Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression.

BACKGROUND: The aim of this study is to seek an association between markers of metastatic potential, drug resistance-related protein and monocarboxylate transporters in prostate cancer (CaP). METHODS: We evaluated the expression of invasive markers (CD147, CD44v3-10), drug-resistance protein (MDR1) and monocarboxylate transporters (MCT1 and MCT4) in CaP metastatic cell lines and CaP tissue microarrays (n=140) by immunostaining. The co-expression of CD147 and CD44v3-10 with that of MDR1, MCT1 and MCT4 in CaP cell lines was evaluated using confocal microscopy. The relationship between the expression of CD147 and CD44v3-10 and the sensitivity (IC(50)) to docetaxel in CaP cell lines was assessed using MTT assay. The relationship between expression of CD44v3-10, MDR1 and MCT4 and various clinicopathological CaP progression parameters was examined. RESULTS: CD147 and CD44v3-10 were co-expressed with MDR1, MCT1 and MCT4 in primary and metastatic CaP cells. Both CD147 and CD44v3-10 expression levels were inversely related to docetaxel sensitivity (IC(50)) in metastatic CaP cell lines. Overexpression of CD44v3-10, MDR1 and MCT4 was found in most primary CaP tissues, and was significantly associated with CaP progression. CONCLUSIONS: Our results suggest that the overexpression of CD147, CD44v3-10, MDR1 and MCT4 is associated with CaP progression. Expression of both CD147 and CD44v3-10 is correlated with drug resistance during CaP metastasis and could be a useful potential therapeutic target in advanced disease.

Mucinous differentiation in colonic adenocarcinoma is associated with a reduction in tumour-infiltrating lymphocytes.

AIMS: The aim of this study was to examine the density of tumour-infiltrating lymphocytes (TILs) in colorectal carcinomas showing mucinous differentiation. METHODS: We examined 33 adenocarcinomas showing variable mucinous differentiation and compared the density of TILs with that of 65 adenocarcinomas of no special type (NOS) showing no mucinous differentiation. RESULTS: Mucinous differentiation is associated with a significantly lower density of TILs compared to adenocarcinoma NOS (P=0.0016; chi-squared test with continuity correction). This reduction in TILs is present also in adjacent foci of adenocarcinoma NOS within mucinous tumours. CONCLUSIONS: There is a reduction in the number of TILs in all areas of colorectal adenocarcinomas that show mucinous differentiation, which may help explain the increased biological aggressiveness associated with this pattern of differentiation.

Malignant phyllodes tumours of the breast display increased stromal p53 protein expression.

AIMS: To determine the variation in p53 protein expression in phyllodes tumours and fibroadenomas of the breast. METHODS AND RESULTS: Fifteen phyllodes tumours (six malignant, nine benign) and 20 fibroadenomas were examined for p53 expression by immunohistochemistry. Five of the six malignant phyllodes tumours showed moderate or strong p53 positivity at sites of peri-epithelial stromal condensation and atypia. All 20 fibroadenomas, nine benign phyllodes tumours and one malignant phyllodes tumour showed either negativity or focal weak nuclear positivity of scattered stromal cells. CONCLUSIONS: Increased p53 immunoreactivity is present in malignant phyllodes tumours in contrast to benign phyllodes tumours and fibroadenomas. Malignant phyllodes tumours display a distinctive pattern of p53 immunostaining which may be of diagnostic value. These findings suggest that p53 protein may be important in the progression of benign to malignant phyllodes tumours.

The lack of interaction between transplanted human fetal pancreas and liver.

Trophism between transplanted hepatocytes and pancreatic endocrine tissue has been demonstrated with both adult and late gestational fetal tissue. Since this effect has not been looked for with fetal tissue obtained early in pregnancy, we conducted a series of experiments transplanting human liver and pancreas, which was obtained early in the second trimester (15-20 weeks gestation), beneath the renal capsule of athymic mice. Fetal pancreatic explants increased in size after transplantation into nondiabetic mice, but their insulin content 11 weeks later was not different from that of grafts that included liver explants. Reversal of diabetes was achieved in 2 of 5 diabetic mice transplanted with pancreas alone, but none of the mice that received pancreas and liver became normoglycemic. Histological examination of grafted liver explants, which consist of hepatocytes and hematopoietic cells, showed that hepatocytes survived for only two weeks regardless of the presence of pancreatic explants. Bile ducts differentiated by this time in both groups and were still present at 7 weeks. In conclusion, there was no trophic effect observed between transplanted fetal human liver and pancreatic endocrine tissue obtained early in pregnancy; bile duct differentiation is a feature of fetal human liver xenografted into the athymic mouse.