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.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

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.

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

https://www.cell.com/cell/pdf/S0092-8674(03)00432-X.pdf

Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

Fibroblasts in cancer

In a search of new, small leucine-rich repeat proteoglycan/protein (SLRP) family members, a novel gene, nephrocan(NPN), has been identified. The gene consists of three exons,and based on the deduced amino acid sequence, NPN has 17leucine-rich repeat motifs and unique cysteine-rich clustersbothintheNandCtermini,indicatingthatthisgenebelongstoa new class of SLRP family. NPN mRNA was predominantlyexpressed in kidney in adult mice, and during mouse embryo-genesis, the expression was markedly increased in 11-day-oldembryos at a time when early kidney development takes place.In the adult mouse kidney, NPN protein was located in distaltubules and collecting ducts. When NPN was overexpressed incell culture, the protein was detected in the cultured medium,and upon treatment with

Nephrocan, a Novel Member of the Small Leucine-rich Repeat Protein Family, Is an Inhibitor of Transforming Growth

The transforming growth factor-β (TGF-β) superfamily consists of multifunctional proteins that include TGF-βs, activins, inhibins, and bone morphogenetic proteins (BMPs), which regulate growth, differentiation, metabolism, and apoptosis of various cell types (1,2). Members of the TGF-β superfamily transduce signals via heteromeric complexes of two different serine/threonine kinase receptors, denoted type I and type II. Both type I and type II receptors are required for signal transduction (3).

Transforming Growth Factor-β Receptors and Signal Transduction

Bone morphogenetic proteins (BMPs) are multipotent signaling molecules that belong to the transforming growth factor-beta (TGF-beta) superfamily. Developmentally these proteins promote endochondral bone formation and are involved in the cascade of body patterning and morphogenesis. Moreover, BMPs play an important role in the pathophysiology of several diseases, including osteoporosis, arthritis, pulmonary hypertension, cerebrovascular diseases, cancer and kidney diseases. In this review, BMP signaling and regulation, the pathophysiological role of BMP in kidney diseases and potential therapeutic applications have been discussed.

[BMP in the kidney: signaling, function and pathophysiological significance].

Some epithelial cells have Na+/H+ exchanger (NHE) activity in both apical and basolateral membranes. Amiloride-sensitive NHE-1 is generally identified in the basolateral membrane. The renal cell line, OK7a, targets amiloride-resistant NHE predominantly to the apical membrane. It is controversial whether the transfected NHE-1 is targeted preferentially to the basolateral membrane in OK7a cells, when human NHE-1 is chronically expressed under control of constitutively active promoters. We tried to identify the membranes in which the transfected human NHE-1 could be detected following acute expression in OK7a cells. We have always observed small Na+-dependent pH recovery in the basolateral membrane in OK7a cells. It is, however, controversial whether or not OK7a cells express NHE activity in the basolateral membrane. We also characterized Na+-dependent pH recovery in the basolateral membrane. It was not inhibited by [4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid] (DIDS), [4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid] (SITS), or contralateral amiloride. Li+ but not K+, chol+, or NMG+ could replace Na+. These results are consistent with the presence of the NHE in the basolateral membrane. NHE activities were predominant in the apical membrane and those in both membranes were resistant to amiloride analogs. After stable transfection with human NHE-1 in a vector utilizing the metallothionein promoter, overnight induction with Zn2+ increased the NHE activity and its sensitivity to amiloride only in the basolateral membrane in OK7a cells. We conclude that the transfected human NHE-1 is exclusively targeted to the basolateral membrane of OK7a cells during acute induction. J Cell Physiol 178:44–50, 1999. © 1999 Wiley-Liss, Inc.

Expression of transfected human na+/h+ exchanger (nhe-1) in the basolateral membrane of opossum kidney cells

L'invention porte sur des compositions et des coffrets contenant un compose inhibiteur de l'atrogine-1 utile pour le traitement d'une myopathie a mediation par la statine. L'invention porte sur des coffrets pour le diagnostic d'une myopathie a mediation par la statine. L'invention porte egalement sur des procedes pour le traitement ou la prevention d'une myopathie a mediation par la statine dans un sujet par l'intermediaire d'une administration d'une quantite therapeutiquement efficace d'un compose inhibiteur de l'atrogine-1. L'invention porte egalement sur des procedes de diagnostic d'un sujet comme ayant une propension a developper une myopathie induite par la statine et sur des procedes de surveillance d'une myopathie induite par la statine ou d'une propension a developper une myopathie a mediation par la statine dans un sujet. L'invention porte egalement sur des procedes pour identifier un compose pour le traitement d'une myopathie a mediation par la statine et sur des procedes d'identification d'un compose de statine comme ayant la propension a induire une myopathie a mediation par la statine.

Jun-ichi Hanai

Papers

Nephrocan, a Novel Member of the Small Leucine-rich Repeat Protein Family, Is an Inhibitor of Transforming Growth

Transforming Growth Factor-β Receptors and Signal Transduction

[BMP in the kidney: signaling, function and pathophysiological significance].

Expression of transfected human na+/h+ exchanger (nhe-1) in the basolateral membrane of opossum kidney cells

Procédés et compositions pour le traitement et le diagnostic de la myopathie induite par la statine