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3A REVIEW STUDY ON COLON CANCER: SYMPTOMS, RISK FACTORS, PATHOPHYSIOLOGY AND TREATMENT STRATEGIES
VARTIKA
General Medicine Student (5019), Karaganda Medical University, Karaganda Kazakhstan
PUNIT KUMAR
Department of Morphology, Karaganda Medical University, Karaganda Kazakhstan
Abstract. The colon is part of the large intestine and extends between the caecum and rectum. It plays an important in terminal digestion. Colon diseases are related to everyday problems like diarrhea or constipation. The more serious clinical condition may lead to colon cancer. Colon cancer, also known as colorectal cancer, is the third most common type of cancer worldwide. This type of cancer mainly affects older people with age above 50 years. Many other factors are also associated with colon cancer such as diet, inflammatory bowel diseases, family history, and mutations etc. This is recognized as heterogeneous disease and develops via genetic and epigenetic changes. This review covers the pathophysiology of colon cancer, its symptoms, risk factors, and explores epidemiology. Including this, treatment options are also discussed.
Keywords: Colorectal Cancer; Mutations; Epigenetic changes; Molecular Marker, CEA
Introduction
The colon is the longest part of the large intestine that is present between the caecum and rectum. The size of the colon is about 1.5m in length. Anatomically it is subdivided not four parts ascending colon, transverse colon, descending colon, and sigmoid colon. Histologically, the colon comprises mucosa, submucosa, muscularis externa, and serosa/adventitia. The mucosa of the colon comprises simple columnar epithelium with microvilli. The mucosa does not have villi and contains crypts of Lieberkuhn where enteroendocrine cells and goblet cells are present. Morphologically colon has semilunar folds that are called haustra. The longitudinal muscles of muscular externa form characteristic features of colon termed as taeniae coli (mesocolic taenia, omental taenia, and free or liberal taenia). The function of colon includes absorption of water, sodium, potassium, chloride, temporary storage and feces transportation. Colon also secrets secrete potassium into the lumen. The colon is also the site of gut microflora (anaerobic bacteria) that cause the decomposition of indigestible food ingredients, produce vitamin K, and also support to immune system (Karunaharamoorthy, 2023).
Colon cancer primarily affects the large intestine, particularly the colon and rectum. It typically develops from adenomatous polyps, which can become malignant over time.
Colon cancer is a significant public health issue due to its high incidence and mortality rates. It is the third most common cancer, responsible for about 10% of all cancer cases, and the second cause of cancer-associated deaths. It is often diagnosed at advanced stages generally when limited treatment options remain available. It is estimated that in 2020, about 930,000 deaths, and more than 1.9 million of new cases of colorectal cancer were found associated with colorectal cancer (WHO, Colorectal cancer, 2023).
This article aims to provide a comprehensive overview of these aspects and highlight recent advancements in treatment.
Pathogenesis
Colon cancer begins with the transformation of normal epithelial cells into adenomatous polyps, which can then progress to carcinoma (Vogelstein et al., 1988). Multiple genetic alterations in both oncogenes and tumor suppressor genes have been found associated with colon cancer. Mutations in the adenomatous polyposis coli (APC) gene are found associated with the development of colorectal tumors (Fearon, 1992). Including APC, genetic mutations such as KRAS, TP53, and epigenetic changes (histone modifications and DNA methylation), are involved in the tumor development .
Further molecular research suggested that most of the colorectal cancer developed from precursor lesions that transform into adenocarcinoma. Three molecular carcinogenesis for colorectal cancer have been suggested; microsatellite instability, chromosomal instability, and CpG island methylator phenotype (Harada and Morlote, 2020).
Furthermore, canonical Wnt signaling pathway (Wnt/p-catenin signaling pathway) is also identified as an important signaling pathway associated with colon cancer development. Wnt signaling pathway is also considered as one of the most representative signaling pathways. In colon cancer, this pathway is found disrupted and cause uncontrolled cell division (Zhao et al., 2022). Including this, overexpression and activation of ERK MAPK perform a key role in the progression of colon cancer. Thus, ERK MAPK may be used as a molecular target for its treatment (Fang and Richardson, 2005). One more pathway, phosphatidyl-inositol 3-kinase (PI3K) pathway, is found deregulated in patients with CRC and this is also an important drug target (Papadatos-Pastos et al., 2015). Including this, several drugs (alone or in combination) are targeting PI3K/Akt/mTOR for the treatment of colorectal cancer in clinical trials (Leiphrakpam and Are, 2024).
Colon cancer symptoms vary depending on the stage and location of the tumor. The common symptoms are fatigue, abdominal pain, constipation, diarrhea, blood in the stool, unexplained weight loss, and low iron levels (WHO, Colorectal Cancer, 2023). Risk factors
Several risk factors (Fig. 1) increase the risk of developing colon cancer (WHO, Colorectal
Cancer, 2023; National Cancer Institute, 2024):
Age: Old age is common risk factor. It is observed that generally, the risk for colorectal cancer increases with age, particularly after 50.
Family History: A family history of colorectal cancer also increases the risk of development of colorectal cancer. Genetic predispositions, such as Lynch syndrome, and familial adenomatous polyposis (FAP) may significantly raise the risk to develop colorectal cancer.
Personal History: having a personal history of colorectal cancer or polyps increases the risk of colorectal cancer. Including this, a personal history of chronic ulcerative colitis or Crohn disease for more than 8 years also increases the risk of developing colorectal cancer.
Lifestyle: lifestyle plays a key role in the development of cancers. Unhealthy lifestyles such as diet high in red and processed meats, lack of vegetables and fruits, low physical activity, smoking, and alcohol consumption. Obesity is also found to increase the risk of colorectal cancer.
Symptoms
Fig. 1: Risk factors associated with colon cancer (colorectal cancer)
Importantly having one or more risk factors does not mean that person will get colorectal cancer. Many people who are exposed to risk factors never develop cancer, while many people develop cancer with no known risk factors. Though, risk factors, epigenetic changes, cell signaling, and mutations play important roles in the development of cancer.
Diagnosis
In addition to the evaluation of family history, and personal history, stool blood analysis, biopsy, imaging, etc., many tests are performed to detect colorectal cancer. Colorectal cancer is classified into Stage 0, Stage I, Stage II, Stage III and Stage IV of colon cancer (National Cancer Institute, 2024). Early detection through screening is crucial for successful treatment.
Digital rectal exam: to identify the presence of lumps or anything unusual in the rectum.
Stool based analysis: Fecal occult blood test (FOBT) is a laboratory test to check stool for the presence of blood cells. The presence of blood may be a sign of polyps, cancer, or other clinical conditions. This test is performed by two methods such as guaiac fecal occult blood test (FOBT), and fecal immunochemical test (FIT). Furthermore, Fecal DNA testing is also performed to detect colon cancer.
Screening Methods: Colonoscopy is considered the gold standard for screening (Medical Advisory Secretariat, 2009). The colonoscope is used for visualization of the rectum and colon for the presence of polyps, abnormal areas, or cancer. A colonoscopy may also have a tool to remove polyps or tissue samples for further analysis. Including colonoscopy, sigmoidoscopy is also used to visualize the rectum and sigmoid colon.
Biopsy: it is a routinely used histological technique for the identification of cancer on the basis of morphology of cells and other properties. During this study tumor tissue is also analyzed to check the presence of mutations and Lynch syndrome.
Imaging Techniques: these are noninvasive approaches for detecting cancer. After the diagnosis of colon cancer, imaging procedures like CT colonography, MRI, PET Scan, Chest X-ray, etc. are performed for further study. These imaging approaches are also used to detect if cancer cells have spread (metastasis) to other body organs and tissues. Computed Tomographic Virtual Colonoscopy has been successfully used in the detection of colorectal neoplasia (Pickhardt et al., 2003). The PET scan (positron emission tomography scan) is based on the use of radioactive sugar which is injected into the blood and computerized pictures are taken to see where this sugar (glucose) is taken up. Furthermore, the combination of FDG PET and CT has been suggested for the assessment of colorectal cancer (O'Connor et al., 2011).
Biochemical Markers: carcinoembryonic antigen (CEA) is a glycoprotein and normally not produced after birth in significant quantities but its elevated level suggests the presence of colorectal cancer. CEA measurement plays a key role in the diagnosis, treatment, and follow-up of patients. It is also found that higher preoperative CEA levels are associated to advance stage or metastatic state of disease and poorer prognosis (Hall et al., 2019; Goldstein and Mitchell, 2005). High level of preoperative CEA are also associated with decreased overall survival after surgical resection. Further, postoperative not reduction in the level of CEA to normal levels suggests inadequate resection of occult systemic disease. Frequent monitoring of postoperative levels of CEA might be potentially beneficial (Goldstein and Mitchell, 2005).
Treatment And Prognosis
Treatment varies based on the stage and may include surgery, radiation, chemotherapy, immunotherapy, and targeted therapy (National Cancer Institute, 2024).
Surgical Options: it is the most commonly used treatment option. It includes polypectomy, Local excision, resection of the colon with anastomosis, Resection of the colon with colostomy, Radiofrequency ablation, and Cryosurgery (National Cancer Institute, 2024).
Radiation Therapy: to shrink tumors before surgery. It makes it easier to remove cancer. Two preoperative methods are commonly used with different objectives such as; short-course radiotherapy and long-course chemoradiotherapy. Both of these approaches reduce the risk of local relapse (Hafner and Debus, 2016).
Chemotherapy: Chemotherapy is used in different ways neoadjuvant chemotherapy, palliative chemotherapy, and adjuvant chemotherapy. Drugs, the drug 5-fluorouracil (5-FU) is used as the first choice, and other drugs include irinotecan (Camptosar) and oxaliplatin (Eloxatin) (Robinson, 2024).
The chemotherapy is also classified as systemic chemotherapy and regional chemotherapy. In systemic chemotherapy drugs are orally consumed, or injected into vein or muscle. In regional chemotherapy the drug is directly injected into hepatic artery. This process is termed as chemoembolization. This process is also used for cancer treatment that has spread to the liver. The chemotherapy is also combined with other targeted drugs like cetuximab, bevacizumab, or panitumumab (National Cancer Institute, 2024).
Advanced Techniques:
Targeted Therapies: Targeted therapy includes monoclonal antibodies and small molecules. These therapies are generally administered when chemotherapy is not responsive. Some examples of targeted therapies include Tucatinib (Tukysa), Regorafenib (Stivarga), Entrectinib (Rozlytrek), Encorafenib (Braftovi), Lapatinib(Tykerb), Larotrectinib (Vitrakvi), Aflibercept (Zaltrap), Fam-trastuzumab deruxtecan (Enhertu), Bevacizumab (Avastin), Cetuximab (Erbitux), Pertuzumab(Perjeta), Panitumumab (Vectibix), Ramucirumab (Cyramza), and Trastuzumab (Herceptin, other names) ((Robinson, 2024).
Cell Therapy: Chimeric antigen receptor-T (CAR-T) immunotherapy is being explored for its potential in treating solid tumors like colorectal cancer. In this therapy, patient's T-cells are engineered to express a specific receptor that binds to the tumor antigen. These engineered cell are reintroduced control the resilient cancer cells (Sur et al., 2020).
Gene Therapy: These approaches include introducing corrective genes to target mutations. As common genetic mutations associated with colorectal cancer are p53 and KRAS mutations, thus gene therapy approaches targeting defected genes like TP53 (encodes for p53) and KRAS (oncogene) in colorectal cancer potentially work as alternative treatment options in addition to standard therapy for colorectal cancer (Hasbullah and Musa, 2021).
Recently US Food and Drug Administration has approved targeted therapy adagrasib (Krazati®) in combination with cetuximab (Erbitux®) for advanced colorectal cancer caused by a gene mutation KRAS-G12C (Grisham, 2024).
Conclusion and Future Suggestions
Colorectal cancer is one of the major causes of cancer-related death around the world. Understanding the pathogenesis, molecular basis, and epidemiology of this disease is crucial for developing effective prevention, diagnosis, and treatment strategies. At the molecular level, it is suggested that colorectal cancer is developed by gene mutations (p53, BRAF, KRAS and microsatellite instability) and epigenetic changes (Vacante et al., 2018). The advancement in understanding the molecular basis of colon cancer has led to significant improvements in treatment. Future research should focus on early detection, personalized medicine, and novel therapeutic approaches for enhanced outcomes, better survival, and reduction in mortality rates.
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