There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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The basics of epithelial-mesenchymal transition

The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Many tumors consist of a hierarchy of cells with different proliferative and developmental potentials. A small number of cancer stem cells (CSCs) give rise to a larger population of highly proliferative, committed progenitor cells, which may then undergo limited differentiation. Importantly CSCs are uniquely capable of initiating and sustaining tumorigenesis, and they have been implicated in driving disease recurrence after cancer therapy. In order to be able to assess stem cell behavior in real-time at a single cell rather than a population level, we have developed and validated a novel lentiviral-based reporter system for direct visualization, quantitation and isolation of cells with CSC properties. The construct consists of a tandemly-repeated composite SOX2-OCT4 response element (“SORE6”) driving expression of a destabilized green fluorescent protein reporter. Using the human MCF10CA1h breast cancer cell line, we have shown that SORE6-GFP+ cells within the cell population are relatively undifferentiated and enriched for stem cell markers. These cells can self-renew and regenerate SORE6-GFP- cells, show enhanced asymmetric division, and are enriched for tumorigenesis and resistance to chemotherapeutics in vivo. We and others have previously suggested that TGF-β can regulate the CSC population with stimulatory or inhibitory effects depending on model. In the MCF10Ca1h breast cancer model, which retains tumor suppressor responses to TGF-β, we hypothesized that endogenous TGF-β suppresses tumorigenesis by direct effects on the CSCs. Using our reporter, we show TGF-β reduces the size of the CSC population and the frequency of asymmetric self-renewing divisions in the MCF10Ca1h model. Although TGF-β had relatively little effect on invasion and migration of the bulk MCF10Ca1h population, it clearly inhibited migration and invasion of the CSCs, suggesting that biological responses to TGF-β can vary depending on the position of the cell in the differentiation hierarchy. Combining our stem cell reporter with a TGF-β pathway reporter, we show that CSCs have higher endogenous activation of the TGF-β pathway than do the bulk cells, and by time-lapse video microscopy we find that CSCs with active TGF-β signaling are relatively quiescent. Furthermore, neutralization of TGF-β in vivo, leads to an increased representation of CSCs in the MCF10Ca1h tumors. Thus our preliminary results suggest that in breast cancer models where TGF-β acts as a tumor suppressor, TGF-β signaling is preferentially activated in the CSC compartment and may keep a subpopulation of CSCs in a proliferatively quiescent and stationary state. Citation Format: Binwu Tang, Asaf Raviv, Dominic Esposito, Catherine Daniel, Kathleen C. Flanders, Yu-an Yang, Lalage M. Wakefield. Transforming Growth Factor-beta (TGF-β) directly regulates breast cancer stem cell dynamics in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2221. doi:10.1158/1538-7445.AM2015-2221

Abstract 2221: Transforming Growth Factor-beta (TGF-β) directly regulates breast cancer stem cell dynamics in vitro and in vivo

and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Transforming Growth Factor‐TGFβ and Fibronectin, Collagens I and III, and Glycosaminoglycans in the Developing Mouse Embryoa

Localization oftransforming growth factor-,B1 inmitochondria ofmurine heart andliver

There is substantial evidence to suggest that transforming growth factor-β (TGF-β) plays an important role in wound healing and tissue repair as well as in carcinogenesis. It has also been observed that naturally occurring bovine papillomavirus type 1 (BPV-l)-induced bovine fibropapillomas occur predominantly at traumatized sites of the body, suggesting that humoral factors released in wounds might be important for papillomavirus infection. We have therefore investigated the possible role of TGF-β1 in BPV-1 infections. Two anti-peptide antibodies which recognize different epitopes in the N-terminus of TGF-β1 were used to localize TGF-β1 in bovine fibropapillomas and normal bovine skin using im-munohistochemical methods. Staining by anti-LC(l-30) is intracellular in suprabasal keratinocytes of the epidermis as well as the hair follicles and sebaceous glands and correlates with known sites of TGF-β1 mRNA synthesis. Anti-CC(l-30) staining is extracellular in the immediately underlying dermis. Neither...

Transforming growth factor-beta expression in fibropapillomas induced by bovine papillomavirus type 1, in normal bovine skin, and in BPV-1-transformed cells.

Kathleen C. Flanders

Papers

Abstract 2221: Transforming Growth Factor-beta (TGF-β) directly regulates breast cancer stem cell dynamics in vitro and in vivo

and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

Transforming Growth Factor‐TGFβ and Fibronectin, Collagens I and III, and Glycosaminoglycans in the Developing Mouse Embryoa

Localization oftransforming growth factor-,B1 inmitochondria ofmurine heart andliver

Transforming growth factor-beta expression in fibropapillomas induced by bovine papillomavirus type 1, in normal bovine skin, and in BPV-1-transformed cells.