O câncer colorretal (CCR) é importante causa de morte no Brasil, representando a segunda causa de morbimortalidade por câncer nas regiões Sudeste e Sul. Foi uma das primeiras neoplasias malignas a ter modelo de carcinogênese identificado. Os objetivos deste trabalho foram avaliar a expressão do NF-KB e da survivina na progressão do CCR, sua relação com alvos moleculares envolvidos na sobrevivência celular [proibitina, fator de necrose tumoral (TNFR1), p53, B- catenina]; invasão (metaloproteinases 2 e 9 - MMP), angiogênese (fator de crescimento endotelial vascular VEGF) e apoptose (caspase 3 e método do Túnel). Trata-se de estudo retrospectivo baseado na análise histopatológica de dezoito casos de adenomas com displasia de alto (AG) e baixo grau (BG), respectivamente; dez casos de adenocarcinoma bem, moderado e pouco diferenciado, respectivamente, nove casos de lesões serrilhadas e nove biópsias colorretais (controle) selecionados aleatoriamente no Serviço de Patologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, no período de 2000 a 2009. Foram construídos arranjos de matriz tecidual para representar os casos de adenocarcinomas e cinco casos de adenomas >1 cm de diâmetro. A detecção do NF-KB foi realizada pelo método de Southwestern imunoistoquímica. Avaliou-se a expressão imunoistoquímica da survivina, proibitina, TNFR1, p53, B-catenina, MMPs 2 e 9, VEGF, caspase 3 e Túnel. Não observamos expressão imunoistoquímica do NF-KB em 70% dos casos de adenocarcinomas, em 72% dos adenomas AG e em 89% das lesões serrilhadas; a marcação foi positiva em 66% e 56% dos casos de adenoma do BG e controle, respectivamente. Expressões da survivina, proibitina citoplasmática, TNFR1, p53, MMP 2 e 9 foram crescentes na seqüência adenoma-carcinoma, sem aparente modulação pelo NF-KB. A survivina suprimiu ação da caspase 3, exceto nos adenomas BG e controle, com baixos níveis de apoptose ao túnel. Lesões serrilhadas e controle apresentaram baixa expressão do TNFR1 e da proibitina citoplasmática, ausência de marcação da p53 e MMPs 2 e 9, exceto um caso controle. Identificou-se marcação nuclear da proibitina nos adenocarcinomas pouco diferenciados, adenomas AG e BG. A expressão da p53 relacionou-se ao grau de displasia nos adenomas e à desregulação da survivina. Observou-se expressão citoplasmática e nuclear da B- catenina nos adenocarcinomas, adenomas AG e BG. As lesões serrilhadas exibiram expressão citoplasmática em 44% dos casos. O grupo controle exibiu expressão preservada da B-catenina. Identificou-se expressão do VEGF nos adenocarcinomas, relacionada à perda de diferenciação celular, presença de metástases, não correlacionada ao NF-KB. Com base nos nossos resultados, sugerimos a desregulação da B- catenina como possível responsável pela inibição do NF-KB; além de sua participação na desregulação da survivina juntamente com a p53. As lesões serrilhadas não exibiram indícios sugestivos de inibição do NF- KB pela B-catenina.A survivina, devido propriedades anti-apoptóticas, emerge como potencial alvo terapêutico no tratamento do CCR, confirmando estudos anteriores. / Colorectal cancer (CRC) is an important cause of death in Brazil, representing the second leading cause of cancer mortality in the Southeast and South. It was among the first malignancies that have the carcinogenesis model identified.The aim of this study was to evaluate the expression of NF-KB and survivin in the progression of CRC, its relationship with molecular targets involved in cell survival [prohibitin, tumor necrosis factor (TNFR1), p53,B-catenina], invasion (metalloproteinases 2 and 9 - MMP), angiogenesis (vascular endothelial growth factor VEGF) and apoptosis (caspase 3 and method Tunnel). This is a retrospective study based on the histopathological analyses of eighteen cases of high- (HG) and low- grade dysplastic (LG) adenomas, respectively; ten cases of adenocarcinoma well, moderately and poorly differentiated, respectively, nine cases of serrated lesions e nine biopsies (control); randomly selected in the Pathology Service of the University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo from 2000 to 2009. Tissue microarray were constructed to represent the cases of adenocarcinomas and five cases of adenomas > 1cm in diameter. Detection of NF-KB was performed by the Southwestern immunohistochemistry method. We evaluated immunohistochemical expression of survivin, prohibitin, TNFR1, p53, B- catenin, MMPs 2 and 9, VEGF, caspase 3 and method Tunnel. We did not observe immunohistochemical expression of NF-KB in 70% of cases of adenocarcinomas, in 72% of HG adenomas and 89% of lesions serrated; staining was positive in 66% and 56% of cases of LG adenoma and control, respectively. Expressions of survivin, cytoplasmic prohibitin, TNFR1, p53, MMPs 2 and 9 were increasing in adenoma-carcinoma sequence, without apparent modulation by NF-KB. Survivin suppressed action of caspase 3, except in BG adenomas and control, with low levels of apoptosis to the tunnel. Serrated lesions and control showed low expression of TNFR1 and cytoplasmic prohibitin, the absence of staining of p53 and MMPs2 and 9, except for one control. We identified nuclear staining of prohibitin in poorly differentiated adenocarcinomas, HG and LG adenomas. Expression of p53 was related to the grade of dysplasia in adenomas and deregulation of survivin.The expression of the cytoplasmic and nuclear B-catenin was observed in adenocarcinoma, HG and LG adenoma. Serrated lesions exhibited cytoplasmic expression in 44% of cases. Control group exhibited preserved expression of B-catenin. It was identified VEGF expression in adenocarcinomas, related to the loss of cellular differentiation, metastasis, not correlated with NF-KB. According to our results, we suggest that deregulation of catenin is possible responsible for the inhibition of NF-KB besides their participation in the deregulation of survivin with p53.Serrated lesions exhibited no evidence suggestive of inhibition of NF-KB by B-catenin. Survivin emerges as a potential therapeutic target in the treatment of CRC due to their anti-apoptotic properties, confirming previous studies.

Introdução: A expectativa global para 2030 é uma incidência de 26,4 milhões de casos e 17 milhões de mortes causadas pelo câncer. O câncer colorretal (CCR) já é terceiro tumor mais incidente no mundo. No Brasil, o CCR é o terceiro tumor mais incidente em homens e o segundo em mulheres na região sul. Neste cenário pessimista, é importante avaliar a relação entre o custo e o benefício de tecnologias para o tratamento quimioterápico, sobretudo na gestão dos gastos na saúde pública. Objetivo: O presente trabalho objetivou avaliar as alternativas para o CCR, XELOX e mFOLFOX6, sob o aspecto econômico. Metodologia: As informações sobre a efetividade foram obtidas através de uma revisão narrativa da literatura. Realizou-se também uma revisão narrativa de estudos farmacoeconômicos e por fim uma análise de custo minimização (ACM) sob a perspectiva de um hospital de caráter público. O microcusteio foi utilizado como método para estimar o custo de cada componente que incluiu medicamentos, materiais, exames laboratorial e de imagem, atendimentos ambulatoriais, diárias de internação e recursos humanos e administrativos, permitindo identificar o custo individual por paciente, com cada alternativa. O sistema informatizado do hospital foi utilizado para a coleta dos dados. Resultados: Foram encontrados 14 estudos farmacoeconômicos, dentre os quais apenas 2 estudos nacionais, ambos em cenário metastático da doença. A ACM revelou um custo por paciente de R$ 9.925,98 (adjuvância) e R$ 8.036,95 (paliativo) para mFOLFOX6, e R$ 8.407,13 (adjuvância) e R$ 6.946,47 (paliativo) para tratamento com XELOX. Os custos de materiais e medicamentos representam cerca de 85% do custo total de XELOX; para mFOLFOX6 esse custo é menor, em torno de 36%. Por outro lado, os custos com internação e colocação de cateter ocorrem exclusivamente para mFOLFOX6, que também apresenta maior custo com recursos humanos. Conclusão: O número de pacientes e a falta de dados no sistema informatizado da instituição reforçam a necessidade de mais estudos para se afirmar que XELOX é menos oneroso que mFOLFOX6 no sistema público. O estudo é inédito por se tratar de uma ACM utilizando o método de microcusteio para comparar as alternativas em um hospital público e universitário do país, especialmente na adjuvância do CCR. / Introduction: The global expectation for 2030 is an incidence of 26.4 million cases and 17 million deaths caused by cancer. Colorectal cancer (CRC) is already the third most incident tumor in the world. In Brazil, CRC is the third most incident tumor in men and the second in women in the southern region. In this pessimistic scenario, it is important to evaluate the relationship between the cost and the benefit of technologies for chemotherapy treatment, especially in the management of public health expenditures. Objective: The present study aimed to evaluate the alternatives for CRC, XELOX and mFOLFOX6, under the economic aspect. Methodology: Information on effectiveness was obtained through a narrative review of the literature. A narrative review of pharmacoeconomic studies was also conducted, and finally, a cost minimization analysis (CMA) from a public hospital perspective was carried out. The micro-costing was used as a method to estimate the cost of each component that included medicines, materials, laboratory and imaging exams, outpatient visits, hospital stay and human and administrative resources, allowing the individual cost per patient to be identified for each alternative. The computerized system of the hospital was used to collect the data. Results: We found 14 pharmacoeconomic studies, of which only 2 national studies, both in the metastatic setting of the disease. The CMA revealed a cost per patient of BRL$ 9,925.98 (adjuvant) and BRL$ 8,036.95 (palliative) for mFOLFOX6, and BRL$ 8,407.13 (adjuvant) and BRL$ 6,946.47 (palliative) for treatment with XELOX. Material and drug costs account for about 85% of the total cost of XELOX; For mFOLFOX6 this cost is lower, around 36%. On the other hand, costs with hospitalization and catheter placement occur exclusively for mFOLFOX6, which also presents higher cost with human resources. Conclusion: The number of patients and the lack of data in the computerized system of the institution reinforce the need for further studies to assert that XELOX is less costly than mFOLFOX6 in the public system. The study is notorious because it is a CMA using the micro-costing method to compare the alternatives in a public and university hospital in the country, especially in the adjuvant treatment of CRC.

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. In some CRC patients, the presence of the tumor elicits a systemic inflammatory response and metabolic derangements that lead to progressive tissue wasting. Systemic inflammation has been associated with decreased survival independent of tumor stage. However, the mechanisms and downstream effects of systemic inflammation in CRC are uncertain. The aim of these studies was to examine the determinants of systemic inflammation in CRC. The study material consisted of tumor and serum samples collected from patients with stage I–IV CRC operated at the Oulu University Hospital (n=336). From preoperative serum samples, the levels of cell death marker keratin 18, matrix metalloproteinase 8 (MMP8), and ten metabolites (apolipoprotein A1 and nine amino acids) were measured. CRC patients with systemic inflammation, assessed using a modified Glasgow Prognostic Score, had elevated serum levels of MMP8 and phenylalanine. On the contrary, the concentrations of apolipoprotein A1, glutamine, and histidine were lower compared to patients without systemic inflammation. Increased serum keratin 18 level associated with systemic inflammation in patients with metastatic disease. Elevated keratin 18 and MMP8 levels and decreased apolipoprotein A1 level were independent predictors of worse survival. These studies describe biomarkers of systemic inflammation that provide insight into the mechanisms of systemic inflammation, have potential prognostic value in CRC, and are possible therapeutic targets. The results suggest that cell death and systemic inflammation are strongly connected in CRC, but the potential mechanistic link between them and tissues involved remain to be elucidated. / Tiivistelmä Paksusuolisyöpä on kolmanneksi yleisin syöpä ja toiseksi yleisin syöpäkuoleman aiheuttaja Suomessa. Osalla potilaista syöpään liittyy systeemisen tulehdusreaktion aktivoituminen ja aineenvaihduntahäiriö, joka johtaa yleiseen näivettymiseen. Systeemisen tulehduksen on havaittu olevan yhteydessä huonoon ennusteeseen riippumatta kasvaimen levinneisyydestä. Systeemisen tulehduksen aktivaatiomekanismit ja vaikutukset paksusuolisyövässä ovat kuitenkin huonosti tunnettuja. Tutkimuksen tarkoituksena oli selvittää systeemistä tulehdusta määrittäviä tekijöitä paksusuolisyövässä. Aineisto koostui Oulun yliopistollisessa sairaalassa leikattujen paksusuolisyöpäpotilaiden (syövän levinneisyysaste I–IV) kasvain- ja seeruminäytteistä (n=336). Seeruminäytteistä mitattiin solukuolemaa osoittavan keratiini 18:n pitoisuudet, matriksin metalloproteinaasi 8 (MMP8):n määrät sekä 10 metaboliitin (apolipoproteiini A1 ja 9 aminohappoa) tasot. Paksusuolisyöpäpotilailla, joilla systeemistä tulehdusta osoittava mGPS-indeksi oli korkea, seerumin MMP8- ja fenyylialaniinitasot olivat koholla. Sen sijaan apolipoproteiini A1:n, glutamiinin ja histidiinin pitoisuudet olivat matalammat verrattuna potilaisiin, joilla ei ollut systeemistä tulehdusta. Kohonnut keratiini 18 -pitoisuus oli yhteydessä systeemiseen tulehdukseen etäpesäkkeistä tautia sairastavilla potilailla. Kohonnut keratiini 18- ja MMP8-taso sekä matala apolipoproteiini A1-pitoisuus liittyivät potilaiden huonoon ennusteeseen. Tutkimuksessa löydettiin systeemisen tulehduksen merkkiaineita, jotka tuovat hyödyllistä tietoa systeemisen tulehduksen mekanismeista ja potilaiden ennusteesta paksusuolisyövässä, ja ovat mahdollisia terapeuttisia kohteita. Tulosten perusteella paksusuolisyövässä solukuolema liittyy vahvasti systeemiseen tulehdukseen, mutta lisätutkimuksia tarvitaan selvittämään näiden tapahtumien mahdolliset syy-seuraussuhteet sekä tapahtumaan liittyvät kudokset.

This research explores the ways in which communities can connect their experiential knowledge of space and place with observed spatial patterns of disease to increase our abilities to both understand underlying processes and implement effective interventions. We develop and test new methods for integrating observed patterns of disease with community knowledge, validate these methods through generation of new knowledge and hypotheses about processes that have produced cancer patterns, begin to translate this new knowledge into potential interventions, generate much needed recommendations for best practices in research that integrates Geographic Information Science (GISc) and community engagement, and generate new hypotheses for future research. Methods include the creation of continuous surface representation maps of cancer burdens and selected behaviors related to health risks, using adaptive spatial filtering, and a community-based project in which community members generate hypotheses regarding high rates of cancer in their community and explore and annotate cancer burden map layers in a GIS environment. We partner with community and public health practice partners in order to increase the likelihood of translation of research results into evidence-based intervention. Methods of spatial data analysis, community mapping and concept mapping are used.

Une collaboration entre les chercheurs du laboratoire Pharma-Dev et de l'Institut de Recherche en Santé Digestive a été mise en place depuis plusieurs années avec pour objectif le criblage thérapeutique de nouvelles molécules naturelles issues de la biodiversité végétale. Dans ce contexte, le travail présenté dans ce manuscrit est consacré à l'étude phytochimique du latex de Hura crepitans L. (Euphorbiaceae) et à la valorisation biologique de ses constituants sur des lignées cancéreuses colorectales humaines. La richesse en structures diterpéniques originales de la famille des Euphorbiaceae et le rôle de ces noyaux structuraux dans l'activation de Protéines Kinases C (PKC) impliquées dans la carcinogenèse colorectale, font de H. crepitans une espèce au potentiel thérapeutique important. Au cours de ce travail, une approche déréplicative par UHPLC-MS/MS a permis de mettre en évidence la présence de cérébrosides et une richesse notable en diterpènes de type daphnane chez H. crepitans. Au total, 33 daphnanes dont 25 nouvelles structures ont été détectées. Le fractionnement du latex a permis l'isolement de 7 daphnanes mono-estérifiés (D1) et de 6 dérivés di-estérifiés. L'évaluation biologique a révélé une activité cytostatique des D1 spécifique sur la lignée cancéreuse Caco-2 comparée à d'autres lignées intestinales normales ou cancéreuses. Cette activité est inhibée par les cérébrosides. Le D1 majoritaire, la huratoxine, a montré une activité cytostatique dès 1 µg/ml et comparativement plus spécifique que le 5-Fluoro-Uracile, cytotoxique utilisé comme référence. De plus, nous avons montré que les effets cytostatiques de la huratoxine et de l'ester de phorbol TPA sont corrélés à la régulation de signaux clés de la carcinogenèse colorectale, GSK3ß et AKT notamment, et à des changements morphologiques. Finalement, nous avons pu identifier une isoenzyme PKC comme cible potentielle de ces composés naturels. / A collaboration between the researchers of the laboratory Pharma-Dev and the Research institute in Digestive Health has been established since several years with as main objective the therapeutic screening of new natural molecules from the plant biodiversity. In this context, the work presented in this manuscript deals with the phytochemical study of the latex of Hura crepitans L. (Euphorbiaceae) and the biological valuation of its constituents on human colorectal cancerous cell lines. The wealth in original diterpene like structures within the family of Euphorbiaceae and the role of these structural cores in the activation of Proteins Kinases C (PKC) involved in the colorectal carcinogenesis, make of H. crepitans a species with a promising therapeutic potential. In the course of this work, a dereplicative approach by UHPLC-MS/MS allowed to highlight the presence of cerebrosides and a notable wealth in daphnane type diterpene in H. crepitans. This led to the annotation of 33 daphnanes including 25 new structures. Therefore, 7 mono-esterified daphnanes (D1) and 6 di-esterified derivatives could be isolated. The biological evaluation revealed, for D1, a specific cytostatic activity on the cancerous cell line Caco-2 when compared to other non-cancerous or cancerous intestinal cell lines. This activity is inhibited by cerebrosides. The main D1, huratoxine, is cytostatic from 1 µg/ml and was showed to be more specific than 5-Fluoro-Uracile, a cytotoxic drug used as reference. Furthermore, we demonstrated that the cytostatic effects of huratoxine and phorbol ester TPA are correlated to the regulation of key signals of the colorectal carcinogenesis, particularly GSK3ß and AKT, and in cells morphological changes. Finally, we were able to identify a PKC isoenzyme as a potential target of these natural products.

No description available.

Multiple research studies have demonstrated racial, socioeconomic status (SES), and neighborhood disparities in first-line treatment of colorectal cancer patients, including those with metastatic colorectal cancer. However, disparities in adjunct monoclonal antibody treatment disparities have not been explored. The purpose of this study was to assess racial, SES, and neighborhood disparities in adjunct monoclonal antibody treatment of elderly metastatic colorectal cancer patients. The research was rooted in 3 theories: the fundamental cause theory, the diffusion of innovations theory, and theory of health disparities and medical technology. Data from the SEER-Medicare database and logistic regression were used to assess the relationship between the variables of interest and adjunct monoclonal antibody therapy. In this study, race (p = 0.070), SES (p = 0.881), and neighborhood characteristics (p = 0.309) did not significantly predict who would receive monoclonal antibody therapy. The results demonstrated a potential improvement in historically documented colorectal cancer treatment disparities. Specifically, historical treatment disparities may not be relevant to newer therapies prescribed to patients with severe disease. The difference could be related to improved access to care or a change in treatment paradigm due to the severity of metastatic colorectal cancer. Future studies aimed at understanding the causes of this social change (i.e., reduced treatment disparities) are warranted. Understanding the root cause of the reduced treatment disparities observed in this study could be used to reduce treatment disparities in other cancer populations.

Background. CRC risk can be reduced though lifestyle modification and regular screenings. Providing CRC risk feedback that promotes preventive behaviors to those at average risk has the potential to significantly reduce CRC morbidity and mortality. Purpose. The purpose of this dissertation was to examine the impact of CRC risk assessment feedback among adults aged 50-75 with no personal or family history of the disease. The specific aims were to: (1a) test personalized (vs. generic) risk assessment feedback on individuals’ risk perceptions and intentions to engage in three risk-reducing behaviors (e.g., physical activity, diet, and screening); (1b) determine if the provision of CRC risk information influences breast cancer risk perceptions and mammography intentions; (2a) examine individuals’ accuracy of perceived lifetime risk of CRC; (2b) assess whether improved accuracy following risk assessment was associated with changes in behavioral intentions; and finally, (3) evaluate the use of a unique sampling procedure designed to increase diversity of survey respondents. Methods. A pre-post parallel, two arm randomized controlled trial examined the effects of providing CRC risk assessment feedback that included lifetime risk estimates and information about CRC risk factors that was either personalized (treatment) or generic (control). N=419 average risk adults between the ages of 50-75 were recruited from a commercial online panel. Results. There were no differences in risk perception between study arms. Overall participants, perceived lifetime risk of CRC lowered at post-test and seemingly produced a spillover effect in lowered perceived lifetime risk of breast cancer among females. CRC screening intentions increased in both study arms and mammography intentions increased in the control arm. Accuracy of lifetime risk improved at post-test, but was not associated with changes in intentions to perform risk reducing behaviors. Quota sampling acquired a targeted and diverse sample quickly and efficiently. Conclusion. Communicating CRC risk information to average risk adults can improve CRC risk perception accuracy and enhance colorectal and mammography screening intentions. Risk assessment feedback did not consistently influence intentions to improve diet and physical activity.

Type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) are 2 chronic diseases with common risk factors related to physical inactivity, obesity, and diet. Literature on T2DM as a risk factor for CRC development and survival in Oman is scarce. Using de-identified archival data provided by Sultan Qaboos University Hospital (SQUH) Oman, a retrospective, case-control, and time-to-event study designs were used to compare odds of developing CRC, and survival rates among adults with and without T2DM. The ecosocial theory provided the theoretical base for this research. Logistic regression was used to examine the odds of developing CRC among 114 cases versus 170 hospital controls. The Cox proportional hazards regression was used to compare survival rates among 228 CRC cases by T2DM status and survival rates by T2DM status across strata of gender, age group, and tumor location and cancer stage. According to the study findings, after having adjusted for potential confounding variables, there was no association between T2DM and odds of developing CRC (OR = 1.49, 95% CI: 0.29-7.68, p = 0.64) or between T2DM and CRC survival rates (HR = 1.07, 95% CI: 0.65 -1.75, p = 0.80). There was also no association between T2DM and CRC survival rates across the strata of potential effect modifiers examined. This research could contribute to positive social change by creating awareness among policy makers that will provide them with information on CRC risk-reduction strategies in the Omani population.

MUCDHL est une cadhérine atypique encore peu étudiée. Les données obtenues à ce jour suggèrent que ce gène joue un rôle suppresseur de tumeurs dans l’intestin, notamment par son interaction et son effet inhibiteur sur la β-caténine, et que son expression est fréquemment diminuée dans les cancers colorectaux (CCR). Parallèlement à cette fonction anti-oncogénique, d’autres travaux ont suggéré que MUCDHL est impliquée dans la structuration de la bordure en brosse (BB) intestinale, en contribuant à la formation d’un complexe d’interaction inter-microvillositaire. Notre objectif était de déterminer la fonction et le mode d’action de MUCDHL dans le système digestif. Par la caractérisation détaillée de l’interaction avec la β-caténine, nous avons montré que le mode d’action anti-oncogénique de MUCDHL est plus complexe qu’une simple séquestration membranaire de la β-caténine. De plus, nous avons confirmé le rôle suppresseur de tumeurs de MUCDHL sur une cohorte importante de CCR humains et montré pour la première fois que sa perte amplifie la tumorigenèse intestinale dans un model murin. Par ailleurs, l’étude phénotypique des souris Mucdhl-/- a démontré son importance dans l’homéostasie du système digestif. En effet, l’absence de MUCDHL cause des altérations morphologiques de la BB intestinale, mais également de nombreuses perturbations métaboliques. Ces travaux apportent donc des informations inédites sur la fonction et le mode d’action de MUCDHL dans le système digestif. / MUCDHL is an atypical cadherin that has been poorly studied. The data obtained so far suggest that this gene has tumor suppressive activity in the intestine, namely by its interaction and inhibitory effect on β-catenin, and that its expression is frequently decreased in colorectal cancers (CCR). In parallel to this anti-oncogenic function, other studies have suggested that MUCDHL is involved in the assembly of the intestinal brush border (BB), by contributing to the formation of an inter-microvilli interaction complex. Our objective was to determine the function and mode of action of MUCDHL in the digestive system, Through a detailed characterization of the interaction with β-catenin, we showed that the anti-oncogenic mode of action of MUCDHL is more complex than a simple membrane sequestration of β-catenin. In addition, we confirmed the tumor suppressive function of MUCDHL on a very large cohort of human CCR and showed for the first time that its loss amplifies intestinal tumorigenesis in a murine model. Moreover, the study of the phenotype of Mucdhl-/- mice allowed us to demonstrate the importance of MUCDHL in the homeostasis of the digestive system. Indeed, the absence of MUCDHL causes morphological alterations of the intestinal BB, but also numerous metabolic disturbances. Thus, this work provides new information on the function and mode of action of MUCDHL in the digestive system.