Ulcerative Colitis and Colorectal Cancer: Challenges and Opportunities







Authored by Siddhartha Kumar Mishra 

Editorial

Inflammatory bowel disease (IBD) is chronic inflammatory disease affecting approximately 1.4 million people in the United States. IBD comprises mainly two disorders, ulcerative colitis (UC) and Crohn disease (CD). UC is restricted to the colon and rectal segments, while CD is a variable disorder. CD may affect essentially any segment of the gastrointestinal tract, with a preference for the terminal ileum [1]. UC is caused by an abnormal immune response by body due to mistaken identity food, bacteria, and other materials in the intestine for foreign or invading substances by immune system. This leads to recruitment and influx of immune cells in intestinal epithelial cells causing chronic inflammation and ulcerations. While UC causes mucosal inflammation, CD is associated with granulomatous features and transmural inflammation that can be complicated by intestinal wall fibrosis and stenosis, internal and external fistulas, and intra-abdominal infections. Irrespective of the IBD subtypes, the involvement of the colon and rectum and chronic inflammation leads to increased risk for colorectal cancer (CRC) [1]. Although patients with colitis-associated cancer (CAC) represent only about 1% of CRC cases, colitis patients are at highest risk of CRC [2]. Patients with prolonged (>20 years) and extensive colitis have even higher (20%) risk of CRC development. Furthermore, a certain subset of patient with inflammation in the biliary tract featuring primary sclerosing cholangitis have an even greater (50%) lifetime risk of CRC [2].
CRC, also known as bowel cancer, is cancer of colon and rectum. It is the second most common cancer worldwide, after lung cancer. CRC is highly spread in the US probably due to dietary and living habits with about 1 in 20 people in the US will developing CRC. CRC may be benign or malignant. CAC represents only a small fraction of the overall burden of CRC.The molecular pathogenesis of CAC is mainly inflammation- associated carcinogenesis [3]. CRC is mostly due to lifestyle factors include diet, obesity, smoking, and lack of physical activity. The other major risk factor for CRC is IBD. Certain inheritable genetic disorders are also the major causes of CRC especially familial adenomatous polyposis and hereditary non-polyposis colon cancer yet their ratio is less than 5% of total CRC cases. CRC is a disease originated from the epithelial cells lining the colon or rectum of the gastrointestinal tract. Aberrant mutations in the Wnt signaling pathway increases CRC induction and progression signaling activities. These mutations are inherited or acquired and may occur in the intestinal crypt stem cell [4]. APC is the most commonly mutated gene in CRC. This produced APC protein which prevents the accumulation of β-catenin protein. When APC is absent (or mutated), β-catenin accumulation is multifold high and it translocates into the nucleus. Inside nucleus, β-catenin binds to DNA and activates the transcription of proto-oncogenes mainly cMyc and Cyclin D1 [4] . These gene expressions favor cell cycle and proliferation in aberrant manner causing stem cell renewal and differentiation. Along with Wnt signaling pathway, mutations in other genes like p53 make a worsen disease scenario [3]. Furthermore, proteins responsible for programmed cell death are generally deactivated in CRC such as TGF-β and DCC (Deleted in Colorectal Cancer). TGF-β has a deactivating mutation in at least half of CRC, as well as a downstream protein named SMAD is also deactivated [3].
Connecting the epithelial cell inflammation and cancer induction, another major key player is nuclear factor NF-kB which nearly always activated in mucosa under IBD condition[5] . NF-kB is a pleiotropic transcription factor with a key role in innate and adaptive immunity [5,6]. NF-kB is a key player in CAC whose function is regulated by NF-kB inhibitors that may prevent its nuclear accumulation and DNA binding [5,6]. The NF-kB activation dynamically regulates various cellular stimuli including proinflammatory cytokines, microbial products, and various forms of cellular stress including DNA damage [6] . NF-kB is essentially required for the expression of various proinflammatory factors such as proinflammatory cytokines and chemokines and adhesion molecules in CRC [5]. An animal model of CAC induced by azoxymethane and dextran sulfate sodium (AOM/DSS) has shown dramatic activation of NF-kB in the intestinal epithelium causing tumor multiplication by enabling the role of NF-kB signaling in CAC [7]. NF-kB activation in the immune compartment is important for tumor growth which has trophic effects on the outgrowth and/or progression of neoplastic colon cancer cells probably via over expression of certain cytokines such as IL1β and 1L-6 [7]. Thus, blockade of NF-kB can ameliorate or prevent the development of colitis and CRC and that this has been a therapeutic approach in several studies. We have recently reported that an aqueous extract of edible mushroom chaga (Inonotus obliquus) and its ergosterol peroxide caused down regulation of β-catenin and NF-kB signaling in human colon cancer cell lines and in intestinal inflammation and CRC in animal models [8-10]. Thus, a recent attention has shifted in CRC management by regulating β-catenin and NF-kB signaling pathways by using natural products because of their lesser side-effects as compared to conventional antiinflammatory therapies.
In conclusion, UC and CRC are resultant of chronic inflammation in mucosal and epithelial cells due to aberrant activation of immune cells. A recent trend in managing this inflammatory is by suppressing inflammation pathways and tumor growth signaling such as NF-kB and Wnt/β-catenin signaling. These two signaling can be targeted by multiplesagents from synthetic sources to natural products.



 

Comments

Post a Comment

Popular posts from this blog

Milk Curd Syndrome: A Forgotten Entity_Juniper Publishers

Image
ADVANCED RESEARCH IN GASTROENTEROLOGY & HEPATOLOGY JUNIPER PUBLISHERS   Authored by Kashish Khanna Abstract A full term neonatal baby girl presented with a lumbosacral meningomyelocele and underwent successful excision and repair. In the postoperative period, she developed abdominal distension, bilious vomiting and did not pass stools. Conservative management for ileus/intestinal obstruction failed. The abdominal exploration revealed milk curd syndrome (MCS) as a cause of intestinal obstruction. This article highlights the varied presentation of MCS and salient features to differentiate it from other causes of neonatal intestinal obstruction. Keywords: Neonatal intestinal obstruction; Milk curd syndrome; Inspissated milk syndrome; Milk plug syndrome Abbreviations: MCS: Milk Curd Syndrome; SBE: Small Bowel Obstruction; NEC: Necrotising Enterocolitis; MMC: Meningomyelocele; TCA: Total Colonic Aganglionosis ...
Read more

A Modified Sequential Regimen of Helicobacterpylori Treatment Enforced by Bacillus clausii and Zinc Carnosine Complex Yields High Eradication Rates_Juniper Publishers

Image
  ADVANCED RESEARCH IN GASTROENTEROLOGY & HEPATOLOGY JUNIPER PUBLISHERS   Authored by Dajani AI      Abstract Introduction: Over the past decade a worldwide trend of decline in the cure rates of Helicobacter pylori is observed. Current eradication rates achieved by the standard triple therapy are below 70%. Sequential therapy had provided a potential alternative that would compensate for the unmet performance of triple therapy. Despite its superiority to triple therapy, the excellent results reported initially were not reproduced by other investigators work. Adding adjuvant agents was also found to improve further the success rate of eradication. Probiotics emerged as a useful adjunct in treatment and prophylaxis of Helicobacter pylori infection. The nutritional supplement Zinc carnosine complex is another adjuvant which is believed to add value to the treatment. Patients and method: an open label randomized observational clinical study ...
Read more

Updating on Neuroendocrine Tumors New Clinical Evidence in the Search of the Ideal Treatment Sequence_Juniper Publishers

Image
ADVANCED RESEARCH IN GASTROENTEROLOGY & HEPATOLOGY JUNIPER PUBLISHERS Authored by Juan Manuel O'Connor   Introduction Neuroendocrine tumors (NETs) represent a heterogeneous clinical entity with an increasing incidence as shown by the different registers available. As opposed to other solid tumors, NETs represent a challenge, not only from the diagnostic standpoint but also in terms of treatment strategies. According to the data published by our Working group, ARGENTUM GROUP [ 1 ], with more than 600 patients assessed, roughly 60% of the cases present with metastatic disease from the onset. The reason why the incidence of advanced disease is high since early onset may be due to a bias, for most of the physicians in our Group are oncologists. Moreover, about 20% of the patients included present poorly differentiated NETs, a heterogeneous subgroup, with high risk and poor outcome according to the different series reported. G grading...
Read more