Candesartan does not activate PPAR(γ) and its target genes in early gestation trophoblasts

Angiotensin II receptor 1 blockers are commonly used to treat hypertension in women of childbearing age. While the fetotoxic effects of these drugs in the second and third trimesters of pregnancy are well documented, their possible impacts on placenta development in early gestation are unknown. Candesartan, a member of this group, also acts as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, a key regulator shown to be important for placental development. We have previously shown that trophoblasts do not express the candesartan target-receptor angiotensin II type 1 receptor AGTR1. This study investigated the possible role of candesartan on trophoblastic PPARγ and its hallmark target genes in early gestation. Candesartan did not affect the PPARγ protein expression or nuclear translocation of PPARγ. To mimic extravillous trophoblasts (EVTs) and cytotrophoblast/syncytiotrophoblast (CTB/SCT) responses to candesartan, we used trophoblast cell models BeWo (for CTB/SCT) and SGHPL-4 (EVT) cells as well as placental explants. In vitro, the RT-qPCR analysis showed no effect of candesartan treatment on PPARγ target genes in BeWo or SGHPL-4 cells. Treatment with positive control rosiglitazone, another PPARγ agonist, led to decreased expressions of (LEP) and (PPARG1) in BeWo cells and an increased expression of PPARG1 in SGHPL-4 cells. Our previous data showed early gestation-placental AGTR1 expression in fetal myofibroblasts only. In a CAM assay, AGTR1 was stimulated with angiotensin II and showed increased on-plant vessel outgrowth. These results suggest candesartan does not negatively affect PPARγ or its target genes in human trophoblasts. More likely, candesartan from maternal serum may first act on fetal-placental AGTR1 and influence angiogenesis in the placenta, warranting further research

Placental kisspeptins differentially modulate vital parameters of estrogen receptor-positive and-negative breast cancer cells

Kisspeptins (KPs) are major regulators of trophoblast and cancer invasion. Thus far, limited and conflicting data are available on KP-mediated modulation of breast cancer (BC) metastasis; mostly based on synthetic KP-10, the most active fragment of KP. Here, we report for the first time comprehensive functional effects of term placental KPs on proliferation, adhesion, Matrigel invasion, motility, MMP activity and pro-inflammatory cytokine production in MDA-MB-231 (estrogen receptor-negative) and MCF-7 (estrogen receptor-positive). KPs were expressed at high level by term placental syncytiotrophoblasts and released in soluble form. Placental explant conditioned medium containing KPs (CM) significantly reduced proliferation of both cell types compared to CM without (w/o) KP (CM-w/o KP) in a dose-and time-dependent manner. In MDA-MB-231 cells, placental KPs significantly reduced adhesive properties, while increased MMP9 and MMP2 activity and stimulated invasion. Increased invasiveness of MDA-MB-231 cells after CM treatment was inhibited by KP receptor antagonist, P-234. CM significantly reduced motility of MCF-7 cells at all time points (2-30 hr), while it stimulated motility of MDA-MB-231 cells. These effects were reversed by P-234. Co-treatment with selective ER modulators, Tamoxifen and Raloxifene, inhibited the effect of CM on motility of MCF-7 cells. The level of IL-6 in supernatant of MCF-7 cells treated with CM was higher compared to those treated with CM-w/o KP. Both cell types produced more IL-8 after treatment with CM compared to those treated with CM-w/o KP. Taken together, our observations suggest that placental KPs differentially modulate vital parameters of estrogen receptor-positive and-negative BC cells possibly through modulation of pro-inflammatory cytokine production. © 2016 Rasoulzadeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

PLAC1: biology and potential application in cancer immunotherapy

The emergence of immunotherapy has revolutionized medical oncology with unprecedented advances in cancer treatment over the past two decades. However, a major obstacle in cancer immunotherapy is identifying appropriate tumor-specific antigens to make targeted therapy achievable with fewer normal cells being impaired. The similarity between placentation and tumor development and growth has inspired many investigators to discover antigens for effective immunotherapy of cancers. Placenta-specific 1 (PLAC1) is one of the recently discovered placental antigens with limited normal tissue expression and fundamental roles in placental function and development. There is a growing body of evidence showing that PLAC1 is frequently activated in a wide variety of cancer types and promotes cancer progression. Based on the restricted expression of PLAC1 in testis, placenta and a wide variety of cancers, we have designated this molecule with new terminology, cancer�testis�placenta (CTP) antigen, a feature that PLAC1 shares with many other cancer testis antigens. Recent reports from our lab provide compelling evidence on the preferential expression of PLAC1 in prostate cancer and its potential utility in prostate cancer immunotherapy. PLAC1 may be regarded as a potential CTP antigen for targeted cancer immunotherapy based on the available data on its promoting function in cancer development and also its expression in cancers of different histological origin. In this review, we will summarize current data on PLAC1 with emphasis on its association with cancer development and immunotherapy. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature

Supplementary Material for: Different Preference of Degradome in Invasion versus Angiogenesis

Proteases are required for a multitude of cellular processes including homeostatic tissue remodelling, invasion and angiogenesis. The physiological function of a cell or tissue is reflected by the set of proteases expressed, also termed degradome. The role of proteases in invasion and angiogenesis has been studied intensively, mostly in cancer. We aimed to compare the set of proteases required for physiological invasion versus physiological angiogenesis from cells deriving from the same organ, and to identify the proteases specific for each process. The human placenta comprises trophoblasts that invade the maternal uterus in a regulated, physiological manner, and it is the source of primary endothelial cells. We isolated the trophoblasts and endothelial cells and verified their invasive phenotype and angiogenic properties, respectively. We then performed gene expression analysis of the degradome, e.g. cysteine, metallo, serine, threonine and aspartic proteases, identified the differentially expressed proteases among the trophoblasts and endothelial cells, and clustered them hierarchically. The results revealed that the set of proteases in trophoblasts versus in endothelial cells overlaps, with a total of 69% in common. Nevertheless, 42% of the studied degradomes differed, with a fold change ≥2. For instance, metalloproteinases were predominantly expressed in trophoblasts, and 31% of the proteases were exclusively expressed in either trophoblasts or endothelial cells; this suggests particular roles for these proteases in either invasion or angiogenesis. Our data identify common and distinct proteases in cells capable of performing invasion and angiogenesis, and may provide basic information for the design of techniques to specifically investigate invasion or angiogenesis

Melanocytes, Organogenesis, and Angiogenesis: Evidence for More than a Pigment-Producing Capability of Melanocytes.

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