439 results on '"Fodde, R."'
Search Results
2. Smad4 haploinsufficiency in mouse models for intestinal cancer
- Author
-
Alberici, P, Jagmohan-Changur, S, De Pater, E, Van Der Valk, M, Smits, R, Hohenstein, P, and Fodde, R
- Published
- 2006
- Full Text
- View/download PDF
3. Correction: Teeuwssen and fodde; colon cancer heterogeneity and phenotypic plasticity in metastasis formation (Cancers (2019) 11, 9, 1368)
- Author
-
Teeuwssen, M. (Miriam), Fodde, R. (Riccardo), Teeuwssen, M. (Miriam), and Fodde, R. (Riccardo)
- Abstract
The authors would like to make a correction to their published paper [1]. The authors would like to change one incorrect sentence in reference [1]. On page 9, in paragraph 2, the sentence "In colon cancer, CAFs release exosomes containing miR-92a-3p and promote invasion and chemotherapy resistance. miR-92a-3p directly binds to FBXW7 and MOAP1 thereby activating Wnt-induced EMT and mitochondrial apoptosis [89]'should be changed to "In colon cancer, CAFs release exosomes containing miR-92a-3p and promote invasion and chemotherapy resistance. miR-92a-3p directly binds to FBXW7 and MOAP1 thereby activating Wnt-induced EMT and inhibiting mitochondrial apoptosis [89]." The change does not affect the scientific results. The rest of the manuscript does not to be changed. The authors would like to apologize for any inconvenience caused. The manuscript will be updated, and the original will remain available on the article webpage.
- Published
- 2020
- Full Text
- View/download PDF
4. Expression and genomic profiling of colorectal cancer
- Author
-
Cardoso, J., Boer, J., Morreau, H., and Fodde, R.
- Published
- 2007
- Full Text
- View/download PDF
5. Radiation induces different changes in expression profiles of normal rectal tissue compared with rectal carcinoma
- Author
-
Nagtegaal, I. D., Gaspar, C. G. S., Peltenburg, L. T. C., Marijnen, C. A. M., Kapiteijn, E., van de Velde, C. J. H., Fodde, R., and van Krieken, J. H. J. M.
- Published
- 2005
- Full Text
- View/download PDF
6. Early morbidity encountered in the dietary-related mouse model of Barrettʼs esophagus: a question of zinc?
- Author
-
Grotenhuis, B. A., Franken, P. F., Swinkels, W. J. C., Boonstra, A., van der Valk, M. A., van Lanschot, J. J. B., and Fodde, R.
- Published
- 2011
- Full Text
- View/download PDF
7. The Role of the APC Tumor Suppressor in Chromosomal Instability
- Author
-
Alberici, P., primary and Fodde, R., additional
- Published
- 2006
- Full Text
- View/download PDF
8. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP)
- Author
-
Nielsen, M, Franken, P F, Reinards, T H C M, Weiss, M M, Wagner, A, van der Klift, H, Kloosterman, S, Houwing-Duistermaat, J J, Aalfs, C M, Ausems, M G E M, Bröcker-Vriends, A H J T, Garcia, E B Gomez, Hoogerbrugge, N, Menko, F H, Sijmons, R H, Verhoef, S, Kuipers, E J, Morreau, H, Breuning, M H, Tops, C M J, Wijnen, J T, Vasen, H F A, Fodde, R, and Hes, F J
- Published
- 2005
9. Cell heterogeneity and phenotypic plasticity in metastasis formation: The case of colon cancer
- Author
-
Teeuwssen, M. (Miriam), Fodde, R. (Riccardo), Teeuwssen, M. (Miriam), and Fodde, R. (Riccardo)
- Abstract
The adenoma-to-carcinoma progression in colon cancer is driven by a sequential accumulation of genetic alterations at specific tumor suppressors and oncogenes. In contrast, the multistage route from the primary site to metastasis formation is underlined by phenotypic plasticity, i.e., the capacity of disseminated tumor cells to undergo transiently and reversible transformations in order to adapt to the ever-changing environmental contexts. Notwithstanding the considerable body of evidence in support of the role played by epithelial-to-mesenchymal transition (EMT)/mesenchymal-to-epithelial transition (MET) in metastasis, its rate-limiting function, the detailed underlying cellular and molecular mechanisms, and the extension of the necessary morphologic and epigenetic changes are still a matter of debate. Rather than leading to a complete epithelial or mesenchymal state, the EMT/MET-program generates migrating cancer cells displaying intermediate phenotypes featuring both epithelial and mesenchymal characteristics. In this review, we will address the role of colon cancer heterogeneity and phenotypic plasticity in metastasis formation and the contribution of EMT to these processes. The alleged role of hybrid epithelial/mesenchymal (E/M) in collective and/or single-cell migration during local dissemination at the primary site and more systemic spreading will also be highlighted.
- Published
- 2019
- Full Text
- View/download PDF
10. The inflammatory cytokine IL-6 induces FRA1 deacetylation promoting colorectal cancer stem-like properties
- Author
-
Wang, TY, Song, P., Zhong, T.T., Wang, X.J. (Xian Jiang), Xiang, X.P., Liu, Q., Chen, H. (Huiyong), Xia, T., Liu, H, Niu, Y.M., Hu, YS, Xu, L. (Lei), Shao, Y.K., Zhu, L.J. (Lihua Julie), Qi, H.Y., Shen, J. (Jie), Hou, T.J., Fodde, R. (Riccardo), Shao, J.M., Wang, TY, Song, P., Zhong, T.T., Wang, X.J. (Xian Jiang), Xiang, X.P., Liu, Q., Chen, H. (Huiyong), Xia, T., Liu, H, Niu, Y.M., Hu, YS, Xu, L. (Lei), Shao, Y.K., Zhu, L.J. (Lihua Julie), Qi, H.Y., Shen, J. (Jie), Hou, T.J., Fodde, R. (Riccardo), and Shao, J.M.
- Abstract
Colorectal cancer (CRC) has long been known for its tight association with chronic inflammation, thought to play a key role in tumor onset and malignant progression through the modulation of cancer stemness. However, the underlying molecular and cellular mechanisms are still largely elusive. Here we show that the IL-6/STAT3 inflammatory signaling axis induces the deacetylation of FRA1 at the Lys-116 residue located within its DNA-binding domain. The HDAC6 deacetylase underlies this key modification leading to the increase of FRA1 transcriptional activity, the subsequent transactivation of NANOG expression, and the acquisition of stem-like cellular features. As validated in a large (n = 123) CRC cohort, IL-6 secretion was invariably accompanied by increased FRA1 deacetylation at K116 and an overall increase in its protein levels, coincident with malignant progression and poor prognosis. Of note, combined treatment with the conventional cytotoxic drug 5-FU together with Tubastatin A, a HDAC6-specific inhibitor, resulted in a significant in vivo synergistic inhibitory effect on tumor growth through suppression of CRC stemness. Our results reveal a novel transcriptional and posttranslational regulatory cross-talk between inflammation and stemness signaling pathways that underlie self-renewal and maintenance of CRC stem cells and promote their malignant behavior. Combinatorial treatment aimed at the core regulatory mechanisms downstream of IL-6 may offer a novel promising approach for CRC treatment.
- Published
- 2019
- Full Text
- View/download PDF
11. Expression and genomic profiling of hereditary colorectal cancer
- Author
-
Fodde, R.
- Published
- 2004
12. Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer
- Author
-
Watson, P, Narod, S A, Fodde, R, Wagner, A, Lynch, J F, Tinley, S T, Snyder, C L, Coronel, S A, Riley, B, Kinarsky, Y, and Lynch, H T
- Published
- 2003
13. Rapidly progressive adenomatous polyposis in a patient with germline mutations in both the APC and MLH1 genes: the worst of two worlds
- Author
-
Scheenstra, R, Rijcken, F E M, Koornstra, J J, Hollema, H, Fodde, R, Menko, F H, Sijmons, R H, Bijleveld, C M A, and Kleibeuker, J H
- Published
- 2003
14. Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree
- Author
-
Wagner, A, Hendriks, Y, Meijers-Heijboer, E J, de Leeuw, W J F, Morreau, H, Hofstra, R, Tops, C, Bik, E, Bröcker-Vriends, A H J T, van der Meer, C, Lindhout, D, Vasen, H F A, Breuning, M H, Cornelisse, C J, van Krimpen, C, Niermeijer, M F, Zwinderman, A H, Wijnen, J, and Fodde, R
- Published
- 2001
15. The APC gene in colorectal cancer
- Author
-
Fodde, R.
- Published
- 2002
- Full Text
- View/download PDF
16. 12 DOC1-dependent recruitment of NURD reveals antagonism with SWI/SNF during epithelial-mesenchymal transition in oral cancer cells
- Author
-
Mohd-Sarip, A., primary, Teeuwssen, M., additional, Bot, A., additional, Baatenburg de Jong, R.J., additional, Looijenga, L.H.J., additional, Van Ijcken, W.F.J., additional, Van de Werken, H.J.G., additional, Demmers, J.A., additional, Fodde, R., additional, and Verrijzer, C.P., additional
- Published
- 2018
- Full Text
- View/download PDF
17. DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition i
- Author
-
Mohd-Sarip, A. (Adone), Teeuwssen, M. (Miriam), Bot, A.G. (Alice), Herdt, M.J. (Maria) de, Willems, S.M. (Stefan Martin), Baatenburg de Jong, R.J. (Robert Jan), Looijenga, L.H.J. (Leendert), Zatreanu, D. (Diana), Bezstarosti, K. (Karel), Riet, J. (Job) van, Oole, E. (Edwin), IJcken, W.F.J. (Wilfred) van, Werken, H.J.G. (Harmen) van de, Demmers, J.A.A. (Jeroen), Fodde, R. (Riccardo), Verrijzer, C.P. (Peter), Mohd-Sarip, A. (Adone), Teeuwssen, M. (Miriam), Bot, A.G. (Alice), Herdt, M.J. (Maria) de, Willems, S.M. (Stefan Martin), Baatenburg de Jong, R.J. (Robert Jan), Looijenga, L.H.J. (Leendert), Zatreanu, D. (Diana), Bezstarosti, K. (Karel), Riet, J. (Job) van, Oole, E. (Edwin), IJcken, W.F.J. (Wilfred) van, Werken, H.J.G. (Harmen) van de, Demmers, J.A.A. (Jeroen), Fodde, R. (Riccardo), and Verrijzer, C.P. (Peter)
- Abstract
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation. Strikingly, depletion of SWI/SNF mimics the effects of DOC1 re-expression. Our results suggest that SWI/SNF and NURD function antagonistically to control chromatin state and transcription. We propose that disturbance of this dynamic equilibrium may lead to defects in gene expression that promote oncogenesis.
- Published
- 2017
- Full Text
- View/download PDF
18. ??¢-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis
- Author
-
van Veelen, W., Le, N. H., Helvensteijn, W., Blonden, L., Theeuwes, M., Bakker, E. R. M., Franken, P. F., van Gurp, L., Meijlink, F., van der Valk, M. A., Kuipers, E. J., Fodde, R., and Smits, R.
- Published
- 2011
- Full Text
- View/download PDF
19. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial
- Author
-
Burn, J., Gerdes, A.M., Macrae, F., Mecklin, J.P., Moeslein, G., Olschwang, S., Eccles, D., Evans, D.G., Maher, E.R., Bertario, L., Bisgaard, M.L., Dunlop, M.G., Ho, J.W.C., Hodgson, S.V., Lindblom, A., Lubinski, J., Morrison, P.J., Murday, V., Ramesar, R., Side, L., Scott, R.J., Thomas, H.J.W., Vasen, H.F., Barker, G., Crawford, G., Elliott, F., Movahedi, M., Pylvanainen, K., Wijnen, J.T., Fodde, R., Lynch, H.T., Mathers, J.C., Bishop, D.T., CAPP2 Investigators, and Pathology
- Subjects
Adenoma ,Heterozygote ,medicine.medical_specialty ,Colorectal cancer ,Placebo ,Chemoprevention ,law.invention ,Double-Blind Method ,Randomized controlled trial ,SDG 3 - Good Health and Well-being ,law ,Internal medicine ,Adenoma - prevention and control ,Dietary Carbohydrates ,medicine ,Humans ,media_common.cataloged_instance ,European union ,media_common ,Aspirin ,Intention-to-treat analysis ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Cancer ,Starch ,General Medicine ,Anti-Inflammatory Agents, Non-Steroidal - therapeutic use ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Lynch syndrome ,Surgery ,Colorectal Neoplasms, Hereditary Nonpolyposis - genetics - prevention and control ,Aspirin - therapeutic use ,business ,medicine.drug - Abstract
BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55.7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0.63 (95% CI 0.35-1.13, p=0.12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32-0.99, p=0.05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0.41 (0.19-0.86, p=0.02) and an IRR of 0.37 (0.18-0.78, p=0.008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma., link_to_OA_fulltext
- Published
- 2011
20. CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models
- Author
-
Cremers, N. (Natascha), Neeb, A. (Antje), Uhle, T. (Tanja), Dimmler, A. (Arno), Rothley, M. (Melanie), Allgayer, H. (H.), Fodde, R. (Riccardo), Sleeman, J.P. (Jonathan Paul), Thiele, W. (Wilko), Cremers, N. (Natascha), Neeb, A. (Antje), Uhle, T. (Tanja), Dimmler, A. (Arno), Rothley, M. (Melanie), Allgayer, H. (H.), Fodde, R. (Riccardo), Sleeman, J.P. (Jonathan Paul), and Thiele, W. (Wilko)
- Abstract
CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice.
- Published
- 2016
- Full Text
- View/download PDF
21. Identification of gene expression profiling to predict pathologic response of rectal carcinoma after preoperative chemoradiotherapy
- Author
-
Nitti, D., Fodde, R., Mescoli, C., Frisos, M. L., Pasetto, L. M., Esposito, G., Digito, M., Ambrosi, A., Gaspar, G., marco agostini, Pucciarelli, S., ESMO - JSMO, European Multidisciplinary Colorectal Cancer Congress, Pucciarelli, S, Agostini, M, Gaspar, G, Ambrosi, Alessandro, Digito, M, Esposito, G, Pasetto, Lm, Frisos, Ml, Mescoli, C, Fodde, R, and Nitti, D.
- Published
- 2008
22. Prevalence and molecular heterogeneity of alfa+thalassemia in two tribal populations from Andhra Pradesh, India
- Author
-
Fodde, R., Losekoot, M., van den Broek, M. H., Oldenburg, M., Rashida, N., Schreuder, A., Wijnen, J. T., Giordano, P. C., Nayudu, N. V. S., Khan, P. Meera, and Bernini, L. F.
- Published
- 1988
- Full Text
- View/download PDF
23. Use of Aspirin Postdiagnosis Improves Survival for Colon Cancer Patients
- Author
-
Bastiaannet, E., Sampieri, K., Dekkers, O.M., Craen, A.J.M. de, Herk-Sukel, M.P.P. van, Coebergh, J.W., Herings, R.M.C., Velde, C.J.H. van de, Fodde, R., and Liefers, G.J.
- Published
- 2011
24. A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis
- Author
-
Burn, J., Bishop, D.T., Chapman, P.D., Elliott, F., Bertario, L., Dunlop, M.G., Eccles, D., Ellis, A., Evans, D.G., Fodde, R., Maher, E.R., Moslein, G., Vasen, H.F.A., Coaker, J., Phillips, R.K.S., Bulow, S., Mathers, J.C., Int CAPP Consortium, and Pathology
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Colorectal cancer ,Rectum ,Placebo ,Gastroenterology ,Article ,law.invention ,Familial adenomatous polyposis ,Young Adult ,Randomized controlled trial ,Double-Blind Method ,SDG 3 - Good Health and Well-being ,law ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Child ,Aspirin ,large-bowel cancer chain fatty-acids colorectal-cancer cell-proliferation lynch syndrome dietary fiber butyrate risk neoplasia apoptosis ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,International Agencies ,Starch ,medicine.disease ,Prognosis ,digestive system diseases ,Surgery ,medicine.anatomical_structure ,Oncology ,Adenomatous Polyposis Coli ,Relative risk ,Drug Therapy, Combination ,Female ,business ,medicine.drug - Abstract
Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54–1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73–1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin—mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas. Cancer Prev Res; 4(5); 655–65. ©2011 AACR.
- Published
- 2011
25. CANONICAL WNT SIGNALING REGULATES HEMATOPOIESIS IN A DOSAGE-DEPENDENT FASHION
- Author
-
Luis, T.C., Ghazvini, M., Naber, B.A.E., Haas, E.F.E. de, Dongen, J.J.M. van, Fodde, R., and Staal, F.J.T.
- Published
- 2010
26. 68 CCAT2 LNCRNA INDUCES DE NOVO MYELODYSPLASTIC SYNDROME IN VIVO
- Author
-
Shah, M., primary, Redis, R., additional, Fabris, L., additional, Ivan, C., additional, Gagea, M., additional, Fodde, R., additional, Bueso-Ramos, C., additional, Garcia-Manero, G., additional, and Calin, G., additional
- Published
- 2015
- Full Text
- View/download PDF
27. Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia
- Author
-
Onouchi, T. (Takanori), Kobayashi, K. (Kumiko), Sakai, D.S. (Debbie), Shimomura, A. (Atsushi), Smits, M.J.M. (Ron), Sumi-Ichinose, C. (Chiho), Kurosumi, M. (Masafumi), Takao, M. (Masashi), Nomura, R. (Ryuji), Iizuka-Kogo, A. (Akiko), Suzuki, H. (Hidekazu), Kondo, K., Akiyama, T. (Tetsu), Miyakawa, T. (Tsuyoshi), Fodde, R. (Riccardo), Senda, T. (Takao), Onouchi, T. (Takanori), Kobayashi, K. (Kumiko), Sakai, D.S. (Debbie), Shimomura, A. (Atsushi), Smits, M.J.M. (Ron), Sumi-Ichinose, C. (Chiho), Kurosumi, M. (Masafumi), Takao, M. (Masashi), Nomura, R. (Ryuji), Iizuka-Kogo, A. (Akiko), Suzuki, H. (Hidekazu), Kondo, K., Akiyama, T. (Tetsu), Miyakawa, T. (Tsuyoshi), Fodde, R. (Riccardo), and Senda, T. (Takao)
- Abstract
Background: Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc 1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling. Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc 1638T/1638T mice. Apc 1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc 1638T/1638T mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia. Conclusions: Our results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system.
- Published
- 2014
- Full Text
- View/download PDF
28. Effect of protein kinase A on osteogenic differentiation and in vivo bone formation by human mesenchymal stem cells
- Author
-
Siddappa, R., van Rijn, L., Gaspar, C., Fodde, R., van Blitterswijk, Clemens, and de Boer, Jan
- Published
- 2005
29. Functional interaction between PKA and BM? Signaling during osteogenic differentiation of human mesenchymal stem cells
- Author
-
Siddappa, R., Gaspar, C., Fodde, R., van Blitterswijk, Clemens, and de Boer, Jan
- Subjects
METIS-237054 - Published
- 2005
30. De moleculaire basis van darmkanker: van gen tot genezing
- Author
-
Fodde, R.
- Published
- 2003
31. EXCO1 variants occur commonly in normal population: vidence against a role in hereditary nonpolyposis colorectal cancer
- Author
-
Jagmmohan-Changur, S., Poikonen, T., Vilkki, S., Launonen, V., Wikman, Friedrik, Ørntoft, Torben Falck, Moller, P., Vasen, H., Tops, C., Kolodner, R.D., Mecklin, J.P., Jarvinen, H., Bevan, S., Houlston, R.S., Aaltonen, L.A., Fodde, R., Wijnen, J., and Karhu, A.
- Published
- 2003
32. Wnt Signaling Regulates the Lineage Differentiation Potential of Mouse Embryonic Stem Cells through Tcf3 Down-Regulation
- Author
-
Atlasi, Y. (Yaser), Noori, R. (Rubina), Gaspar, C.F.C. (Claudia), Franken, P.F. (Patrick), Sacchetti, A. (Andrea), Rafati, H. (Haleh), Mahmoudi, T. (Tokameh), Decraene, C. (Charles), Calin, G.A. (George), Merrill, B.J. (Bradley), Fodde, R. (Riccardo), Atlasi, Y. (Yaser), Noori, R. (Rubina), Gaspar, C.F.C. (Claudia), Franken, P.F. (Patrick), Sacchetti, A. (Andrea), Rafati, H. (Haleh), Mahmoudi, T. (Tokameh), Decraene, C. (Charles), Calin, G.A. (George), Merrill, B.J. (Bradley), and Fodde, R. (Riccardo)
- Abstract
Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells.
- Published
- 2013
- Full Text
- View/download PDF
33. CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer
- Author
-
Ling, H. (Hui), Spizzo, R. (Riccardo), Atlasi, Y. (Yaser), Nicoloso, M. (Milena), Shimizu, M. (Masayoshi), Redis, R.S. (Roxana), Nishida, T., Gafà, R. (Roberta), Song, J. (Jian), Guo, Z. (Zhiyi), Ivan, C. (Cristina), Barbarotto, E. (Elisa), Vries, I. (Ingrid) de, Zhang, X. (Xinna), Ferracin, M. (Manuela), Churchman, M. (Mike), Galen, J.F. (Janneke ) van, Beverloo, H.B. (Berna), Shariati, M. (Maryam), Haderk, F. (Franziska), Estecio, M.R. (Marcos), Garcia-Manero, G. (Guillermo), Patijn, G.A. (Gijs), Gotley, D.C. (David), Bhardwaj, V. (Vikas), Shureiqi, I. (Imad), Sen, S. (Semi), Multani, A.S. (Asha), Welsh, J., Yamamoto, K. (Ken), Taniguchi, Y. (Yoshihito), Song, M.-A. (Min-Ae), Gallinger, S. (Steve), Casey, G. (Graham), Thibodeau, S.N. (Stephen), Le Marchand, L. (Loic), Tiirikainen, M. (Maarit), Mani, A.R. (Ali), Zhang, W. (Wei), Davuluri, R.V. (Ramana), Mimori, K. (Koshi), Mori, M. (Mayra), Sieuwerts, A.M. (Anieta), Martens, J.W.M. (John), Tomlinson, I.P. (Ian), Negrini, J.F. (Jean-François), Berindan-Neagoe, I. (Ioana), Foekens, J.A. (John), Hamilton, S.R. (Stanley), Lanza, G. (Giovanni), Kopetz, S. (Scott), Fodde, R. (Riccardo), Calin, G.A. (George), Ling, H. (Hui), Spizzo, R. (Riccardo), Atlasi, Y. (Yaser), Nicoloso, M. (Milena), Shimizu, M. (Masayoshi), Redis, R.S. (Roxana), Nishida, T., Gafà, R. (Roberta), Song, J. (Jian), Guo, Z. (Zhiyi), Ivan, C. (Cristina), Barbarotto, E. (Elisa), Vries, I. (Ingrid) de, Zhang, X. (Xinna), Ferracin, M. (Manuela), Churchman, M. (Mike), Galen, J.F. (Janneke ) van, Beverloo, H.B. (Berna), Shariati, M. (Maryam), Haderk, F. (Franziska), Estecio, M.R. (Marcos), Garcia-Manero, G. (Guillermo), Patijn, G.A. (Gijs), Gotley, D.C. (David), Bhardwaj, V. (Vikas), Shureiqi, I. (Imad), Sen, S. (Semi), Multani, A.S. (Asha), Welsh, J., Yamamoto, K. (Ken), Taniguchi, Y. (Yoshihito), Song, M.-A. (Min-Ae), Gallinger, S. (Steve), Casey, G. (Graham), Thibodeau, S.N. (Stephen), Le Marchand, L. (Loic), Tiirikainen, M. (Maarit), Mani, A.R. (Ali), Zhang, W. (Wei), Davuluri, R.V. (Ramana), Mimori, K. (Koshi), Mori, M. (Mayra), Sieuwerts, A.M. (Anieta), Martens, J.W.M. (John), Tomlinson, I.P. (Ian), Negrini, J.F. (Jean-François), Berindan-Neagoe, I. (Ioana), Foekens, J.A. (John), Hamilton, S.R. (Stanley), Lanza, G. (Giovanni), Kopetz, S. (Scott), Fodde, R. (Riccardo), and Calin, G.A. (George)
- Abstract
The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
- Published
- 2013
- Full Text
- View/download PDF
34. The 'just-right' signaling model: APC somatic mutations are selected based on a specific level of activation of the β-catenin signaling cascade
- Author
-
Albuquerque, C., Breukel, C., Luijt, R., Fidalgo, P., PEDRO LAGE, Slors, F. J. M., Nobre Leitão, C., Fodde, R., Smits, R., Pathology, and Gastroenterology & Hepatology
- Abstract
According to the classical interpretation of Knudson's 'two-hit' hypothesis for tumorigenesis, the two 'hits' are independent mutation events, the end result of which is loss of a tumor suppressing function. Recently, it has been shown that the APC (adenomatous polyposis coli) gene does not entirely follow this model. Both the position and type of the second hit in familial adenomatous polyposis (FAP) polyps depend on the localization of the germline mutation. This non-random distribution of somatic hits has been interpreted as the result of selection for more advantageous mutations during tumor formation. However, the APC gene encodes for a multifunctional protein, and the exact cellular function upon which this selection is based is yet unknown. In this study, we have analyzed somatic APC point mutations and loss of heterozygosity (LOH) in 133 colorectal adenomas from six FAP patients. We observed that when germline mutations result in truncated proteins without any of the seven β-catenin downregulating 20-amino-acid repeats distributed in the central domain of APC, the majority of the corresponding somatic point mutations retain one or, less frequently, two of the same 20-amino-acid repeats. Conversely, when the germline mutation results in a truncated protein retaining one 20-amino-acid repeat, most second hits remove all 20-amino-acid repeats. The latter is frequently accomplished by allelic loss. Notably, and in contrast to previous observations, in a patient where the germline APC mutation retains two such repeats, the majority of the somatic hits are point mutations (and not LOH) located upstream and removing all of the 20-amino-acid repeats. These results indicate selection for APC genotypes that are likely to retain some activity in downregulating β-catenin signaling. We propose that this selection process is aimed at a specific degree of β-catenin signaling optimal for tumor formation, rather than at its constitutive activation by deletion of all the β-catenin downregulating motifs in APC.
- Published
- 2002
35. Mutations in the APC tumor suppressor gene cause chromosomal instability in colorectal cancer
- Author
-
Fodde, R., Kuipers, J., Rosenberg, C., Smits, R., Kielman, M., Gaspar, C., Es, J.H. van, Breukel, C., Wiegant, J., Giles, R.H., Clevers, J.C., and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Published
- 2001
36. Use of Aspirin postdiagnosis improves survival for colon cancer patients
- Author
-
Bastiaannet, E. (Esther), Sampieri, K. (K.), Dekkers, O.M. (Olaf), Craen, A.J. (Anton) de, Herk-Sukel, M.P.P. (Myrthe) van, Lemmens, V.E.P.P. (Valery), Broek, C.B.M. (Colette) van den, Coebergh, J.W.W. (Jan Willem), Herings, R.M.C. (Ron), Velde, C.J.H. (Cornelis) van de, Fodde, R. (Riccardo), Liefers, G.-J. (Gerrit-Jan), Bastiaannet, E. (Esther), Sampieri, K. (K.), Dekkers, O.M. (Olaf), Craen, A.J. (Anton) de, Herk-Sukel, M.P.P. (Myrthe) van, Lemmens, V.E.P.P. (Valery), Broek, C.B.M. (Colette) van den, Coebergh, J.W.W. (Jan Willem), Herings, R.M.C. (Ron), Velde, C.J.H. (Cornelis) van de, Fodde, R. (Riccardo), and Liefers, G.-J. (Gerrit-Jan)
- Abstract
Background: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients. Methods: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.Results:In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001). Conclusion: Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-cont
- Published
- 2012
- Full Text
- View/download PDF
37. Generation and characterization of an inducible transgenic model for studying mouse esophageal biology
- Author
-
Roth, S.G. (Sabrina), Franken, P.F. (Patrick), Monkhorst, K. (Kim), Kong-a-San, J. (John), Fodde, R. (Riccardo), Roth, S.G. (Sabrina), Franken, P.F. (Patrick), Monkhorst, K. (Kim), Kong-a-San, J. (John), and Fodde, R. (Riccardo)
- Abstract
Background: To facilitate the in vivo study of esophageal (stem) cell biology in homeostasis and cancer, novel mouse models are necessary to elicit expression of candidate genes in a tissue-specific and inducible fashion. To this aim, we developed and studied a mouse model to allow labeling of esophageal cells with the histone 2B-GFP (H2B-GFP) fusion protein. Results: First, we generated a transgenic mouse model expressing the reverse tetracycline transactivator rtTA2-M2 under control of the promoter (ED-L2) of the Epstein-Barr virus (EBV) gene encoding the latent membrane protein-1 (LMP-1). The newly generated ED-L2-rtTA2-M2 (ED-L2-rtTA) mice were then bred with the previously developed tetO-HIST1H2BJ/GFP (tetO-H2B-GFP) model to assess inducibility and tissue-specificity. Expression of the H2B-GFP fusion protein was observed upon doxycycline induction but was restricted to the terminally differentiated cells above the basal cell layer. To achieve expression in the basal compartment of the esophagus, we ubsequently employed a different transgenic model expressing the reverse transactivator rtTA2S-M2 under the control of the ubiquitous, methylation-free CpG island of the human hnRNPA2B1-CBX3 gene (hnRNP-rtTA). Upon doxycycline administration to the compound hnRNP-rtTA/tetO-H2B-GFP mice, near-complete labeling of all esophageal cells was achieved. Pulse-chase experiments confirmed that complete turnover of the esophageal epithelium in the adult mouse is achieved within 710 days. Conclusions: We show that the esophagus-specific promoter ED-L2 is expressed only in the differentiated cells above the basal layer. oreover, we confirmed that esophageal turn-over in the adult mouse does not exceed 710 days.
- Published
- 2012
- Full Text
- View/download PDF
38. Paneth cells in intestinal homeostasis and tissue injury
- Author
-
Roth, S.G. (Sabrina), Franken, P.F. (Patrick), Sacchetti, A. (Andrea), Kremer, A. (Andreas), Anderson, K.I. (Kurt), Sansom, O.J. (Owen), Fodde, R. (Riccardo), Roth, S.G. (Sabrina), Franken, P.F. (Patrick), Sacchetti, A. (Andrea), Kremer, A. (Andreas), Anderson, K.I. (Kurt), Sansom, O.J. (Owen), and Fodde, R. (Riccardo)
- Abstract
Adult stem cell niches are often co-inhabited by cycling and quiescent stem cells. In the intestine, lineage tracing has identified Lgr5+ cells as frequently cycling stem cells, whereas Bmi1+, mTert+, Hopx+ and Lrig1+ cells appear to be more quiescent. Here, we have applied a non-mutagenic and cell cycle independent approach to isolate and characterize small intestinal label-retaining cells (LRCs) persisting in the lower third of the crypt of Lieberkühn for up to 100 days. LRCs do not express markers of proliferation and of enterocyte, goblet or enteroendocrine differentiation, but are positive for Paneth cell markers. While during homeostasis, LR/Paneth cells appear to play a supportive role for Lgr5+ stem cells as previously shown, upon tissue injury they switch to a proliferating state and in the process activate Bmi1 expression while silencing Paneth-specific genes. Hence, they are likely to contribute to the regenerative process following tissue insults such as chronic inflammation.
- Published
- 2012
- Full Text
- View/download PDF
39. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer
- Author
-
Sijmons, Rolf, Hofstra, Roelof, Hollema, Harmen, Mensink, R, VANDERHOUT, A, Hoekstra, Harald, Kleibeuker, Jan, Molenaar, Willemina, Wijnen, Juul, Fodde, R, Vasen, H, Buys, Carolus, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Targeted Gynaecologic Oncology (TARGON)
- Subjects
RISK ,congenital, hereditary, and neonatal diseases and abnormalities ,MUTATIONS ,INSTABILITY ,SURVIVAL ,nutritional and metabolic diseases ,HNPCC ,neoplasms ,digestive system diseases - Abstract
Sarcomas, including the malignant fibrous histiocytomas (MFHs), are not known to be part of the tumour spectrum of hereditary non-polyposis colorectal cancer (HNPCC) as epidemiologically established. Therefore, occurrence of MFH in an HNPCC family may very well be coincidental. HNPCC is associated with germline mutations in DNA mismatch repair genes, including the MSH2 gene. We analysed an MFH diagnosed in a 45-year-old male HNPCC patient carrying a germline MSH2 mutation for HNPCC-associated molecular characteristics, to investigate a possible relationship between the tumour and that mutation. DNA analysis revealed microsatellite instability and loss of one MSH2 copy, and immunohistochemistry showed absence of nuclear MSH2 protein staining. To investigate whether this is a common finding in MFH, microsatellite instability and nuclear MSH2 protein staining was tested for in 5 and 6 sporadic MFHs, respectively. None showed microsatellite instability and all stained positively for MSH2. Together, these findings show that in rare cases, MFH may be part of the HNPCC tumour spectrum. (C) 2000 Wiley-Liss, Inc.
- Published
- 2000
40. The nature of intestinal stem cells' nurture
- Author
-
Roth, S.G. (Sabrina), Fodde, R. (Riccardo), Roth, S.G. (Sabrina), and Fodde, R. (Riccardo)
- Published
- 2011
- Full Text
- View/download PDF
41. Familial adenomatous polyposis-associated desmoids display significantly more genetic changes than sporadic desmoids
- Author
-
Robanus-Maandag, E.C. (Els), Bosch, C.A.J. (Cathy), Amini-Nik, S. (Saeid), Knijnenburg, J. (Jeroen), Szuhai, K. (Karoly), Cervera, P. (Pascale), Poon, R. (Raymond), Eccles, D. (Diana), Radice, P. (Paolo), Giovannini, M. (Marcello), Alman, B.A. (Benjamin A.), Tejpar, S. (Sabine), Devilee, P. (Peter), Fodde, R. (Riccardo), Robanus-Maandag, E.C. (Els), Bosch, C.A.J. (Cathy), Amini-Nik, S. (Saeid), Knijnenburg, J. (Jeroen), Szuhai, K. (Karoly), Cervera, P. (Pascale), Poon, R. (Raymond), Eccles, D. (Diana), Radice, P. (Paolo), Giovannini, M. (Marcello), Alman, B.A. (Benjamin A.), Tejpar, S. (Sabine), Devilee, P. (Peter), and Fodde, R. (Riccardo)
- Abstract
Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression.
- Published
- 2011
- Full Text
- View/download PDF
42. beta-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis
- Author
-
van Veelen, W., Le, N.H., Helvensteijn, W., Blonden, L., Theeuwes, M., Bakker, E.R., Franken, P.F., van Gurp, L., Meijlink, F., van der Valk, M.A., Kuipers, E.J., Fodde, R., Smits, R.E.H.M., van Veelen, W., Le, N.H., Helvensteijn, W., Blonden, L., Theeuwes, M., Bakker, E.R., Franken, P.F., van Gurp, L., Meijlink, F., van der Valk, M.A., Kuipers, E.J., Fodde, R., and Smits, R.E.H.M.
- Abstract
Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or beta-catenin genes underlies colorectal carcinogenesis. As a result, beta-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear beta-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate beta-catenin at tyrosine residues, which is thought to increase beta-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of beta-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous beta-catenin gene was introduced. Results This study provided in vivo evidence that beta-catenin(E654) is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the beta-catenin(E654) targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of betacatenin. Surprisingly, the expression of beta-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of beta-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that beta-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. [KEYWORDS: Adenoma/genetics/metabolism, Animals, COS C, Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or beta-catenin genes underlies colorectal carcinogenesis. As a result, beta-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear beta-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate beta-catenin at tyrosine residues, which is thought to increase beta-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of beta-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous beta-catenin gene was introduced. Results This study provided in vivo evidence that beta-catenin(E654) is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the beta-catenin(E654) targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of betacatenin. Surprisingly, the expression of beta-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of beta-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that beta-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. [KEYWORDS: Adenoma/genetics/metabolism, Animals, COS C
- Published
- 2011
43. [Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer]
- Author
-
Fh, Menko, Griffioen G, Jt, Wijnen, Cm, Tops, Fodde R, and Hans Vasen
- Subjects
Adult ,Aged, 80 and over ,Male ,Genes, APC ,Adolescent ,Brain Neoplasms ,Genetic Carrier Screening ,Peutz-Jeghers Syndrome ,Middle Aged ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Neoplasms, Multiple Primary ,Adenomatous Polyps ,Adenomatous Polyposis Coli ,Child, Preschool ,Humans ,Female ,Child ,Hamartoma Syndrome, Multiple ,Germ-Line Mutation ,Aged ,Netherlands - Abstract
About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.
- Published
- 1999
44. A new conditional Apc-mutant mouse model for colorectal cancer
- Author
-
Robanus-Maandag, E.C. (Els), Koelink, P.J. (Pim), Breukel, C. (Cor), Salvatori, D.C.F. (Daniela), Jagmohan-Changur, S.C. (Shantie), Bosch, C.A.J. (Cathy), Verspaget, H.W., Devilee, P. (Peter), Fodde, R. (Riccardo), Smits, M.J.M. (Ron), Robanus-Maandag, E.C. (Els), Koelink, P.J. (Pim), Breukel, C. (Cor), Salvatori, D.C.F. (Daniela), Jagmohan-Changur, S.C. (Shantie), Bosch, C.A.J. (Cathy), Verspaget, H.W., Devilee, P. (Peter), Fodde, R. (Riccardo), and Smits, M.J.M. (Ron)
- Abstract
Mutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc-mutant allele, Apc15lox, with exon 15 flanked by loxP sites. Similar survival of Apc1638N/15loxand Apc1638N/1mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in ApcD15/1mice, showing a severe ApcMin/1-like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of FabplCre;Apc15lox/1mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the FabplCre;Apc15lox/1mouse should be an attractive model for studies on prevention and treatment of colorectal cancer.
- Published
- 2010
- Full Text
- View/download PDF
45. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.
- Author
-
Siddappa, R., Martens, A.C.M., Doorn, J., Leusink, A., Olivo, C., Licht, R., van Rijn, L., Gaspar, C., Fodde, R., Janssen, F., van Blitterswijk, C., de Boer, J., Siddappa, R., Martens, A.C.M., Doorn, J., Leusink, A., Olivo, C., Licht, R., van Rijn, L., Gaspar, C., Fodde, R., Janssen, F., van Blitterswijk, C., and de Boer, J.
- Published
- 2008
46. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome
- Author
-
Burn, J. (John), Bishop, D.T. (David Timothy), Mecklin, J.-P. (Jukka-Pekka), Macrae, F.A. (Finlay), Möslein, G. (Gabriela), Olschwang, S. (Sylviane), Bisgaard, M.-L. (Marie-Luise), Ramesar, R.S. (Rajkumar), Eccles, D. (Diana), Maher, E.R. (Eamonn), Bertario, L. (Lucio), Jarvinen, H.J. (Heikki), Lindblom, A. (Annika), Evans, D.G. (Gareth), Lubinski, J. (Jan), Morrison, P.J. (Patrick), Ho, J.W.C. (Judy), Vasen, H. (Hans), Side, L. (Lucy), Thomas, H.J.W. (Huw ), Scott, R.J. (Rodney), Dunlop, M.G. (Malcolm), Barker, G. (Gail), Elliott, F. (Faye), Jass, J.R. (Jeremy ), Fodde, R. (Riccardo), Lynch, H. (Henry), Mathers, J.C. (John ), Burn, J. (John), Bishop, D.T. (David Timothy), Mecklin, J.-P. (Jukka-Pekka), Macrae, F.A. (Finlay), Möslein, G. (Gabriela), Olschwang, S. (Sylviane), Bisgaard, M.-L. (Marie-Luise), Ramesar, R.S. (Rajkumar), Eccles, D. (Diana), Maher, E.R. (Eamonn), Bertario, L. (Lucio), Jarvinen, H.J. (Heikki), Lindblom, A. (Annika), Evans, D.G. (Gareth), Lubinski, J. (Jan), Morrison, P.J. (Patrick), Ho, J.W.C. (Judy), Vasen, H. (Hans), Side, L. (Lucy), Thomas, H.J.W. (Huw ), Scott, R.J. (Rodney), Dunlop, M.G. (Malcolm), Barker, G. (Gail), Elliott, F. (Faye), Jass, J.R. (Jeremy ), Fodde, R. (Riccardo), Lynch, H. (Henry), and Mathers, J.C. (John )
- Abstract
BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. RESULTS: Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P = 0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. CONCLUSIONS: The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.) Copyright
- Published
- 2008
- Full Text
- View/download PDF
47. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.
- Author
-
Infection & Immunity, CTI, Siddappa, R., Martens, A.C.M., Doorn, J., Leusink, A., Olivo, C., Licht, R., van Rijn, L., Gaspar, C., Fodde, R., Janssen, F., van Blitterswijk, C., de Boer, J., Infection & Immunity, CTI, Siddappa, R., Martens, A.C.M., Doorn, J., Leusink, A., Olivo, C., Licht, R., van Rijn, L., Gaspar, C., Fodde, R., Janssen, F., van Blitterswijk, C., and de Boer, J.
- Published
- 2008
48. Protective effect of nonsteroidal anti-inflammatory drugs on colorectal adenomas is modified by a polymorphism in peroxisome proliferator-activated receptor delta.
- Author
-
Siezen, C.L., Tijhuis, M.J., Kram, N.R., Soest, E.M. van, Jong, D.J. de, Fodde, R., Kranen, H.J. van, Kampman, E., Siezen, C.L., Tijhuis, M.J., Kram, N.R., Soest, E.M. van, Jong, D.J. de, Fodde, R., Kranen, H.J. van, and Kampman, E.
- Abstract
Item does not contain fulltext, OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a decreased risk of colorectal tumors. Single nucleotide polymorphisms (SNPs) in target genes of NSAID action, and their haplotypes, might modulate this protective effect. METHODS: A case-control study including 724 cases and 682 controls was used to evaluate the effect of NSAIDs on colorectal adenoma risk in The Netherlands, a country in which NSAID use is relatively low. Cases and controls were classified according to presence or absence of endoscopy-proven, pathology-confirmed colorectal adenomas, ever in their lives. Thirteen SNPs in four genes (PPARdelta, PPARgamma, PTGS1 and PTGS2) were genotyped in 787 subjects (384 cases and 403 controls). RESULTS: Compared to non-regular users (< 12 times/year), regular users of NSAIDs (> or = 12 times/year) had a lower risk of colorectal adenomas (odds ratio (OR): 0.75, 95% confidence interval (CI): 0.56-0.99). The results were similar for aspirin only. We found an interaction between SNP c.-789C>T in PPARdelta and NSAID use (P=0.03). The protective effect of NSAIDs was strengthened for regular users with the PPARdelta CT or TT genotypes (OR: 0.35, 95%CI: 0.11-1.13), whereas a positive association was observed for non-regular users with these genotypes (OR: 2.24, 95%CI: 1.06-4.73) as compared to non-regular users with the CC genotype. Also, a statistically significant interaction between a major haplotype containing the minor allele of this SNP and NSAID use was observed. CONCLUSIONS: This study confirms the protective effect of NSAIDs and suggests a modulating effect of a SNP in the promoter of PPARdelta.
- Published
- 2006
49. Role of CLASP2 in microtubule stabilization and the regulation of persistent motility.
- Author
-
Drabek, K., Ham, M. van der, Stepanova, T., Draegestein, K., Horssen, R. van, Sayas, C.L., Akhmanova, A., Hagen, T. Ten, Smits, R., Fodde, R., Grosveld, F., Galjart, N., Drabek, K., Ham, M. van der, Stepanova, T., Draegestein, K., Horssen, R. van, Sayas, C.L., Akhmanova, A., Hagen, T. Ten, Smits, R., Fodde, R., Grosveld, F., and Galjart, N.
- Abstract
Contains fulltext : 50157.pdf (publisher's version ) (Closed access), In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT "plus-end-tracking proteins," or +TIPs, have been proposed to regulate selective MT stabilization, including the CLASPs, a complex of CLIP-170, IQGAP1, activated Cdc42 or Rac1, a complex of APC, EB1, and mDia1, and the actin-MT crosslinking factor ACF7. By using mouse embryonic fibroblasts (MEFs) in a wound-healing assay, we show here that CLASP2 is required for the formation of a stable, polarized MT array but that CLIP-170 and an APC-EB1 interaction are not essential. Persistent motility is also hampered in CLASP2-deficient MEFs. We find that ACF7 regulates cortical CLASP localization in HeLa cells, indicating it acts upstream of CLASP2. Fluorescence-based approaches show that GFP-CLASP2 is immobilized in a bimodal manner in regions near cell edges. Our results suggest that the regional immobilization of CLASP2 allows MT stabilization and promotes directionally persistent motility in fibroblasts.
- Published
- 2006
50. Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16
- Author
-
Wijnen, J., Meera Khan, P., Vasen, H., Menko, F., Klift, H. D., Broek, M. D., Leeuwen-Cornelisse, I., Nagengast, F., Meijers-Heijboer, E. J., Dick Lindhout, Griffioen, G., Cats, A., Kleibeuker, J., Varesco, L., Bertario, L., Bisgaard, M. -L, Mohr, J., Kolodner, R., Fodde, R., Other departments, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Repair ,Molecular Sequence Data ,Polymerase Chain Reaction ,GRADIENT GEL-ELECTROPHORESIS ,Proto-Oncogene Proteins ,Humans ,GENETIC INSTABILITY ,neoplasms ,Germ-Line Mutation ,Adaptor Proteins, Signal Transducing ,DNA Primers ,Genes, Dominant ,SPECTRUM ,Base Sequence ,COLON-CANCER ,Nuclear Proteins ,nutritional and metabolic diseases ,Exons ,SINGLE-BASE CHANGES ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Neoplasm Proteins ,Pedigree ,DNA-Binding Proteins ,Europe ,POLYPOSIS ,HOMOLOG ,MutS Homolog 2 Protein ,Mutation ,Electrophoresis, Polyacrylamide Gel ,Female ,Carrier Proteins ,MutL Protein Homolog 1 ,Research Article - Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.
- Published
- 1996
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.