Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.

Objective To evaluate the impact of Covid‐19 vaccination (Pfizer–BioNTech BNT162b2) during the third trimester of pregnancy on maternal and neonatal outcomes. Design A multicentre, retrospective computerised database. Population Women who gave birth at >24 weeks of gestation in Israel, between January and April 2021, with full records of Covid‐19 disease and vaccination status. Methods Women who received two doses of the vaccine were compared with unvaccinated women. Women who were recorded as having disease or a positive Covid‐19 polymerase chain reaction (PCR) swab during pregnancy or delivery were excluded from both study groups. Univariate analysis was followed by multivariate logistic regression. Main outcome measures Composite adverse maternal outcomes. Secondary outcomes were vaccination rate and composite adverse neonatal outcomes. Results The overall uptake of one or both vaccines was 40.2%; 712 women who received two doses of the Covid‐19 vaccine were compared with 1063 unvaccinated women. Maternal composite outcomes were comparable between the groups; however, women who received the vaccine had higher rates of elective caesarean deliveries (CDs) and lower rates of vacuum deliveries. An adjusted multivariable logistic regression analysis demonstrated that Covid‐19 vaccination was not associated with maternal composite adverse outcome (aOR 0.8, 95% CI 0.61–1.03); a significant reduction in the risk for neonatal composite adverse outcomes was observed (aOR 0.5, 95% CI 0.36–0.74). Conclusions In a motivated population covered by a National Health Insurance Plan, we found a 40.2% rate of vaccination for the Covid‐19 vaccine during the third trimester of pregnancy, which was not associated with adverse maternal outcomes and, moreover, decreased the risk for neonatal adverse outcomes. Tweetable abstract Covid‐19 vaccine during pregnancy is safe for both mother and fetus.

Iron deficiency anemia at delivery is associated with an increased risk for cesarean section and adverse maternal and neonatal outcomes in otherwise healthy women. Monitoring/correction of hemoglobin concentrations even in late pregnancy may prevent these adverse events.

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Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of “cancer driver” GPCRs. Emerging data on GPCR biology point to functional selectivity and “biased agonism”; hence, there is a diminishing enthusiasm for the concept of “one drug per GPCR target” and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics.

ABSTRACT

Protease activated receptors (PAR) form a family of G-protein coupled receptors (GPCR) encoding their own ligands and uniquely activated via proteolytic cleavage. Although proteases in general have been implicated in the remodeling of the extracellular tumor microenvironment, the role of cell surface receptors activated by proteolysis is now emerging. In our present study we investigated the expression pattern of protease activated receptor 1 hPar1 in ovarian carcinoma tissue samples. Abundant hPar1 mRNA and protein were detected in "low malignant potential" and in invasive carcinomas, regardless of the histological subtype. In contrast, no hPar1 expression was detected on the cell surface of normal ovarian epithelium. The differential expression pattern of hPar1 was shown by in situ hybridization, immunohistochemistry and semi-quantitative RT-PCR analyses. In early stages of ovarian carcinoma (Ia), the contra lateral normal ovary showed strong PAR1 expression as opposed to the lack of expression in the ovarian epithelium obtained from normal individuals. In parallel, we analyzed the expression pattern of ␣v␤5 integrin and of activated focal adhesion kinase (FAK), a major focal contact protein, in these tissues. Although abundant expression of ␣v␤5 integrin was observed in all tissues specimens examined, regardless of either normal or malignant, the level of activated FAK was differentially expressed. Phosphorylated FAK was seen in invasive ovarian carcinoma, but not in the normal ovarian epithelium. The abundant hPar1 levels in pathological malignant ovarian carcinoma is likely to transmit signals leading to the phosphorylation of FAK and thereby alterations in the integrin functional state. Altogether our data suggest that hPar1 and FAK cooperate to promote ovarian cancer malignancy.

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