1.1 Bowel Cancer
Bowel Cancer also known as colorectal cancer (CRC) encompasses any cancer of the large bowel (colon cancer) and cancer of the back passage (rectal cancer). The large bowel is approximately 5 feet long and has 4 sections (Ascending colon, Transverse colon, Descending colon and sigmoid colon); cancer can develop in any of these sections. Most bowel cancers begin as small benign growths known as polyps in the inner lining of the bowel wall. The majority of polyps are a characteristic of old age and are not pre-cancerous, but one type known as adenomas can develop into a more dangerous advanced carcinoma with the ability to metastasize. Cancerous polyps grow into the muscle layers and then through the bowel wall, spreading through the lymphatic system into organs in the vicinity of the bowel. The most common site of metastasis for colorectal cancer is the liver. Howard Hughes Medical Institute investigators have used mutational analysis to estimate that it takes ≈17 years for a large benign tumor to evolve into an advanced carcinoma but <2 years for cells within that cancer to acquire the ability to metastasize. They also concluded that metastatic colon cancers carry the ability to metastasize from the time they become cancerous as they carry all the necessary mutations(1). These results have important implications for the understanding of human tumor pathogenesis and metastasis.
CRC is an increasingly crucial public health issue; it is the third most frequently diagnosed cancer and the fourth cause of cancer death in the UK and worldwide(2). Annually, about one million novel cases of colorectal cases are reported around the globe plus half a million deaths (3). The global burden of CRC is expected to rise by 60% cases (i.e. to 2.2 million new cases and 1.1. million deaths) in a period of 14 years(4). Therefore, developing a better understanding of the mechanisms behind the progression of bowel cancer is vital to increase survivial rates.
1.1.1 Screening and diagnosis
The fact that early diagnosis of colorectal ensures higher cure rates and lower mortality and that the adenomatous polyp has been identified as a well determined premalignant lesion makes colorectal cancer an ideal candidate for screening(5). CRC screening has been shown to save lives. It facilitates the detection of colorectal cancer at an early asymptomatic stage while it’s still localized and amenable to treatment(6). The two most widely utilized strategies for CRC screening are: faecal occult blood test (FOBT) and endoscopy (colonoscopy). FOBT has been shown to be successive at reducing mortality from colorectal cancer by up to 25%. The Advisory Committee on Cancer prevention in the EU has advised that screening programmed for colorectal cancer be offered to men and women aged 50 years until ~ 74 years with an interval of 1-2 years(5).
Colon cancer can be diagnosed when the patient presents with symptoms or as a result of screening. Rudimentary stages of CRC are asymptomatic and most of the symptoms are non-specific (e.g. change in bowel habits, abdominal discomfort, and weight loss), thus it is essential to be detected by screening measures. The characteristic signs and symptoms of colorectal cancer include a positive fecal occult blood test, rectal bleeding, constipation, diarrhea, nausea, and bowel obstruction. Endoscopy is the main tool for diagnosis and can be performed via either a sigmoidoscopy or a colonoscopy. Recently, research is interested in finding serological markers that would allow the detection and diagnosis of CRC in its early stages. For instance, blood tests that utilize tumor-related antigens would aid the diagnosis of CRC. Recent evidence suggests that CA11-19 a serological tumor antigen can be used for the detection of CRC, with a reported sensitivity of 98%(7). Howard Hughes Medical Institute investigators have found
1.1.2 Risk Factors
1.1.3 Histopathology of colorectal cancer
1.2 The intestine at a cellular level
1.3 Early onset CRC in Bangladeshi communities
A study was conducted by our laboratory in association with the Royal London Hospital and collaborators from Oxford (Julie Adam, OCDEM) to ascertain the relationship between diabetes and CRC. It was found that 40% of a large cohort of CRC patients residing in the Tower Hamlet’s area, a majority being of Bengali origin, are diabetic. In addition to this, recent research presented evidence of early onset CRC in Bangladeshi individuals with a reported 58%-61% of cases below the age of 50 years in Britain and Bangladesh (8,9).Consequently, this population of CRC patients served as the consummate model to study the link between diabetes and CRC. S(2- succinyl)-cysteine (2SC) a biomarker of nutrient excess and mitochondrial stress was used as a parameter, comparing the non-diabetic and diabetic cancer sections. 2SC has been shown to increase under conditions associated with Type 2 diabetes (T2D). Congruently, the study also found significantly higher levels of 2SC in cancers from diabetics compared to non-diabetic cancers.
1.3.1 Link to Type II Diabetes
Type 2 diabetes mellitus (T2D) is associated with an increased risk of colorectal cancer, but there are limited studies available to substantiate this and the underlying pathological mechanisms underlying the link are still equivocal. A Netherlands Cohort study investigated how T2D was associated with subsite-specific CRC risk in 120,852 men and women. Results showed an elevated risk of proximal colon cancer in women with T2D compared with non-T2D women. Similarly, a recent Chinese study incorporating 250 CRC patients found a higher expression of IGF-1, IGF-R and IR proteins in CRC patients with preexisting type 2 diabetes (preT2D).The insulin resistance in T2D leads to high serum insulin levels, thus inhibiting IGF binding proteins and increasing the bioactivity of IGF-1, resulting in increased mitogenic activity. Furthermore, heightened insulin, IGF-I and IGF-II levels are also associated with tumor growth. A prospective mechanism would involve the imbalance of IGF/insulin pathways as it seems to be a shared occurrence between hyperinsulinemia, insulin resistance and tumor pathogenesis. In contrast to non-diabetic CRC patients, patients with T2D tend to have more right-sided and advanced CRCs, a younger age of presentation and greater use of exogenous insulin. Thus corroborating the link between insulin imbalance, T2D and CRC outcome and diagnosis.
1.3.2 Mouse Models
1.4 Biomarkers
1.5 Goblet Cells
Goblet cells are one type of secretory cells that reside in the mucosal epithelium throughout the length of the small and large intestine. They are highly polarized with a basally located nucleus and an apical concentration of secretory granules. The central role of goblet cells is as gatekeepers of the mucosal immune system, producing and maintaining a protective mucus blanket overlying the epithelium via the secretion of high-molecular-weight glycoproteins called mucins. The unassailable mucus barrier contains other components including water, electrolytes, sloughed epithelial cells, and secreted immunoglobulins. Hence, effectively protecting against luminal agents such as enteric bacteria, bacterial and environmental toxins, and some dietary components
1.5.1 Goblet cell maturation and differentiation
1.5.2 Goblet cell situational and structural diversity
1.5.3 Mucin Secretion
1.6 Changes due to Pathophysiological Alterations
1.6.1 Inflammatory Bowel Diseases(IBD)
1.6.2 Intestinal Neoplasia
1.6.3 Goblet cells numbers and Mucin expression as a biomarker for CRC and Diabetes