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Colon cancer is one of the most common types of cancers currently diagnosed. This being the case, it is important to understand the mechanisms of action behind colon cancer so that preventive measures can be taken when possible. The purpose of this paper is to discuss the development and treatment of colon cancer. This includes the mechanisms of action that takes place within the body as well as how a diagnosis is made and the course of action that is taken to treat colon cancer.
Understanding Colon Cancer
Cancer is a general term used to describe a large category of disease that encompasses about one hundred different types of specific diseases with different etiologies. It is an important topic to discuss because of its high prevalence in society; in 2012, the expected number of newly diagnosed cancer cases is 1,638,910 (American Cancer Society, 2012). When looking at the different types of cancers, colon cancer is one of the most common types diagnosed in individuals, being expected to account for 103,170 of the newly diagnosed cases in 2012 (American Cancer Society, 2012). As one of the most common types of cancer, the aim of this paper is to explore what mechanisms of action occur in the body that attribute to the development of colon cancer. Also, an explanation of the symptoms, diagnosis, staging, and common treatments for colon cancer will be discussed.
The Development of Colon Cancer
Cancer Cell Growth
In order to understand the development of colon cancer, it is important to first have a basic understanding of how cancer cells develop in general. Cancer develops when abnormal cells begin to grow out of control (American Cancer Society, 2012). When compared to normal cells, cancer cells do not follow the normal cell cycle. A normal cell cycle is comprised of four stages, M phase, G1 phase, S phase, and G2 phase. During M phase, the cell undergoes nuclear division which is referred to as mitosis (Rozen, Young, Levin & Spann, 2006). The next phase, G1, is considered the resting phase. The third phase, S phase, is when the DNA synthesis and the chromosomal replication occur. The final phase, G2, is where more preparations for cell divisions are made (Rozen et al., 2006). Throughout this cycle there are certain processes that occur in order to check that each phase was completed successfully before the cell moves on to the next phase (Collins, Jacks & Pavletich, 1997). One such check point is referred to as tumor suppressor proteins (Delves, Martin, Burton & Roitt, 2011). These proteins help to signal networks that check if there are any abnormalities in the genome before it enters the cell cycle. If something is detected the cell cycle is stopped to allow for DNA repair or cell death. Cancer cells are able to slip through these checkpoints due to acquired mutations (Delves et al., 2011). Faulty replication is not the only cause of abnormal DNA. Abnormal DNA can also be inherited or caused by environmental factors. Unlike normal cells, cancer cells continue to multiply instead of dying; also cancer cells are able to invade other tissues in the body which normal cells cannot do (American Cancer Society, 2012).
The Mechanisms of Action Behind Colon Cancer
When looking at the different classifications of colon cancer, the most common are adenocarcinomas, meaning that the carcinoma is made up of glandular tissue (Gill, Brown, Miller & Bathe, 2011). It is important to note that the make-up of the carcinoma is one factor that contributes to the prognosis and treatment of the disease. One model of colorectal tumor development by Fearon and Vogelstein (1990) presents four main factors that occur within the body that contribute to the development of colorectal tumors. First, tumors develop in the colon when there is an activation of oncogenes and a deactivation of tumor suppressor genes. This is typically due to mutations that occur to the DNA (Fearon & Vogelstein, 1990). Second, in order for a cancerous tumor to develop there must be at least four to five genes that are mutated. Third, it is thought that the amount of changes in the genes versus the order when compared to one another is what accounts for the tumors biological properties (Fearon & Vogelstein, 1990). The last factor that sometimes occurs is that mutated tumor suppressor genes seem to take on a phenotypic form when in the heterozygous state, which means that some of these genes may not be recessive at the cellular level (Fearon & Vogelstein, 1990).
The model presented above is based on the idea that abnormalities occur in the DNA which causes genomic instability (Gill et al., 2011). These instabilities can be broken down into two general groups, chromosomal and microsatellite. This chromosomal instability pathway (CIN) occurs from gain of function mutations which sets into motion oncogenes such as RAS. RAS is a protein that is responsible for sending many signals that effect functions that occur during mitosis such as "lipid metabolism, DNA synthesis, and cytoskeletal organization" (Goodsell, 1999, p. 263). When these signals are disrupted because of a mutation of the RAS gene, it contributes to tumor development (Goodsell, 1999). This pathway is also characterized by the inactivation of tumor suppressor genes. One example of this is adenomatous polyposis coli (APC) which is located on chromosome 5q (Gill et al., 2011). Individuals with mutations in the APC gene are put at a higher risk of developing colon cancer. This is because APC acts as a gate-keeper with regards to epithelial cell proliferation in the colon (Kinzler & Vogelstein, 1996). If there is a mutation with this gene then the balance between cell division and cell death is disturbed. Other tumor suppressor genes that are affected are p53 which is located on chromosome 17, and DCC which is located on chromosome 18q (Gill et al., 2011).
Another pathway that is commonly discussed when researching the development of colon cancer is the microsatellite pathway (MSI). This pathway is related to abnormalities in DNA mismatch repair (Gill et al., 2011). The abnormalities in the mismatch repair function leads to a buildup of mutations in the microsatellite region of the genome which causes microsatellite instability (Noffsinger, 2009). Microsatellite instability seems to be one trademark within individuals that have the Hereditary Nonpolyposis Colorectal Cancer gene (HNPCC) which is also referred to as Lynch syndrome, which is an inherited condition (Noffsinger, 2009). Tumors that are found to have developed from a mismatch repair pathway or the MSI pathway tend not to show chromosomal gains or losses (Noffsinger, 2009).
Although chromosomal and microsatellite instabilities are most commonly found to contribute to the development of colon cancer, those two pathways are by no means the only ways this disease develops. One major risk factor that could contribute to colon cancer is diet (Rozen et al., 2006). Consuming a lot of foods that are high in animal fat, fried, or charred can increase an individual's chances of developing colon cancer (Rozen et al., 2006). Men also have a greater risk of developing colon cancer then women do (Rozen et al., 2006). Other factors that could affect an individual's likelihood of developing colon cancer include lifestyle choices such as smoking, alcohol use, and decreased physical activity (Rozen et al., 2006). Determining whether an individual will develop colon cancer depends on the interaction between that individuals inherited risk factors, and environmental risk factors (Rozen et al., 2006).
Symptoms and Diagnosis
There are many symptoms of colon cancer. As with all illnesses these symptoms may be experienced differently in all individuals and can occur gradually or suddenly. The first symptom is a change in bowel movements. This can include anything from seeing blood in the stools to something as simple as constipation (Johnston, 2000). Other symptoms include rectal bleeding between bowel movements, abdominal pain, vomiting, nausea, weight loss, and fatigue. The difficulty in detecting these symptoms is that unless they are severe, an individual may overlook them, which could lead to a delayed diagnosis (Johnston, 2000). If a physician sees an individual with these symptoms and colon cancer is suspected, there are specific tests that are done to help make a diagnosis. The most commonly used procedure is a colonoscopy, which allows the physician to look at the inside of the colon (Johnston, 2000). Blood tests are also done in order to check the number of red blood cells, white blood, cells and platelets in the individual (Johnston, 2000). Other tests that can be done are a Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) scan in order to make a definitive diagnosis (Johnston, 2000). The decision on what tests to use and how many tests to give is based on the results of the tests. Once someone is diagnosed with colon cancer typically the course of treatment is shaped by the preliminary staging of the cancer and what is thought to have contributed to the development of the cancer. For example, someone who is thought to have developed colon cancer and is found to have the HNPCC gene may be recommended to receive more radical treatment as compared to someone who has been diagnosed with a random occurrence of colon cancer.
When staging colon cancer the TNM system is used. This system is describes the stage of cancer based on the assessment of the primary tumor (T), assessment of regional lymph nodes (N), and the assessment of distant metastasis (M) (Johnston, 2000). The first category of assessment, the primary tumor, is broken down into seven possible groupings. The first grouping is labeled as TX. A label of TX means that the tumor cannot be evaluated. Next, is T0, a categorization of this means that a primary tumor cannot be determined (Johnston, 2000). The next stage, is Tis, a tumor that is identified as Tis is contained within the glandular basement membrane (Johnston, 2000). If the tumor invades the second layer which is known as the submucosa, it is considered T1. When the tumor begins to invade the muscle layer of the intestines which is approximately half way through, it is considered T2 (Johnston, 2000). As the tumor invades further into the intestines and reaches subserosa it is considered T3. Once the tumor begins to invade other organs or structures it is considered T4 (Johnston, 2000).
Next the cancer is evaluated based on whether or not the lymph nodes have been infected with cancer cells (Johnston, 2000). As with the assessment of the primary tumor, the lymph nodes (N) are rated from an X to a two. If assessed as NX it means that the regional lymph nodes cannot be assessed (Johnston, 2000). If no regional lymph nodes are invaded then it is staged as N0. If one to three lymph nodes are invaded it is considered N1, and if more than 4 lymph nodes are invaded it is considered N2 (Johnston, 2000). The next part of staging is to identify if there are any metastasis (M). If this cannot be assessed an MX is given, if there is no metastasis a M0 is given. If a metastasis is identified then it is considered M1 (Johnston, 2000).
After assessing the development of the tumor and how much it is invaded the colon, the physician typically stages the cancer from Stage 0 -Stage IV (Johnston, 2000). In order to be considered Stage 0, the tumor is contained entirely within the glandular basement membrane, and has not affected any lymph nodes, or metastasized (Johnston, 2000). If the primary tumor has grown into the submucosa, or the muscle layer of the intestines, but has not invaded the lymph nodes or metastasized it is considered Stage 1 (Johnston, 2000). A primary tumor that is assessed as a T3 or T4 but has not invaded any lymph nodes or metastasized is considered Stage 2 (Johnston, 2000). If any of the lymph nodes are invaded it moves that diagnosis to a Stage III, and if it has metastasized it is considered Stage 4 (Johnston, 2000). When physicians view the tumor through different tests they are able to give patients a preliminary idea of what stage the cancer is at based off of what they see, however a final staging is given once the tumor is removed and the lymph nodes surrounding the area are biopsied.
After a preliminary staging is done, a physician can discuss treatment options with the patient. The most common form of treatment for colon cancer is surgery, which can be done both open or laparoscopically, and it is typically referred to as a resection and anastomis, this simply means a removal and reconnection (Ahuja, 2011). In deciding if surgery is a viable treatment option for an individual the doctor must look at the patient's physical fitness which could affect his/her likelihood of making it through surgery, and assess the extent of the tumor (Rozen et al., 2006). The location of the tumor will dictate what type of procedure will be done. A hemicolectomy is one surgical option. This surgery is made up of the removal of the diseased part of the colon and the reconnecting of the two remaining ends (Johnston, 2000). Depending on the location of the tumor, a right, left, transverse, or sigmoid hemicolectomy is performed (Ahuja, 2011). For example, with a right hemicolectomy the right portion of the colon is to be removed including the cecum, the ascending colon, the area where the ascending colon connects to the transverse colon, the beginning area of the transverse colon, and part of the terminal ileum, along with surrounding lymph nodes are removed (Ahuja, 2011). After this resection takes place the ileum and the right transverse colon are reconnected either side by side or end to end (Ahuja, 2011).
Other surgical options include partial colectomy with a colostomy (Johnston, 2000). With this surgery, part of the colon is removed, and an opening in the abdominal wall called a stoma, is made in order for stool to pass, from the remaining end of the colon (Johnston, 2000). Another surgical procedure that is done is a total colectomy and ileostomy. During this procedure the entire colon and anus is removed and an opening through the abdominal wall is created using the small intestines, in order for waste to be excreted from the body (Johnston, 2000). Again, these are just some of the surgical treatment options. The type of surgery that is chosen is based heavily on the diagnosis, the family history, the individual ability to survive the surgery, and the quality of life expected after the surgery.
Although surgery is the typically the first line of treatment for colon cancer, sometimes after surgery, physicians give chemotherapy to the patients, to prevent likelihood of recurrence, this is referred to as adjuvant therapy (El-Shami, Nallapareddy & Messersmith, 2011). It was found that the use of the two drugs fluorouracil (5-FU) and leucovorin were effective in reducing rates of recurrence (El-Shami, 2011). These two substances are administered intravenously to the patient on a schedule specific to him/her. The 5-FU works by inhibiting the enzyme thymidylate synthase (Rozen et al., 2006). This enzyme's function is to regulate the "de-novo synthesis of thymidine nucleotides that are required for DNA synthesis" (Rozen et al., 2006, p. 143). Leucovorin contributes to this by modulating the 5-FU which increases the response rate (Rozen et al., 2006). Radiation is not a typical treatment used for colon cancer, but may be considered a viable option on a case to case basis (Johnston, 2000).
As mentioned before, colon cancer is one of the most common types of cancer presently diagnosed. There are many theories as to what may cause the development of colon cancer and what the best way to treat colon cancer may be; unfortunately none of these theories have led to definite preventive measures or a cure for this disease. In researching this topic the challenge was to narrow down and present the most commonly accepted and widely researched information on colon cancer. The abundance of research on cancer in general, and colon cancer specifically makes me hopeful that one day there will be a cure.