Periodic Reporting for period 2 - WORMTUMORS (Worm power: Can helminths modify the development of colorectal cancer?)
Reporting period: 2017-08-01 to 2018-07-31
Colorectal cancer (CRC) causes ~694,000 deaths a year and is the 3rd most prevalent cancer in the world. Currently, the incidence of CRC is predicted to increase significantly more in low- and middle-income countries (LMIC) than in high-income countries (HIC) by 2035. In LMIC, infectious disease, including helminth infection, contribute to a third of all cancer cases and 20% of cancer deaths. Helminth infection affects more than 1.5 billion people in LMIC and can protect against immune-mediated diseases, in fact, live infection or helminth products are being used within clinical trials as novel therapeutics to treat inflammatory bowel disease. As LMIC develop economically, exposure to dietary and lifestyle risk factors associated with cancer will collide with existing high rates of infection with pathogens such as helminths. In this scenario, the ability of helminths to subvert or suppress the immune system of the host may be detrimental to cancer development. Currently it is unknown how helminth modulation of immunity influences CRC. The overriding objective of this proposal therefore, is to determine how helminth exposure influences colorectal cancer development.
We have found that helminth infection increases inflammation and tumor development in a mouse model of disease. Changes in diet to one rich in fatty acids consumed in HIC also increased disease. Diet change clashed with underlying helminth infection resulting in a very poor outcome in this model. Increases in colorectal cancer following helminth infection and diet change are reliant on live helminth infection and are regulated by IL-4Ra signalling. Increased tumour development is associated with a reduced anti-tumor response and the increased production of inflammatory lipid mediators in the colon, where administration of one mediator increased tumor formation in naive mice. We conclude that helminth infection and diet change exacerbate colorectal cancer through regulation of fatty acid metabolism and increased production of lipid inflammatory mediators.
We have found that helminth infection increases inflammation and tumor development in a mouse model of disease. Changes in diet to one rich in fatty acids consumed in HIC also increased disease. Diet change clashed with underlying helminth infection resulting in a very poor outcome in this model. Increases in colorectal cancer following helminth infection and diet change are reliant on live helminth infection and are regulated by IL-4Ra signalling. Increased tumour development is associated with a reduced anti-tumor response and the increased production of inflammatory lipid mediators in the colon, where administration of one mediator increased tumor formation in naive mice. We conclude that helminth infection and diet change exacerbate colorectal cancer through regulation of fatty acid metabolism and increased production of lipid inflammatory mediators.
I have determined that exposure to H. polygyrus infection exacerbates the pathology associated with inflammation-associated colorectal cancer (CRC). Infection was associated with increased weight loss, increased mortality and increased tumour formation (Fig. 1). Diet also has a profound impact on disease and clashed with helminth infection, resulting in a profound exacerbation of CRC (Fig. 2). My experiments demonstrated that live infection is associated with exacerbation of CRC, as clearance of chronic parasite infection using the anthelminthic drug Ivermectin improved weight loss and survival following initiation of CRC (Fig. 3).
Thorough analysis of the immune system demonstrated that helminth infection could modify both innate and adaptive anti-tumor responses; and in particular, reduce IFN-gamma production by CD4+ and CD8+ T cells (typical anti-tumor responses) (Fig. 4). Although helminth infection was associated with typical type-2 responses, use of infected mice deficient in the signaling molecule required for generation of this response (IL-4Rα) actually exhibited worse disease (increased weight loss, mortality and tumor formation) than naive mice (Fig. 5). These results reveal an unexpected role for IL-4Rα signaling in protecting against helminth induced CRC. Through extensive lipidomics we found that increased CRC was associated with the production of certain lipid inflammatory mediators in the colon (Fig. 6). One of these mediators increased tumor formation in naive mice (Fig. 7). We conclude that helminth infection and diet change exacerbate inflammation-associated colorectal cancer through regulation of fatty acid metabolism and the production of inflammatory lipid mediators. These results were presented at the Cardiff Infection and Immunity Meeting (Nov 2017), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and have been assembled for publication (anticipated Jan 2019).
We have also shown that administration of H. polygyrus excretory/secretory products (HES) but not H. polygyrus adult antigen increases tumour growth in vivo. This increase in tumor burden was associated with a significant increase in the total number of CD3+CD4+Foxp3+ regulatory T cells (Treg) within the draining lymph node of the tumor, as well as the tumor itself (Fig. 8). We have begun to explore how parasite products can drive tumor growth in vivo. These results were presented at the SASBMB meeting (July 2018), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and are being assembled for publication (anticipated 2019).
Thorough analysis of the immune system demonstrated that helminth infection could modify both innate and adaptive anti-tumor responses; and in particular, reduce IFN-gamma production by CD4+ and CD8+ T cells (typical anti-tumor responses) (Fig. 4). Although helminth infection was associated with typical type-2 responses, use of infected mice deficient in the signaling molecule required for generation of this response (IL-4Rα) actually exhibited worse disease (increased weight loss, mortality and tumor formation) than naive mice (Fig. 5). These results reveal an unexpected role for IL-4Rα signaling in protecting against helminth induced CRC. Through extensive lipidomics we found that increased CRC was associated with the production of certain lipid inflammatory mediators in the colon (Fig. 6). One of these mediators increased tumor formation in naive mice (Fig. 7). We conclude that helminth infection and diet change exacerbate inflammation-associated colorectal cancer through regulation of fatty acid metabolism and the production of inflammatory lipid mediators. These results were presented at the Cardiff Infection and Immunity Meeting (Nov 2017), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and have been assembled for publication (anticipated Jan 2019).
We have also shown that administration of H. polygyrus excretory/secretory products (HES) but not H. polygyrus adult antigen increases tumour growth in vivo. This increase in tumor burden was associated with a significant increase in the total number of CD3+CD4+Foxp3+ regulatory T cells (Treg) within the draining lymph node of the tumor, as well as the tumor itself (Fig. 8). We have begun to explore how parasite products can drive tumor growth in vivo. These results were presented at the SASBMB meeting (July 2018), the Molecular and Cellular Biology of Helminth Parasites meeting in Hydra (Sept 2018) and are being assembled for publication (anticipated 2019).
Currently it is not clear how helminth modulation of immunity influences colorectal cancer incidence and progression. I have successfully shown in a model of inflammation-associated colorectal cancer and a pre-clinical model of tumor progression, that exposure to helminths can exacerbate cancer formation and growth in vivo. An increase in colitis-associated cancer following H. polygyrus infection was exacerbated by diet change and the presence of live infection. Disease was associated with changes to both innate and adaptive anti-tumor responses but was independent of IL-4Rα signalling. Poor outcome was also associated with increased production of lipid inflammatory mediators in the colon, one of which could drive tumor formation in vivo. Overall, the data suggest a detrimental impact of chronic parasite infection and changes in diet on cancer development in the host, via fatty acid metabolism. These findings may have an impact on parasite endemic regions, particularly the developing world, where tumor incidence is anticipated to increase substantially by 2035. Our results reveal potential biomarkers and novel targets for the treatment of colitis-associated cancer and motivate for global helminth eradication.
As part of NRF funding I have received, I am supervising a PhD student working on research related to this project. The MSc student also funded by NRF on a project allied to this research recently submitted her MSc thesis and has secured a PhD studentship, with full scholarship, at Oxford University, UK. We recently published some of the work from her MSc in Scientific Reports (July 2018). Both studentships have allowed for the strengthening of the international collaboration I have established, between Cardiff University and UCT and set a platform for the development of this research at the host institution (a developing country). This has wider implications for strengthening scientific strengths in South Africa, building on the research taking place in this country and with international collaborators.
As part of NRF funding I have received, I am supervising a PhD student working on research related to this project. The MSc student also funded by NRF on a project allied to this research recently submitted her MSc thesis and has secured a PhD studentship, with full scholarship, at Oxford University, UK. We recently published some of the work from her MSc in Scientific Reports (July 2018). Both studentships have allowed for the strengthening of the international collaboration I have established, between Cardiff University and UCT and set a platform for the development of this research at the host institution (a developing country). This has wider implications for strengthening scientific strengths in South Africa, building on the research taking place in this country and with international collaborators.