Colorectal Cancer is the main type of cancer in Spain. Up to 90% of the cases are sporadic in nature and its aetiology is still unclear. It is supposed to be a multi-factorial disease, where factors play an important role in the tumor onset and development, like microbiota. The main goal of this study was to describe and quantify the bacterial community of the intestinal mucosa associated to colorectal cancer patients. This work has revealed the existence of a bacterial dysbiosis in colorectal cancer patients, which is in agreement with previous research. Specific phylotypes previously descrived using stool samples and also new phylotypes were associated with this disease.Furthermore, streptococcal populations have been studied and also a case report from a patient who present an infection caused by E. faecalis at the same time of CRC diagnosed. Future research should focus on specific aspects of intestinal microbiota such as its interaction with the host, together with the mechanisms by which bacteria can affect on the onset of tumor in the colon. / El càncer colorectal és el tipus de càncer més abundant a Espanya. Fins el 90% dels casos són d'origen espontani i la seva etiologia és desconeguda malgrat existeixen diversos factors que poden afectar en el desenvolupament tumoral, com la microbiota. L'objectiu d'aquesta tesi ha estat analitzar la composició de la comunitat microbiana en mostres de mucosa intestinal quantitativa i qualitativament. Els resultats mostren una disbiosi en els malalts de càncer colorectal i una associació amb l'augment o disminució d'espècies bacterianes, així com l'augment de determinats filotips/gèneres. També s'ha analitzat les poblacions d'estreptococs i l'exposició d'un cas clínic d'un pacient amb càncer colorectal amb una infecció causada per E. faecalis. Estudis focalitzats en aspectes més específics de la relació hoste-microbiota, així com explorar nous mecanismes induïts per bacteris són necessaris per comprendre alguns aspectes de la carcinogènesis colorectal.

Background: Clinical and epidemiologic studies have investigated the effects of diet, physical activity, and inflammation on the risk of colorectal adenoma occurrence and recurrence. Inflammation has been proposed as a mechanism of action for the development of colorectal adenoma and cancer. Research indicates that fruit phenolic exposure may attenuate the inflammatory response and some data suggest that berries are effective in mitigating this process. Inflammatory cytokines such as interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-α) are of particular interest due to their role in adenoma development. Epidemiological investigations have studied the association between bioactive fruit phenolic compounds and colorectal neoplasia; however, epidemiological data for the association between consumption of berries, which contain high concentrations of these compounds, and colorectal adenoma recurrence are limited. In addition to a potential role of phenolics in reducing inflammation, physical activity has also been proposed as a mitigator of this process. Numerous studies have investigated the association between physical activity and colorectal neoplasia, yet data on sedentary behavior and colorectal adenoma recurrence are limited. This dissertation was designed to further elucidate the role of fruit phenolics and sedentary behavior on colorectal adenoma recurrence and to specifically highlight the potential role of black raspberries in mitigating the postprandial inflammatory response among overweight and obese individuals. Methods: Ten overweight or obese males (BMI>25 kg/m²), ages 55-72, participated in an open-label, randomized, 14-day, pilot crossover study. Subjects consumed a high- fat, high- calorie (HFHC) meal, with (Group 1) or without (Group 2) a 5 day regimen of 45 g of black raspberry powder in the form of a slurry. The study included a two-day washout period before Group 1 and Group 2 were crossed over. The two-day washout period was based on a pharmacokinetic study conducted with black raspberry powder (1); peak plasma concentrations of ellagic acid and anthocyanin metabolites peaked at 1 to 2 hours following consumption of 45 grams of black raspberry powder and by 12 hours, plasma concentrations of these metabolites were almost fully washed out, with plasma concentrations returning to near baseline levels. Blood samples were obtained prior to consumption of the HFHC breakfast and at 1, 2, 4, 8, and 12 hours afterwards, during two 14-hour clinic visits. The primary study outcomes were changes in areas under the curves (AUCs) of serum biomarkers of TNF-α, CRP, and IL-6. A secondary pooled analysis was conducted among participants from two randomized, double blind, placebo-controlled Phase III clinical trials to investigate the association between berry consumption and colorectal adenoma recurrence, and the association between sedentary behavior and colorectal adenoma recurrence. Analyses included 2,502 subjects who had completed the baseline Arizona Food Frequency Questionnaire to ascertain berry consumption history in the past year and 1,730 men and women who had completed the baseline Arizona Activity Frequency Questionnaire to ascertain sedentary behavior. All subjects had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior or berry consumption on colorectal adenoma recurrence. Results: The mean AUC of serum IL-6 was significantly lower (p=0.03) with black raspberry (BRB) feeding (45.5±36.3 pg/mL; mean±SD), compared to high fat, high calorie meal alone (56.7±50.0 pg/mL). No statistically significant differences were observed in the mean AUC of serum TNF-α or CRP. In the pooled analysis, no significant associations were observed between berry consumption and adenoma recurrence in the pooled population or when stratified by sex. In the evaluation of association between sedentary behavior and adenoma recurrence, subjects in the second, third, and fourth quartiles of sedentary behavior experienced higher odds of adenoma recurrence; however, the difference was only statistically significant for the third quartile. Sex-stratified analyses revealed that in men, sedentary activity was statistically significantly associated with 45% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary activity, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.31 (0.93, 1.84), 1.47 (1.04, 2.09), and 1.45 (1.02, 2.06) respectively (P trend=0.03). In contrast, no association with sedentary activity was observed in women. Conclusion: Polyphenol exposure in the form of a black raspberry slurry significantly decreased post-prandial IL-6 in a clinical trial among ten older overweight and obese men. These findings suggest short-term attenuation of an inflammatory maker may not translate to decreased adenoma recurrence, however, long term randomized clinical trials with black raspberries are needed to evaluate this further. However, in an epidemiological analysis, consumption of up to 1 cup per week of whole berries was not associated with lower odds for adenoma recurrence among a pooled population of participants in the Wheat Bran Fiber and Ursodeoxycholic Acid Phase III clinical trials. While the epidemiological results indicated that berry consumption are not associated with the development of early colorectal neoplasia, the effects on later stages of carcinogenesis are unknown. Higher levels of berry consumption may be required in order to reach a cancer inhibitory effect. Finally, results of the physical activity study suggest that sedentary behavior is associated with a higher risk of adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway. Efforts to further evaluate these findings in other cohorts or in an intervention trial should be considered.

Les réponses adaptatives fonctionnelles (secondaires à des modulations de la signalisation cellulaire) peuvent contribuer à la résistance des tumeurs humaines aux traitements ciblés. Ce travail vise à caractériser les changements induits par la chimiothérapie dans le phosphokinome de cellules de cancer du côlon, et à sélectionner des combinaisons de médicaments synergiques en ciblant les kinases dont l’activation est la plus importante. Nous avons créé des scripts informatiques pour l’analyse sur le logiciel de calcul R de données provenant de tests cytotoxiques avec des matrices de combinaison de doses à deux ou trois médicaments. Nous avons profilé les changements induits par différents médicaments sur des cellules de la lignée HT29 xénogreffées dans des souris immunodéprimées. Nous avons testé le 5FU, l’oxaliplatine, l’irinotecan, le cetuximab ainsi que les combinaisons de ces médicaments. Nous avons sélectionné les kinases activées par le traitement par irinotecan, notamment AKT et MEK1, et nous avons testés in vitro et in vivo des combinaisons à deux médicaments d’inhibiteurs de ces deux kinases et l’irinotecan sur 6 lignées de cancer du côlon. Enfin nous avons testés in vitro la combinaison des trois médicaments. Nous avons observé que la combinaison d’un inhibiteurs d’AKT et de MEK ainsi que la combinaison des trois médicaments étaient caractérisées par un synergisme significatif Cette étude a démontré que la chimiothérapie induit une reprogrammation des voies de signalisation intracellulaires, et fournit le rationnel pour une évaluation du profilage de la reprogrammation du phosphokinome comme outil pour développer de nouvelles combinaisons de médicaments. / Functional (i.e. due to cellular machinery modulations) adaptive responses could also contribute to human tumor resistance to targeted drugs. We hypothesized that the activation of tumor cell kinases in response to chemotherapy treatment could render the cell depending on them, and that the inhibition of these activated kinases could achieve a synergistic effect with chemotherapy agents. We compiled R scripts for analysis of data from cytotoxic tests with dose matrix combinations of 2 or 3 drugs. We evaluated phosphokinome rewiring induced by 5FU, irinotecan, oxaliplatin and cetuximab when these drugs were used alone or in combination on mice xenografted with HT29 cell line. We observed an activation of AKT and MEK1 after irinotecan treatment, and we tested two- and three drug combinations of BKM120, an AKT inhibitor, MEK162, a MEK inhibitor, and irinotecan. We showed that BKM120 and MEK162 are synergistic, as well as the combination of the three drugs. Our study shows that chemotherapy induces a significant rewiring of intracellular signaling pathways, and that profiling phosphokinome remodeling after chemotherapy treatment is useful in order to design synergistic drug combinations.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24832号 / 医博第5000号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤, 学, 教授 今中, 雄一, 教授 阪上, 優 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Background and PurposeGlobally and in the United States (US), colorectal cancer (CRC) is the second leading cause of cancer-related death, following lung cancer. In addition, there are established racial disparities in incidence and mortality for this disease, where ethnic minority groups have higher incidence and mortality rates. Blacks currently have the second-highest rates of CRC incidence and mortality, are diagnosed at more advanced stages, and have the lowest 5-year survival rates of all racial groups. Multiple influences impact this disparity including area- and individual-level factors. Area-level factors, encompassing social determinants of health (e.g. area-level poverty, housing characteristics, etc.), play a role in disease etiology and outcomes. In addition, timely CRC screening (CRCS) reduces CRC incidence and mortality; however, screening patterns, globally and in the US, are not optimal and differ by race, with ethnic minority groups having low CRCS adherence compared to non-Hispanic whites. Differences in CRCS behaviors and outcomes have been noted for Blacks, a term used to describe, for example, a heterogeneous racial group comprised of US-born Blacks and immigrants from Africa and the Caribbean. While CRCS barriers are well documented for the general population, CRCS barriers are less understood for Blacks and very little is known about CRCS habits and CRCS barriers within this heterogeneous racial group, with limited research including Caribbean immigrants and no known research including African-born immigrants. This dissertation uses a mixed-methods approach to describe CRC incidence, advanced stage at diagnosis, and mortality, CRCS behaviors, and CRCS barriers within the heterogeneous Black population in Philadelphia County, Pennsylvania. Aim 1. Assess colorectal cancer incidence, advanced stage at diagnosis, and colorectal cancer mortality, overall and among individuals who identify as Black/African American, and contextual disparities in Philadelphia County utilizing data from the Pennsylvania State Cancer Registry (2010–2016) and relevant US Census and American Community Survey data. Aim 2. Determine colorectal cancer screening adherence for Cancer Prevention Project of Philadelphia (CAP3) participants who self-identify as Black. Aim 3: Conduct gender-specific focus groups to elucidate the principal barriers to colorectal cancer screening adherence within an average-risk group of adults, ages 45–75, who self-identify as Black or African American, in an urban population. Methods Aim 1. Using an ecological design, descriptive, geographic spatial clustering and hierarchical logistic regression analyses were done to describe CRC incidence, advanced stage at diagnosis, and colorectal cancer-specific mortality in Philadelphia County at the individual- and area-level. CRC incidence, stage at diagnosis, and mortality data for histologically confirmed CRC cases were obtained from the Pennsylvania Cancer Registry from 2010 to 2016, with mortality data including deaths through 2020. Area-level data were retrieved from the US Census Bureau, American Community Survey, etc. Individual- and area-level descriptive characteristics were calculated for all CRC incident cases, cases diagnosed at advanced stage, and colorectal cancer-specific mortality, overall and for whites and Blacks. Geographic clusters with higher-than-expected relative risk for each outcome of interest at the census tract level (HRCT) were identified and individual- and area-level descriptive statistics were calculated for Blacks, overall and by HRCT status. Adjusted hierarchical logistic regression analyses using backward stepwise elimination with model quasi-information criterion was performed to identify potential predictors of HRCTs for CRC incidence and advanced stage at diagnosis. Aim 2. Cross-sectional data from age-eligible adults, 50–75 years (N=357) participating in the ongoing CAP3 study was used to measure CRCS prevalence and adherence and region of birth (e.g., Caribbean-, African-, US-born). Prevalence and adherence were based on contemporaneous US Preventive Services Task Force guidelines. Descriptive statistics and adjusted prevalence and adherence proportions were calculated by region of birth. Adjusted logistic regression models were performed to assess the association between region of birth and overall CRCS and modality-specific adherence. Aim 3. To assess CRCS barriers, we conducted six sex-specific focus groups (n=3 female, n=3 male) with individuals, ages 45-75, who self-identified as Black (i.e., US-, Caribbean, or African-born) and were. Focus groups were held in person and via Zoom, recorded and transcribed verbatim. Codes were developed using coding consensus, co-occurrence, and comparison and open, axial, and selective coding rooted in grounded theory. Dedoose was used to determine CRCS barrier themes as well as general and modality-specific barriers by sex and by region of birth. Results Aim 1. In Philadelphia County, there were 4,641 CRC incident cases, of which 2,086 (44.9%) were non-Hispanic Black (NHB), and 2,555 (53.1%) were white. Mean age at diagnosis for CRC incidence (65.0 vs. 68.9 years), advanced stage at diagnosis (63.2 vs. 67.4 years), and colorectal cancer-specific mortality (67.5 vs. 71.7 years) was lower for Blacks compared to whites (p-value<0.001). Blacks were also diagnosed at a more advanced stage (25.0% vs. 22.4%, p-value=0.038) or unknown stage (8.01% vs. 5.64%, p-value=0.001). For each outcome, when compared to whites, higher proportions of Blacks lived in areas with higher proportions of markers of low socio-economic status and lower proportions of CRCS adherence. Geographic clusters at a higher-than-expected risk of CRC incidence were found in Northeast Philadelphia, North Philadelphia, West Philadelphia, and Southwest Philadelphia. Geographic clusters at a higher-than-expected risk of CRC diagnosed at an advanced stage and colorectal cancer-specific mortality overlapped and were in the North, Kensington, and Southwest neighborhoods of Philadelphia. Area-level NHB, the primary independent variable of interest, reduced the odds of HRCT for CRC incidence (OR: 0.971, 95% CI: 0.960, 0.983) and was not significantly associated with HRCT for advanced stage at diagnosis. In addition, after adjustment, for every one-unit increase in the percent of area-level foreign-born Blacks, there was 1.17-increased odds of being a HRCT for CRC incidence (95% CI: 1.07, 1.28). Similarly, there was a significant positive association with area-level foreign-born Black and being in a HRCT for advanced stage at diagnosis (OR: 1.15, 95% CI: 1.05, 1.26). Other area-level variables that were associated with HRCT for CRC incidence were median rent, percent of mortgaged housing units, and per capita income, which reduced the odds of being a HRCT; Percent of mortgaged housing units also reduced the odds of being a HRCT for advanced stage at diagnosis. Further, CRCS adherence reduced the odds of being a HRCT for advanced stage at diagnosis by approximately 15% (OR: 0.849, 95% CI: 0.791, 0.911). Aim 2. Respondents were 69.5% female, 43.3% married/living with a partner, and 38.4% had <$25,000 annual income. Overall, 78.2% reported past CRCS; however, stool test had the lowest prevalence overall (34.6%). Caribbean (95.0%) and African immigrants (90.2%) had a higher prevalence of overall CRCS compared to US-born Blacks (59.2%) (p-value <0.001). African immigrants were five times more likely to adhere to overall CRCS than US-born Blacks (OR: 5.25, 95% CI: 1.34, 20.6). Immigrants had higher odds of being adherent to colonoscopy (Caribbean=OR: 6.84, 95% CI: 1.49, 31.5; African =OR: 7.15, 95% CI: 1.27, 40.3) compared to US-born Blacks. Aim 3. The majority of focus group participants were 60–64 years old and 72% were immigrants (41% African-born, 31% Caribbean-born). Most participants had had CRCS, but 45% were non-adherent to national CRCS guidelines. Overall, lack of knowledge/awareness, fear, and a sense of feeling healthy and subsequently not seeing the need for CRCS emerged as overarching themes to CRCS barriers. General barriers differed by gender: for women lack of physician recommendation or explanation of CRCS was important and for men not knowing anyone with a history of CRCS was commonly cited. .” Differences in modality-specific barriers by gender were also noted. Barriers also differed by region of birth. US-born Blacks described lack of community advocacy promoting CRC and CRCS awareness as a barrier. African-born Blacks expressed lack of routine CRCS and utilization of preventive medicine in their native country as barriers. US- and Caribbean-born Black males, communicated that discussing CRCS was taboo, which was tied to hegemonic masculinity leading to a lack of conversations about CRC and CRCS. The use of traditional home remedies emerged as a barrier given respondents felt these remedies would aid in preventing CRC thereby reducing the need for CRCS. Immigrant Blacks also described limited insurance coverage due to their citizenship status. Conclusions This dissertation provides the first known insight into various outcomes across the colorectal cancer continuum for the heterogeneous Black population including the growing immigrant Black subgroups in Philadelphia County. To reduce CRC incidence and mortality, interventions and resources to increase CRCS uptake need to target geographic locations with higher percentages of foreign-born Blacks, lower CRCS adherence, and areas with worse socio-economic markers. Also, while Black immigrants had higher CRCS adherence compared to US-born Blacks, CRCS is still sub-optimal in the Black population. Further, CRCS barriers exist and differ by gender, and importantly, there are nuanced barriers by region of birth. Thus, efforts to increase CRCS should address the common and unique barriers and promote stool-based testing, as stool test adherence was low and focus group participants were unfamiliar with this modality as it is not widely promoted or available in clinical practice. In short, these findings across the colorectal cancer continuum should be taken into account for resource allocation and when designing targeted or tailored interventions to promote CRCS uptake for the heterogeneous Black population, which would reduce CRC incidence, late-stage diagnosis, and mortality. / Epidemiology

Yes / Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months. Resolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants. Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P

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