Objective: Examine the relationship between antibodies to 25 oral bacteria and pancreatic cancer risk in a prospective cohort study. Design: We measured antibodies to oral bacteria in prediagnosis blood samples from 405 pancreatic cancer cases and 416 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. Results: Individuals with high levels of antibodies against Porphyromonas gingivalis ATTC 53978, a pathogenic periodontal bacteria, had a twofold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (OR 2.14; 95% CI 1.05 to 4.36; >200 ng/ml vs ≤200 ng/ml). To explore the association with commensal (non-pathogenic) oral bacteria, we performed a cluster analysis and identified two groups of individuals, based on their antibody profiles. A cluster with overall higher levels of antibodies had a 45% lower risk of pancreatic cancer than a cluster with overall lower levels of antibodies (OR 0.55; 95% CI 0.36 to 0.83). Conclusions: Periodontal disease might increase the risk for pancreatic cancer. Moreover, increased levels of antibodies against specific commensal oral bacteria, which can inhibit growth of pathogenic bacteria, might reduce the risk of pancreatic cancer. Studies are needed to determine whether oral bacteria have direct effects on pancreatic cancer pathogenesis or serve as markers of the immune response.

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial–mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10⁻⁸). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10⁻¹⁴), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10⁻¹⁰), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10⁻⁸), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10⁻⁸). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter ≈70–90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3 ^−/− mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen α3 chain with concomitant emergence of α4 and α5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3 ^−/− mice or irradiated COL4A3 ^−/− mice with BM from adult COL4A3 ^−/− mice. The α3(IV) collagen produced by BM-derived podocytes integrates into the GBM and associates with other α-chains to form type IV collagen triple helical networks. This study demonstrates that BM-derived stem cells can offer a viable strategy for repairing basement membrane defects and conferring therapeutic benefit for patients with Alport syndrome.

General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist‐to‐hip and waist‐to‐height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer [EBDSC including gallbladder cancer (GBC)] among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested case–control subset. During a mean follow‐up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC [relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.09–5.87; p_trend < 0.0001] and with GBC (RR: 1.56, 95% CI: 1.12–2.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.49–4.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.

The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.