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Articles
Articles
Neuronal Distribution in Colorectal Cancer: Associations With Clinicopathological Parameters and Survival Maartje Massen, Meike S Thijssen , Glenn Rademakers , Musa Idris , Kim A D Wouters , Jaleesa R M van der Meer, Nikkie Buekers , Desirée Huijgen , Iryna V Samarska, Matty P Weijenberg, Piet A van den Brandt , Manon van Engeland, Marion J Gijbels , Werend Boesmans, Kim M Smits , Veerle Melotte Mod Pathol. 2024 Jul 17;37(10):100565.doi: 10.1016/j.modpat.2024.100565
Differences in enteric neuronal density in the NSE-Noggin mouse model across institutes. Schonkeren SL, Thijssen MS, Idris M, Wouters K, de Vaan J, Teubner A, Gijbels MJ, Boesmans W, Melotte V. Sci Rep. 2024 Feb 14;14(1):3686. doi: 10.1038/s41598-024-54337-w. PMID: 38355947
Musa Idris, Louis Coussement, Maria M. Alves, Tim de Meyer, Veerle Melotte. Promoter hypermethylation of neural-related genes relates to stemness in solid cancers, Epigenetics Chromatin. 2023 Aug 3;16(1):31. doi: 10.1186/s13072-023-00505-7. PMID: 37537688
Schonkeren SL, Seeldrayers S, Thijssen MS, Boesmans W, Langen RCJ, Melotte V. An optimization and refinement of the whole-gut transit assay in mice. Neurogastroenterol Motil. 2023 Aug;35(8):e14586. doi: 10.1111/nmo.14586. Epub 2023 Apr 3. PMID: 37010851.
Vaes N, Idris M, Boesmans W, Alves MM, Melotte V. Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol. 2022 Dec;19(12):768-784. doi: 10.1038/s41575-022-00669-9. Epub 2022 Sep 2. PMID: 36056202.
Schonkeren SL, Küthe TT, Idris M, Bon-Frauches AC, Boesmans W, Melotte V. The gut brain in a dish: Murine primary enteric nervous system cell cultures. Neurogastroenterol Motil. 2022 Feb;34(2):e14215. doi: 10.1111/nmo.14215. Epub 2021 Jul 8. PMID: 34236124; PMCID: PMC9285479.
Vaes N, Schonkeren SL, Rademakers G, Holland AM, Koch A, Gijbels MJ, Keulers TG, de Wit M, Moonen L, Van der Meer JRM, van den Boezem E, Wolfs TGAM, Threadgill DW, Demmers J, Fijneman RJA, Jimenez CR, Vanden Berghe P, Smits KM, Rouschop KMA, Boesmans W, Hofstra RMW, Melotte V. Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2. EMBO Rep. 2021 Jun 4;22(6):e51913. doi: 10.15252/embr.202051913. Epub 2021 Apr 23. PMID: 33890711; PMCID: PMC8183412.
Rademakers G, Massen M, Koch A, Draht MX, Buekers N, Wouters KAD, Vaes N, De Meyer T, Carvalho B, Meijer GA, Herman JG, Smits KM, van Engeland M, Melotte V. Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC. Clin Epigenetics. 2021 Apr 15;13(1):80. doi: 10.1186/s13148-021-01067-9. PMID: 33858496; PMCID: PMC8048074.
Vaes N, Lentjes MHFM, Gijbels MJ, Rademakers G, Daenen KL, Boesmans W, Wouters KAD, Geuzens A, Qu X, Steinbusch HPJ, Rutten BPF, Baldwin SH, Sharkey KA, Hofstra RMW, van Engeland M, Vanden Berghe P, Melotte V. NDRG4, an early detection marker for colorectal cancer, is specifically expressed in enteric neurons. Neurogastroenterol Motil. 2017 Sep;29(9). doi: 10.1111/nmo.13095. Epub 2017 May 19. PMID: 28524415.
Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst. 2009 Jul 1;101(13):916-27. doi: 10.1093/jnci/djp131. Epub 2009 Jun 17. PMID: 19535783.
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Thesis
Thesis
Despite improved early detection and treatment options, colorectal cancer (CRC) is one of the deadliest forms of cancer. I discovered that NDRG4, an established biomarker for the early detection of CRC (Cologuard®) is specifically expressed in the gut’s intrinsic nervous system: the enteric nervous system (ENS). While defects in the ENS have been implicated in life-threatening conditions, its contribution to CRC is hardly studied. This is remarkable as cells in the “tumor microenvironment” can contribute to (colorectal) carcinogenesis. I uncovered that NDRG4 affects ENS development and GI functioning. Moreover, the loss of NDRG4 enhanced colorectal tumorigenesis by the increased release of soluble factors. These findings implicate that the ENS is a new member of the (tumor) microenvironment which opens new perspectives for the development of clinical applications (biomarkers and/or treatment) for GI disorders.
This thesis investigates the role of the enteric nervous system, or 'the abdominal brain' in colon cancer. Through this study, it has been shown that there is an interaction between the nerve cells of the gut and the tumor cells, where certain proteins secreted by nerve cells can affect the growth of the tumor. It has also been shown that the presence or absence of nerve fibers in colon tumors may predict the life expectancy of colon cancer patients. Finally, it was discovered that many methylation markers, which can be used for early detection of colon cancer, are involved in nervous system processes. These studies indicate the importance of the enteric nervous system in colon cancer, which has not been extensively studied before. In the future, this research may lead to the development of new diagnostic and prognostic biomarkers as well as new therapies for colon cancer.
The enteric nervous system, also referred to as ‘the brain of the gut’, is important for gut functioning. In recent years, it has become evident that neurons can influence cancer, but how the brain of the gut influences colorectal cancer has hardly been investigated. This thesis focussed on the brain of the gut and its role in the development and progression of colorectal cancer. In addition, available models to study the brain of the gut were evaluated, with a focus on validating and improving these models for biomedical research. This research shows that neurons in the gut can influence colorectal cancer by sending signals to colorectal cancer cells on the one hand, and by influencing the immune system on the other hand.
Biomarkers for the early detection and riskstratification in colorectal cancer (2024)
Biomarkers for the early detection and riskstratification in colorectal cancer (2024)
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