Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

BACKGROUND: Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways. METHODS: Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR. RESULTS: IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration. CONCLUSIONS: IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies

The stomach cancer pooling (STOP) project: a global consortium of epidemiological studies of gastric cancer, updated to 2021

The assessment of risk factors in cancer etiology is necessary for defining optimal preventive strategies, as well as for identifying high risk individuals, and it is therefore relevant for medical practice and cancer prevention. The Stomach cancer Pooling (StoP) Project is a consortium of epidemiological studies of gastric cancer (GC), established in year 2012. The StoP Project aims to examine the role of lifestyle, environmental and genetic determinants of GC through pooled analyses of subject-level data. The consortium is the major GC dataset globally, including original data from 35 studies – with case–control study design, including 5 nested case–control within cohort studies – conducted in the Americas, Asia and Europe (Table 1), for a total of about 13,500 cases and 32,000 controls, and it is continuously expanding. To date, the StoP Project contributed a detailed quantification of the risk of GC associated to several factors, including cigarette smoking (relative risk, RR, of 1.32 for heavy vs. never smokers), alcohol drinking (RR=1.48 for heavy vs. never drinkers), socio-economic status (RR=0.60 for high vs. low education), selected dietary factors (RR=1.30 for high vs. low meat intake; RR=0.65 for high vs. low vegetables consumption; RR=0.80 for high vs. low citrus fruit; RR=0.67 for high vs. low polyphenols intake) and occupational exposures (RR=1.70 for miners; RR=1.30 for construction workers; RR=1.33 for agricultural and animal husbandry workers; RR=1.41 for blacksmiths and machine-tool operators). Planned future developments are to analyze the role of rare exposures on GC risk and to examine risk factors in understudied patient subgroups (e.g., young onset GC, gastric cardia cancer, etc.); to integrate additional studies from East Asia; to develop a genome-wide modeling of polygenic risk score in GC; to include survival analyses and to apply machine learning methods in GC risk prediction and prognostication

Inverse Association between Dietary Iron Intake and Gastric Cancer: A Pooled Analysis of Case‐Control Studies of the Stop Consortium

Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case‐control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83–0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77–0.94) and non‐cardia GC (OR = 0.87, 95% CI = 0.81–0.94), and for diffuse (OR = 0.79, 95% CI = 0.69–0.89) and intestinal type (OR = 0.88, 95% CI = 0.79–0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis

Inverse Association between Dietary Iron Intake and Gastric Cancer: A Pooled Analysis of Case‐Control Studies of the Stop Consortium

Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case‐control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83–0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77–0.94) and non‐cardia GC (OR = 0.87, 95% CI = 0.81–0.94), and for diffuse (OR = 0.79, 95% CI = 0.69–0.89) and intestinal type (OR = 0.88, 95% CI = 0.79–0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.This study was supported by the Fondazione AIRC per la Ricerca sul Cancro, Project no. 21378 (Investigator Grant). The Unidade de Investigação em Epidemiologia—Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020) and the Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR; LA/P/0064/2020) were funded by the Foundation for Science and Technology—FCT (Portuguese Ministry of Science, Technology and Higher Education). SM was supported by the project “NEON‐PC—Neuro‐oncological complications of prostate cancer: longitudinal study of cognitive decline” (POCI‐01‐0145‐FEDER‐032358; ref. PTDC/SAU‐EPI/32358/2017), which is funded by FEDER through the Operational Programme competitiveness and Internationalization, and national funding from FCT and the EPIUnit—Junior Research—Prog Financing (UIDP/04750/2020). The authors thank the European Cancer Prevention (ECP) Organization for providing support for the StoP Project meetings and all MCC‐Spain study collaborators (CIBERESP, ISCIII, ISGlobal, ICO, University of Huelva, University of Oviedo, University of Cantabria, ibs.Granada, Instituto Salud Pública de Navarra, FISABIO, Murcia Regional Health Authority and cols)

The Association between Peptic Ulcer Disease and Gastric Cancer: Results from the Stomach Cancer Pooling (StoP) Project Consortium

Background. Gastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium. Methods. History of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth’s penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC. Results. History of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07–4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77–1.39). Conclusions. In the pooled analysis of 11 case–control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk

The protective effect of dietary folate intake on gastric cancer is modified by alcohol consumption: A pooled analysis of the StoP Consortium

Dietary folate intake has been identified as a potentially modifiable factor of gastric cancer (GC) risk, although the evidence is still inconsistent. We evaluate the association between dietary folate intake and the risk of GC as well as the potential modification effect of alcohol consumption. We pooled data for 2829 histologically confirmed GC cases and 8141 controls from 11 case–control studies from the international Stomach Cancer Pooling Consortium. Dietary folate intake was estimated using food frequency questionnaires. We used linear mixed models with random intercepts for each study to calculate adjusted odds ratios (OR) and 95% confidence interval (CI). Higher folate intake was associated with a lower risk of GC, although this association was not observed among participants who consumed >2.0 alcoholic drinks/day. The OR for the highest quartile of folate intake, compared with the lowest quartile, was 0.78 (95% CI, 0.67–0.90, P-trend = 0.0002). The OR per each quartile increment was 0.92 (95% CI, 0.87–0.96) and, per every 100 μg/day of folate intake, was 0.89 (95% CI, 0.84–0.95). There was a significant interaction between folate intake and alcohol consumption (P-interaction = 0.02). The lower risk of GC associated with higher folate intake was not observed in participants who consumed >2.0 drinks per day, ORQ4v Q1 = 1.15 (95% CI, 0.85–1.56), and the OR100 μg/day = 1.02 (95% CI, 0.92–1.15). Our study supports a beneficial effect of folate intake on GC risk, although the consumption of >2.0 alcoholic drinks/day counteracts this beneficial effect. © 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.This study was funded by the Associazione Italiana per la Ricerca sul Cancro (Project number 21378, Investigator Grant). NL and SM are funded under the Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020) financed by national funds from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education) and the Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR; LA/P/0064/2020). SM also received funding under the scope of the project “NEON-PC – Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline” (POCI-01-0145-FEDER-032358; Ref. PTDC/SAU-EPI/32358/2017) funded by FEDER through the Operational Program Competitiveness and Internationalization, and national funding from FCT, and the EPIUnit – Junior Research – Prog Financing (UIDP/04750/2020). This research was supported in part by the Intramural Research Program of the US National Cancer Institute. The study was also supported by the Italian Ministry of Health through the project “Interaction of genomic and dietary aspects in gastric cancer risk: the global StoP project” (Grant number RF-2021-12373951). This research was funded by the AICO/2021/347 grants for consolidated research groups from the Generalitat Valenciana. MHW and CSR also received funding from National Institutes of Health (ZIA CP010212 - Molecular mechanisms of infection-related cancer). [Correction added on 29 May 2024, after first online publication: The funding information has been updated.]

Education and gastric cancer risk-An individual participant data meta-analysis in the StoP project consortium

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the "Stomach cancer Pooling (StoP) Project". Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44-0.84), while the pooled RII was 0.45 (95% CI, 0.29-0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22-0.70) and cardia GC (OR 0.47, 95% CI, 0.22-0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04-0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10-0.84), in the absence of a significant interaction (p\u2009=\u20090.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48-0.89), while the corresponding RII was 0.40 (95% CI, 0.22-0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population

The Association between Peptic Ulcer Disease and Gastric Cancer: Results from the Stomach Cancer Pooling (StoP) Project Consortium

Background. Gastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium. Methods. History of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth’s penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC. Results. History of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07–4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77–1.39). Conclusions. In the pooled analysis of 11 case–control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk. © 2022 by the authors.This work is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Project no. 21378 (Investigator Grant); Fondazione Italiana per la Ricerca sul Cancro (FIRC); Italian League for the Fight Against Cancer (LILT); European Cancer Prevention (ECP) Organization; and UPMC Start-up Grant (to HNL). P Paragomi was supported by a cancer research training grant from NIH (grant # T32CA186873)

Family history and gastric cancer risk: A pooled investigation in the stomach cancer pooling (STOP) project consortium

Research is still required to establish the relationship between family history (FH) and gastric cancer (GC) in relation to different histological types and anatomical sites. The present work aimed to examine the influence of first-degree FH on the risk of GC, also according to the GC location and histological type, including 5946 cases and 12,776 controls from 17 studies of 11 countries in three continents participating in the Stomach Cancer Pooling (StoP) Project consortium. This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Although there is a clear relationship between family history (FH) and the risk of gastric cancer (GC), quantification is still needed in relation to different histological types and anatomical sites, and in strata of covariates. The objective was to analyze the risk of GC according to first-degree FH in a uniquely large epidemiological consortium of GC. This investigation includes 5946 cases and 12,776 controls from 17 studies of the Stomach Cancer Pooling (StoP) Project consortium. Summary odds ratios (OR) and the corresponding 95% confidence intervals (CIs) were calculated by pooling study-specific ORs using fixed-effect model meta-analysis techniques. Stratified analyses were carried out by sex, age, tumor location and histological type, smoking habit, socioeconomic status, alcohol intake and fruit consumption. The pooled OR for GC was 1.84 (95% CI: 1.64-2.04; I2 = 6.1%, P heterogeneity = 0.383) in subjects with vs. those without first-degree relatives with GC. No significant differences were observed among subgroups of sex, age, geographic area or study period. Associations tended to be stronger for non-cardia (OR = 1.82; 95% CI: 1.59-2.05 for subjects with FH) than for cardia GC (OR = 1.38; 95% CI: 0.98-1.77), and for the intestinal (OR = 1.92; 95% CI: 1.62-2.23) than for the diffuse histotype (OR = 1.62; 95% CI: 1.28-1.96). This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Considering these findings, accounting for the presence of FH to carry out correct prevention and diagnosis measures is of the utmost importance

Coffee consumption and gastric cancer: A pooled analysis from the Stomach cancer Pooling Project consortium

open41siThis study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Project no. 21378 (Investigator Grant), and by the Italian League for the Fight Against Cancer (LILT). The authors thank the European Cancer Prevention (ECP) Organization for providing support for the StoP meetings. The Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit; UIDB/04750/2020) was funded by the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education). SM was also funded by the project “NEON-PC - Neuro-oncological complications of prostate cancer: longitudinal study of cognitive decline” (POCI-01-0145-FEDER-032358; ref. PTDC/SAU-EPI/32358/2017), which is funded by FEDER through the Operational Programme competitiveness and Internationalization, and national funding from FCT. We also thank all MCC-Spain study collaborators (CIBERESP, ISCIII, ISGlobal, ICO, University of Huelva, University of Oviedo, University of Cantabria, ibs.Granada, Instituto Salud Pública de Navarra, FISABIO, Murcia Regional Health Authority and cols).Objective This study aimed to evaluate and quantify the relationship between coffee and gastric cancer using a uniquely large dataset from an international consortium of observational studies on gastric cancer, including data from 18 studies, for a total of 8198 cases and 21 419 controls. Methods A two-stage approach was used to obtain the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for coffee drinkers versus never or rare drinkers. A one-stage logistic mixed-effects model with a random intercept for each study was used to estimate the dose-response relationship. Estimates were adjusted for sex, age and the main recognized risk factors for gastric cancer. Results Compared to never or rare coffee drinkers, the estimated pooled OR for coffee drinkers was 1.03 (95% CI, 0.94-1.13). When the amount of coffee intake was considered, the pooled ORs were 0.91 (95% CI, 0.81-1.03) for drinkers of 1-2 cups per day, 0.95 (95% CI, 0.82-1.10) for 3-4 cups, and 0.95 (95% CI, 0.79-1.15) for five or more cups. An OR of 1.20 (95% CI, 0.91-1.58) was found for heavy coffee drinkers (seven or more cups of caffeinated coffee per day). A positive association emerged for high coffee intake (five or more cups per day) for gastric cardia cancer only. Conclusions These findings better quantify the previously available evidence of the absence of a relevant association between coffee consumption and gastric cancer.openMartimianaki G.; Bertuccio P.; Alicandro G.; Pelucchi C.; Bravi F.; Carioli G.; Bonzi R.; Rabkin C.S.; Liao L.M.; Sinha R.; Johnson K.; Hu J.; Palli D.; Ferraroni M.; Lunet N.; Morais S.; Tsugane S.; Hidaka A.; Hamada G.S.; Lopez-Carrillo L.; Hernandez-Ramirez R.U.; Zaridze D.; Maximovitch D.; Aragones N.; Martin V.; Ward M.H.; Vioque J.; Garcia De La Hera M.; Zhang Z.-F.; Kurtz R.C.; Lagiou P.; Lagiou A.; Trichopoulou A.; Karakatsani A.; Malekzadeh R.; Camargo M.C.; Curado M.P.; Boccia S.; Boffetta P.; Negri E.; La Vecchia C.Martimianaki G.; Bertuccio P.; Alicandro G.; Pelucchi C.; Bravi F.; Carioli G.; Bonzi R.; Rabkin C.S.; Liao L.M.; Sinha R.; Johnson K.; Hu J.; Palli D.; Ferraroni M.; Lunet N.; Morais S.; Tsugane S.; Hidaka A.; Hamada G.S.; Lopez-Carrillo L.; Hernandez-Ramirez R.U.; Zaridze D.; Maximovitch D.; Aragones N.; Martin V.; Ward M.H.; Vioque J.; Garcia De La Hera M.; Zhang Z.-F.; Kurtz R.C.; Lagiou P.; Lagiou A.; Trichopoulou A.; Karakatsani A.; Malekzadeh R.; Camargo M.C.; Curado M.P.; Boccia S.; Boffetta P.; Negri E.; La Vecchia C