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Colon Cancer



Abstract

Colon cancer is a disease of concern to the healthcare system due to its adverse complications. It does not cause negative symptoms in its early stages but poses significant threats to an individual when it is advanced. This paper examines the pathophysiology of colon cancer, its etiology, clinical manifestations, staging, and treatment. It further discusses current research discoveries that can help in the treatment of colon cancer. The typical adenoma-to-carcinoma sequence is discussed. The mutation in the aberrant crypt foci and the way adenomatous polyp develops into the carcinoma of the colon are also examined.

Additionally, the serrated pathway as an unconventional pathway is analyzed. The mutation processes of the KRAS and BRAF genes that lead to colon cancer are explained. Moreover, the TNM staging of colon cancer is discussed. Finally, the paper discusses two current research studies conducted on colon cancer, which can contribute immensely to the development of the therapeutic regimen for colon cancer management.

Keywords: colon cancer, serrated pathway, adenoma-to-carcinoma sequence, polyps, KRAS, BRAF, MAPK, DNA

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Colon Cancer Statistics

Despite the fundamental advances that have led to the understanding of colon cancer, the disease continues to be a threat to the American population. Colon cancer can metastasize, affecting the rectum and other organs in the body. According to the Center for Disease Control and Prevention [CDC] (2016), it affects both men and women, and it is the second leading cause of cancer-related deaths. Additionally, it is the third most common cancer in both males and females. The current statistics from the CDC indicate that 71,099 men and 65,020 women were tested positive for colorectal cancer in 2013 (2016).

Furthermore, 51,813 adults, namely 27,230 men and 24,583 women, died from colorectal cancer in 2013 (CDC, 2016). Therefore, this disease is of great concern to the U.S. healthcare system. The advancement in technology has made it possible to detect colon cancer in its early stages through screening to reduce the mortality rates. This research paper examines colon cancer, focusing on the pathophysiology, etiology, clinical manifestations, staging, and treatment, as well as discusses current research discoveries that can help in its treatment.

Colon Cancer Pathophysiology

This section briefly examines the anatomy and physiology and goes into detail about the pathogenesis of colon cancer. Understanding the location and function of the colon is critical to comprehending the pathophysiology of colon cancer.

According to Rizzo (2015), anatomically, the colon connects to the small intestine at the cecum in the lower abdomen. The cecum is where the colon begins. Further, the colon is divided into four sections: ascending, transverse, descending, and sigmoid colon. Physiologically, the colon absorbs salt, water, and nutrients forming feces. The muscles lining the colon walls aid in peristalsis. In older people, there can be benign growths on the colon mucosa called the polyps that may also affect the rectal mucosa (Bonnington & Rutter, 2016). Usually, the polyps are asymptomatic. However, if noticed during colonoscopy, which is the most useful diagnostic test for the polyps, they are removed by either endoscopic resection or cold forceps polypectomy. If not removed, there is a risk of them developing into colon cancer.

According to Iwatate et al. (2012), bowel polyps can be of three types. The first type involves hyperplastic polyps that rarely develop into cancer and the second type includes adenomas that have a high chance of causing colon cancer. T; the last category includes polyposis syndromes, which are a group of hereditary conditions (Huber, Findeis-Hosey, & Whitney-Miller, 2013). The polyposis syndromes include hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, familial juvenile polyposis, Cowden disease, and Peutz-Jeghers syndrome. Colon cancer arises from two types of precursor polyps, namely conventional adenomas (Armaghany, Wilson, Chu, & Mills, 2012), and serrated adenomas.

Colon Cancer Evolving from Conventional Adenomas

In this case, colon cancer develops when adenomas transform into a carcinoma. This process occurs through the accumulation of various genetic and epigenetic mutations. Physiologically, tumor suppressor genes (anti-oncogene) protect cells from progressing to cancer (Armaghany et al., 2012). However, the ability of anti-oncogenes to inhibit cell proliferation is lost when proto-oncogenes become mutated. Proto-oncogenes are normal genes that can become oncogenes due to mutation. On the other hand, oncogenes are genes that transform the cell into a tumor cell. Inactivation of both alleles (mutated genes found at the same place on a chromosome) causes anti-oncogenes to lose their function (Armaghany et al., 2012). This process leads to increased activity of adenomatous polyposis coli (APC), a protein that, if mutated, results in colon cancer (Armaghany et al., 2012). The over-expression of APC further leads to carcinoma in the colon.

According to Birnbau et al. (2012), a process where an adenoma is transformed into a carcinoma is commonly initiated by biallelic mutation of the APC tumor suppressor gene. The APC mutations most often happen in microadenomas, which are tumors less than 10mm in diameter, and sporadic adenomas, which are mainly asymptomatic but patients may present with anemia, rectal bleeding, or obstructive symptoms. Additionally, Drew et al. (2014) contend that APC mutations have been found in aberrant crypt foci (tube-like glands in colon and rectum) and carcinomas (cancers evolving from epithelium or the mucosal linings).

Explanation of the conventional adenoma-to-carcinoma sequence. According to Pancione, Remo, and Colantuoni (2012), this pathway was the original one, from which alternative pathways can be developed. In the adenoma-to-carcinoma sequence, the first initiating mutation occurs in aberrant crypt foci, where an anti-oncogene such as APC is mutated (Drew et al., 2014). Then, an adenomatous polyp develops. This process happens through mutations in proto-oncogenes, such as BRAF and Kirsten rat sarcoma viral oncogene homolog (KRAS), which are involved in directing normal cell growth (Muhammed, Al-Saadi, & Ali, 2015). Then, other epigenetic and genetic alterations cause the progression of the adenomatous polyp. Consequently, adenocarcinoma (a malignant tumor) develops and invades through the muscular layer of the colon, producing glands with abnormal polarity, leading to colon cancer.

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Factors that Lead to the Development of Colon Cancer

Colon cancer does not have one single cause. Various factors that result in the development of this disease include age, gender, dietary factors, genetic factors, and various inflammatory conditions of the colon.

Age

Statistics from the Colon Cancer Alliance (2016) show that 90% to 95% of deaths occur in people of over 50 years old.

Gender

Men have a higher risk of developing colon cancer as opposed to women.

Diet

Having diets that are low in fiber and high in calories, as well as eating processed meats, can predispose one to colon cancer (Hu, La Vecchia, Negri, & Mery, 2010). Some types of fiber carry bile acids that can potentially lead to bowel cancer. Additionally, smoking and obesity contribute to colon cancer (Hu et al., 2010).

Genes

Most researchers have discovered that genetic factors make a significant contribution to colorectal cancer. Some genes are critical for cancer cell growth and are called oncogenes. The genes that control cell division are called tumor suppressor genes. DNA mutations, as mentioned above, lead to the activation of oncogenes and inhibit the tumor suppressor genes, leading to colon cancer. The mutations that are found in body cells are passed down from generation to generation.

The APC is a tumor suppressor gene, and if mutated, it leads to Gardener syndrome and familial adenomatous polyposis (Leoz, Carballal, Moreira, & Balaguer, 2015). Mutation of APC results in the inhibition of cell growth, causing the formation of hundreds of polyps inside the colon. Over time, these polyps may grow and develop into colon cancer. Hereditary nonpolyposis colorectal cancer is caused by changes in the genes that help to repair an abnormal DNA. Some of the DNA repair enzyme genes include MHS2, MLHI, MSH6, PMS1, and MHL3. If they become mutated, DNA abnormalities cannot be corrected. The defects in the DNA can affect tumor suppressor genes, leading to colon cancer. Additionally, changes in the tumor suppressor genes can lead to Peutz-Jeghers syndrome that results in colon cancer.

Polyps

The presence of precancerous polyps in the colon is another factor that can lead to colon cancer. Hyperplastic polyps at the rectosigmoid junction have the potential to become cancerous if they are not removed (Bonnington & Rutter, 2016). Additionally, adenomatous polyps can become cancerous but rarely develop into cancer. Finally, malignant polyps have cells that mostly become cancerous.

Clinical Manifestations

In the early stages of colon cancer, symptoms do not manifest. However, when cancer grows, one can experience rectal bleeding, fatigue, diarrhea, unexplained weight loss, irritable bowel syndrome, cramping and iron deficiency anemia (American Cancer Society, 2015).

Rectal Bleeding

Polyps in the colon lead to massive cell growth that causes colorectal cancer. Some of the polyps on the lining of the mucosa of the colon overgrow and start bleeding. The bleeding is often seen in the stool.

Fatigue

During the process of colon cancer development, cancerous cells release cytokines that cause fatigue. Additionally, the process of colon cancer development requires more energy, which makes an individual tired. Sometimes, cancer can metastasize to the bone marrow, which can cause anemia and, consequently, little oxygen supply, thus leading to fatigue. Furthermore, colon cancer can cause pain that makes an individual eat less leading, resulting in fatigue and the loss of energy. Lastly, hormonal changes occur during colorectal cancer, which can affect organs such as the thyroid gland and the adrenal glands, leading to fatigue.

Diarrhea

Colon cancer results in an increase in the number of bowel movements, leading to the watery stool. Bloating and cramping in the colon can also cause diarrhea.

Weight Loss

During colorectal cancer, weight loss happens due to fatigue. The actively dividing cells require more energy to continue dividing. Therefore, an individual becomes weak and loses energy, which results in loss of weight. Additionally, colon cancer causes a loss of appetite. Consequently, people cannot keep a well-balanced diet with enough calories, and yet, they need more calories. The result is a progressive weight loss in such patients.

Irritable Bowel Syndrome

The developing polyps can cause the mucosa of the colon to become irritated. Consequently, an individual experiences abdominal pain and diarrhea.

Cramping and Iron Deficiency Anemia

Cramping can also occur due to irritable bowel syndrome, and anemia can result from the metastasis of cancer to the bone.

Diagnosis of Colon Cancer

Various tests are used to diagnose colon cancer, including the blood test, colonoscopy, biopsy, molecular testing of the tumor, and ultrasound (American Cancer Society, 2015).

Blood Test

Blood tests are conducted to establish if there is anemia. Colon cancer leads to the active dividing of cells and overgrowth of the polyps. Some large polyps bleed, leading to anemia. Therefore, the hemoglobin level of the patient needs to be determined to identify if the patient is anemic. Additionally, a complete blood count test can establish the extent of blood loss. Another blood test can detect the level of carcinoembryonic antigen (CEA). If CEA is elevated in the blood, it may indicate that cancer has metastasized to other parts of the body.

Colonoscopy

Colonoscopy can allow the viewing of the inner rectum. This test can diagnose cancer by viewing the characteristics of cells in the colon.

Biopsy

A small tissue of the patient can be removed during the colonoscopy and examined by the pathologist. The pathologist can do cancer staging to determine the extent to which the colon cancer has spread.

Molecular Testing of the Tumor

Molecular testing enables the pathologist to identify specific proteins or genes and other factors that may have resulted in colon cancer to initiate a particular form of treatment. One of the type gene encoding cellular signaling molecules includes protein kinases. If they are found, drugs targeting such mutant kinases can be issued to treat cancer.

Ultrasound

An ultrasound creates a picture of the internal organs, which can enable determining if cancer has metastasized. Notably, endorectal ultrasound can be used to identify how deep colon cancer has spread. However, it is only restricted to the abdomen and cannot test cancer that has spread to the pelvis or the lymph nodes.

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Colon Cancer Staging

After testing colon cancer, it is critical to stage it to decide the kind of treatment that is appropriate. Additionally, staging can help to predict the prognosis of colon cancer. Staging, in this case, involves describing the location of colon cancer and illustrating if it has metastasized.

According to Ueno et al. (2012), a TNM staging system is an effective tool used to diagnose colon cancer. TNM classifications are combined to assign the colon cancer a stage. When staging cancer according to the TNM staging system, the cancer is divided into stages 0, I, IIA, IIB, IIC, IIIA, IIIB, IIIC, IVA, and IVB. There are three categories used in the TNM staging. T (Tumor) describes the layers that the tumor has affected and how deep it has grown into the wall of the colon. N (Node) explains if the tumor has spread to the lymph nodes and the number of the nodes that are affected. M (Metastasis) tells if cancer has spread to other parts of the body.

TX means that the tumor cannot be measured. T0 shows there is no tumor in the colon. This indicates that cancer cells can only be found in the mucosa of the colon. T1 means that colon cancer has grown into the submucosa. T2 denotes that colon cancer involves the muscularis propria, the peristaltic muscle. T3 test shows that, beyond the muscularis propria, cancer affects the subserosa. T4a indicates that the tumor has involved all layers of the colon and has metastasized to the peritoneum. Finally, T4b denotes that the tumor has metastasized to other organs.

MX means that distant metastasis cannot be measured. M0 result signifies that colon cancer has not metastasized to distant parts of the body. M1a indicates that colon cancer has spread to one part of the body apart from the colon. M1b denotes that cancer has metastasized to various parts of the body other than the colon.

Colon Cancer Treatment

Three forms of treatment for colon cancer include surgery, adjuvant chemotherapy, and non-adjuvant chemotherapy. Surgery is the only form of treatment for colon cancer stages I to III because it removes cancerous cells that have an ability to metastasize. Additionally, adjuvant chemotherapy is therapeutic in patients with stages I to III. This form of treatment involves fluorouracil, which interrupts DNA replication (American Cancer Society, 2015). Other drugs such as leucovorin may be given on top of fluorouracil. This treatment lasts up to six months.

However, it is limited to palliative therapy for selected metastatic sites such as bone metastases because its use is controversial. Chemotherapy is the standard management for patients with colorectal cancer that has metastasized. It is effective because various drugs used in combination have proved significant in treating metastatic cases and suppressing cell growth. However, Labianca et al. (2010) argue that it should be used with caution in elderly patients. The drugs are increasingly guided by genetic analysis of the tumors.

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Current Research on Colon Cancer

Sakaguchi et al. (2016) conducted an analysis of PCR-based MiRNA profiling of healthy colon stem cells (NCSCs) and colon cancer stem cells (CSCs). This profiling identified MiRNA that regulates the colon CSC properties. MiRNA-137 expression was downregulated in colon CSCs but was high in NCSCs. On the other hand, doublecortin-like kinase 1 (DCLK1) mRNA was high in CSCs but was downregulated in NCSCs. The study further revealed that miR-137 regulated DCLK1 expression. Moreover, when miR-137 was suppressed, the organoid development of normal colon cells was enhanced. The study concluded that miR-137 could contain colon CSCs. Additionally, the study revealed that if the miR-137 expression were maintained in cells, uncontrolled cell proliferation would be suppressed through inhibition of DCLK1 expression. Therefore, this study can be used to come up with therapeutic targets for colon cancer.

Prasetyanti et al. (2016) developed patient-derived xenografts (PDX) from the four subtypes of colorectal cancer. The four subtypes are epithelial-MSI (CMC1), epithelial-canonical (CMS2), epithelial metabolic (CMS3), and mesenchymal (CMS4). Prasetyanti et al. (2016) performed a transcriptome analysis, which enabled them to assign each tumor and PDX to a CMC subtype. The investigators further dissected the contribution of both stromal and epithelial gene expression to the overall expression phenotype. The study revealed that the expression profile of PDXs remained stable for multiple serial passages in vivo.

Additionally, the analysis identified tumor cell expression markers, which were expressed differentially in CMS4. The authors contend that the presence of an epithelial tumor acquired a signal in mesenchymal tumors that contribute to CMS4 particular gene expression. To validate their research, Prasetyanti et al. (2016) ascertained that CMS4 tumor markers had been confirmed in other CRC expression datasets and associated with disease relapse.

This study concludes that subtypes of CRCs corresponding with PDXs showed the presence of tumor-specific gene expression in mesenchymal CMS4 tumors. Additionally, the primary colorectal cancer cell line panel that consisted of all the four subtypes in the experiment provided a great insight into colorectal cancer heterogeneity, which serves as a valuable model to facilitate the development of effective treatment.

Conclusion and Recommendations

From the comprehensive analysis of colon cancer, it is evident that the disease poses significant threats to both the population and the healthcare system of America. Therefore, the government needs to sensitize more people on the need to have colon cancer screening, since the disease is preventable. Additionally, research has found that the illness is caused by foods that have little fiber and much fat, red meat, and calories. For this reason, people need to receive appropriate advice on proper dietary habits to avoid both colon cancer and other types of cancer resulting from metastasis of colon cancer. Finally, healthcare providers should conduct genetic counseling to prospective parents to make them aware of the chances of having children with colon cancer. This process will enable the couple to make proper choices to prevent colon cancer in their children.

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