Bio-imaging inflammatory signals for colon cancer initiation
Lead Research Organisation:
Quadram Institute
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Prevention and treatment of colorectal cancer is still a major challenge. Each year over 36,500 people in the UK are diagnosed with colorectal cancer and only half of these individuals will live more than 5 years. Epidemiological studies have identified inflammation as a major risk factor for colon cancer incidence, but the underlying mechanisms remain unclear. Increasingly, colorectal cancer is considered a stem cell disease in that (i) intestinal cancer can be initiated by genetic modification of mouse intestinal stem cells and (ii) human colorectal tumours contain a small subset of "cancer stem cells" that posses self-renewal, multipotent and tumourigenic properties. Observations from a number of model systems suggest that inflammatory signals can disrupt normal tissue homeostasis, but the direct effects on intestinal stem cells and consequences for colon cancer initiation are not known. We will test the hypothesis that elevated levels of the inflammatory mediators cause chronic activation of cell signalling pathways within intestinal stem cells to initiate the formation of pre-cancerous aberrant crypt foci and micro-adenoma growth. The project will utilise a unique combination of mouse 3D tissue culture models of the intestinal epithelium. State-of-the-art bio-imaging approaches will monitor the status of intestinal stem cells and interrogate the origins of colon cancer. This platform will be used to develop anti-inflammatory strategies for the prevention of colon cancer initiation.
Planned Impact
unavailable
Organisations
People |
ORCID iD |
| Anastasia Sobolewski (Principal Investigator) |
Publications
Skoczek DA
(2014)
Luminal microbes promote monocyte-stem cell interactions across a healthy colonic epithelium.
in Journal of immunology (Baltimore, Md. : 1950)
| Description | Prevention and treatment of colorectal cancer is still a major challenge. Epidemiological studies have identified inflammation as a major risk factor for colon cancer incidence, but the underlying mechanisms remain unclear. Increasingly, colorectal cancer is considered a stem cell disease in that (i) intestinal cancer can be initiated by genetic modification of mouse intestinal stem cells and (ii) human colorectal tumours contain a small subset of "cancer stem cells" that posses self-renewal, multipotent and tumourigenic properties. Observations from a number of model systems suggest that inflammatory signals can disrupt normal tissue homeostasis, but the direct effects on intestinal stem cells and consequences for colon cancer initiation are not known. In this research we have thus far shown that 1)Wnt signalling helps maintain the renewal of the healthy colonic epithelium and that 2) inflammatory cells known as monocytes can alter epithelial stem cell number and stem cell driven tissue renewal of the gut epithelial barrier. Ongoing work is investigating the consequences of specific prostaglandin receptor activation in maintaining homeostasis with a view to determining what is aberrant in inflammation and ultimately cancer. |
| Exploitation Route | This platform could be used to develop anti-inflammatory strategies for the prevention of colon cancer initiation. |
| Sectors | Pharmaceuticals and Medical Biotechnology Other |
| Description | Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. Each year, over 36,500 people are diagnosed in the UK and only half of these individuals will live more than 5 years (Office for National Statistics, 2006). Bowel cancer is treated by a combination of surgery, chemotherapy and radiation. The above statistics send out a call not only for improved chemotherapies, but also for the development of chemoprevention strategies. In principle, chemoprevention would have a dramatic impact on both the incidence and recurrence of colon cancer. Understanding the risk factors, the cellular origin of intestinal cancer and the physiological processes that are subverted during colon carcinogenesis are fundamental to the development of novel preventative approaches. The emergence of intestinal inflammation as a major risk factor for colon cancer and the demonstration of a central role for intestinal stem cells in carcinogenesis are two of the most exciting advances in the last few years. Thus far we have demonstrated key factors involved in maintaining the healthy gut and currently investigating the functional consequences of these factors being altered during inflammation. Speculatively, in the longer term (>10 years) pharmaceutical companies potentially may be in a position to use our research models; potentially moving from mouse studies to the human we in the longer term be able to develop more targeted treatments for patients with less side effects leading to improved health and longevity of patients and so impact positively on the downstream costs of health care. Public Engagement / Outreach Activities in particular involving school children, high school teachers, undergraduate students and the general public informing them of the impact of our research. The IFR holds Open Days every few years, the last one in 2012. During these events we also convey the gut research we are conducting in the laboratory and also impress upon them the importance of experimental animals models in our work. This project would also allow us to demonstrate the translational pipeline from mouse to human and help increase public understanding of basic research towards the clinic. Presented research at Caf? Scientifique; a forum to present scientific research to the public. The research from this project will also be presented at this forum, which will be sure to evokes a lively debate. Our Gut Health and Food Safety Department has a webpage, which is updated regularly with blogs and tweets concerning ongoing research with in the program in our research group (http://www.ifr.ac.uk/ghfs/) We routinely host undergraduate students for their undergraduate projects in the laboratory (in addition to presenting undergraduate lectures). We also retain these students for future PhD projects or technician posts in our laboratory after their graduation. We routinely host high school students providing them with work experience in the laboratory. This also includes public engagement with regards to understanding the role of animals in research including visits to the animal facility, which we regard to be an important aspect of research to disseminate to the public. We have also hosted high School Teachers and presented research at the IFR Teacher event which entails informing teachers of the nature of the research conducted at IFR and also what careers are open to their children if they choose to pursue a career in science. Research Staff Training-the post-doctoral researcher benefit from improved experimental, modelling and transferable skills that will aid the future earning power of the national workforce. |
| First Year Of Impact | 2014 |
| Sector | Other |
| Impact Types | Societal |