Cytokines of the transforming growth factor β (TGF-β) family, including TGF-βs, bone morphogenic proteins (BMPs), activins, and Nodal, play crucial roles in embryonic development and adult tissue homeostasis by regulating cell proliferation, survival, and differentiation, as well as stem-cell self-renewal and lineage-specific differentiation. Smad proteins are critical downstream mediators of these signaling activities. In addition to regulating the transcription of direct target genes of TGF-β, BMP, activin, or Nodal, Smad proteins also participate in extensive cross talk with other signaling pathways, often in a cell-type- or developmental stage-specific manner. These combinatorial signals often produce context-, time-, and location-dependent biological outcomes that are critical for development. This review discusses recent progress in our understanding of the cross talk between Smad proteins and signaling pathways of Wnt, Notch, Hippo, Hedgehog (Hh), mitogen-activated protein (MAP), kinase, phosphoinositide 3-kinase (PI3K)-Akt, nuclear factor κB (NF-κB), and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways.

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Signaling Cross Talk between TGF-β/Smad and Other Signaling Pathways.

The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.

https://www.mdpi.com/1422-0067/19/7/2011/pdf

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT.

It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit.

Regulation of Ovarian Cancer Prognosis by Immune Cells in the Tumor Microenvironment.

Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial-mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc-finger E-box-binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor-β1, RAC-α serine/threonine-protein kinase, Wnt, nuclear factor-kappa B, peroxisome proliferator-activated receptor, Notch, and RAS), RNA-binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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Small molecule inhibitors of epithelial-mesenchymal transition for the treatment of cancer and fibrosis.

Advanced and recurrent gynecological cancers are associated with poor prognosis and lack of effective treatment. The developments of the molecular mechanisms on cancer progression provide insight into novel targeted therapies, which are emerging as groundbreaking and promising cancer treatment strategies. In gynecologic malignancies, potential therapeutic targeted agents include antiangiogenic agents, poly (ADP-ribose) polymerase (PARP) inhibitors, tumor-intrinsic signaling pathway inhibitors, selective estrogen receptor downregulators, and immune checkpoint inhibitors. In this article, we provide a comprehensive review of the clinical evidence of targeted agents in gynecological cancers and discuss the future implication.

/pdf/targeted-therapies-in-gynecological-cancers-a-comprehensive-2evnt2ds2c.pdf

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence.

Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells.

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial-to-mesenchymal transition and lipid-derived energy production in prostate cancer cells.

Glioblastoma (GBM) is an aggressive tumor with a dismal prognosis. Neural stem-like cells contribute to GBM's poor prognosis by driving drug resistance and maintaining cellular heterogeneity. GBM neural stem-like cells express high levels of brain fatty acid-binding protein (FABP7), which binds to polyunsaturated fatty acids (PUFAs) ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Similar to brain, GBM tissue is enriched in AA and DHA. However, DHA levels are considerably lower in GBM tissue compared to adult brain. Therefore, it is possible that increasing DHA content in GBM, particularly in neural stem-like cells, might have therapeutic value. Here, we examine the fatty acid composition of patient-derived GBM neural stem-like cells grown as neurosphere cultures. We also investigate the effect of AA and DHA treatment on the fatty acid profiles of GBM neural stem-like cells with or without FABP7 knockdown. We show that DHA treatment increases DHA levels and the DHA:AA ratio in GBM neural stem-like cells, with FABP7 facilitating the DHA uptake. We also found that an increased uptake of DHA inhibits the migration of GBM neural stem-like cells. Our results suggest that increasing DHA content in the GBM microenvironment may reduce the migration/infiltration of FABP7-expressing neural stem-like cancer cells.

https://www.mdpi.com/2072-6643/13/8/2664/pdf

FABP7 Facilitates Uptake of Docosahexaenoic Acid in Glioblastoma Neural Stem-like Cells.

Abstract The DEAD box protein DDX1, previously associated with 3’-end RNA processing and DNA repair, forms large aggregates in the cytoplasm of early mouse embryos. Ddx1 knockout causes stalling of embryos at the 2-4 cell stages. Here, we identify a DDX1-containing membrane-bound calcium-containing organelle with a nucleic acid core. We show that aggregates of these organelles form ring-like structures in early-stage embryos which we have named Membrane Associated RNA-containing Vesicles. We present evidence that DDX1 is required for the formation of Membrane Associated RNA-containing Vesicles which in turn regulate the spatial distribution of calcium in embryos. We find that Ddx1 knockout in early embryos disrupts calcium distribution, and increases mitochondria membrane potential, mitochondrial activity, and reactive oxygen species. Sequencing analysis of embryos from Ddx1 heterozygote crosses reveals downregulation of a subset of RNAs involved in developmental and mitochondrial processes in the embryos with low Ddx1 RNA. We propose a role for Membrane Associated RNA-containing Vesicles in calcium-controlled mitochondrial functions that are essential for embryonic development. 

/pdf/ddx1-vesicles-control-calcium-dependent-mitochondrial-2hwdklgr.pdf

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

/pdf/ddx1-vesicles-control-calcium-dependent-mitochondrial-1e6nklc8.pdf

Xia Xu

Papers

Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells.

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial-to-mesenchymal transition and lipid-derived energy production in prostate cancer cells.

FABP7 Facilitates Uptake of Docosahexaenoic Acid in Glioblastoma Neural Stem-like Cells.

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos