic assays and western blotting. Statistical analysis was also carried out that showed P < 0.05 which is a significant value.

According to the findings of study Du et al. (2008) did not support the hypothesis of Ricci-Vitiani et al. (2007) which reported CD133 as colorectal CSC marker because of higher tumorigenicity in immunodeficient mice and CD133+ cells were able to form original tumour whereas CD133- cells could not. The study shows that 105 CD133- cells were not able to provoke tumour while 106 C133+ cells formed tumour within 4 to 5 weeks after transplant so study concluded that tumorigenic CD133+ cells initiate colorectal cancer so they should be target for further therapies.

Ricci-Vitiani et al. (2007) used different techniques for example to examine tumour immunopenotype flow cytometry used for CD133+ cells existence. Results revealed rare cells were present 2.5% ± 1.4%, positive for CD133 without CK20 expression. Also immunohostochemistry used for CD133+cells location in colon. In this case samples from only six patients were used and results were same for all the samples. CD133+ cells were in higher cellular density area whereas results for normal tissues show very rare CD133 expression but the limitation of study is very small numbers of samples were used.

Du et al. (2008) results were unable to support CD133 as a marker of colorectal CSC but could not exclude its role for cancer development. Also small numbers of samples were used and the results might be supported by Dalerba P et al. (2007) which demonstrated some colorectal cancer lack the expression of CD133.

CD133 Expression:

As shown by recent that colorectal cancer cells express CD133 and only CD133+ cells can initiate tumour. In Sergey et al. (2008) studies they showed that expression of CD133 not only restricted to stem cells in colon they are also expressed on differentiated epithelium in colon and to discovered that knockin lacZ model and immunostaining was used. The study also showed that both CD133+ and CD133- metastatic cells were able to form colonospheres in vitro and also form tumorigenesis in vivo.

Sergey et al. (2008) studies also found CD133+ cells can give rise to CD133- cells and those metastatic CD133- cells form aggressive tumours and was capable of tumour initiation in mouse model with expressing CD44 (CD44+ CD24-) phenotypical markers and some CD133+ cells expressed CD44low CD24+. The study also suggested that CD133 expression is not only restricted to intestinal stem cells or cancer initiating cells. Mainly CD133 is a universal marker of organ specific stem cells and tumour initiating stem cells.

Previous studies in which work was carried out to see CD133 expression commercially available antibodies were used which were might not be able to identify CD133 expression in full range. But Sergey et al. (2008) during their work designed a genetic model for CD133 expression in normal epithelium and in colon cancer by using protumorigenic IL10-/- deficient mice. So their studies have stronger point to explain their results compare to earlier studies. Also both results were compared and discussed from normal and colon cancer tissues.

Conclusion

Colorectal cancer is one of the leading causes of death from cancer and the therapies till date are not that useful to cure it in most of the cases as in other diseases. Work done by different groups and end results demonstrate that the reason therapies are not able to cure CRC from the root is the presence of very small number of cells that are resistance to therapies. Because of their resistance they are able to grow tumour again, also proposed that cells have similar properties as SCs like self-renewal and proliferation so called CSCs.

At lot of work is been done on CSCs and studies found couple of surface markers including CD133, CD44 and CD166 but which marker in case of prognosis has greater impact in not known yet. So to treat CRC by using CSCs markers more work needed to be done to know exactly which marker has more prognostic effect towards patient treatment.

In case of CSCs markers if exact markers are known for CRC then future therapies can help to cure CRC permanently and also stop relapses. The therapies that are available to cure CRC till date apart from damaging tumour cells also damage normal cells of the body. One best advantage of therapy against CSCs is it will only target CSCs so very fewer chances for normal cells get affected.