Trends in molecular medicine

let-7 microRNAs in development, stem cells and cancer.

Publication Date: 2008 Jul 30 PMID: 18674967
Authors: Bussing, I. - Slack, F. J. - Grosshans, H.
Journal: Trends Mol Med

MicroRNAs (miRNAs) are small noncoding RNAs, approximately 22 nucleotides in length, that repress target messenger RNAs (mRNAs) through an antisense mechanism. The let-7 miRNA was originally discovered in the nematode Caenorhabditis elegans, where it regulates cell proliferation and differentiation, but subsequent work has shown that both its sequence and its function are highly conserved in mammals. Recent results have now linked decreased let-7 expression to increased tumorigenicity and poor patient prognosis. Moreover, during normal development, accumulation of let-7 can be prevented by LIN28, a promoter of pluripotency. Based on these findings, we propose that let-7 regulates 'stemness' by repressing self-renewal and promoting differentiation in both normal development and cancer. A more complete understanding of its function will thus provide insights into these processes and might yield diagnostic and therapeutic advances for cancer treatment.

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Epigenetic mechanisms in drug addiction.

Publication Date: 2008 Aug PMID: 18635399
Authors: Renthal, W. - Nestler, E. J.
Journal: Trends Mol Med

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.

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Pluripotent human stem cell lines: what we can learn about cancer initiation.

Publication Date: 2008 Aug PMID: 18635398
Authors: Werbowetski-Ogilvie, T. E. - Bhatia, M.
Journal: Trends Mol Med

Although the cancer stem cell (CSC) hypothesis has become an attractive model to account for tumor recurrence, failure to define a cell of origin has created the need to explore alternative models for cancer initiation and maintenance. Recent studies have linked an embryonic stem cell (ESC)-like gene signature with poorly defined high-grade tumors. Here, we review advances in the ESC field with an emphasis on how human pluripotent stem cells (hPSCs) can be used to define early tumorigenic events, including potential miRNA and epigenetic targets, as well as proto-oncogene and tumor suppressor networks that might facilitate hierarchal transformation. These studies allow for investigation of cancer initiation in a manner that cannot be achieved using primary tumors, where only retrospective evaluation of CSC development is possible. By comparing transformed hPSCs with their normal counterparts, we hope to develop novel cell-specific therapies that selectively target CSCs.

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New dimensions in tumor immunology: what does 3D culture reveal?

Publication Date: 2008 Aug PMID: 18614399
Authors: Feder-Mengus, C. - Ghosh, S. - Reschner, A. - Martin, I. - Spagnoli, G. C.
Journal: Trends Mol Med

Experimental models indicate that tumor cells in suspension, unlike solid tumor fragments, might be unable to produce life-threatening cancer outgrowth when transferred to animal models, irrespective of the number of cells transferred, although they induce specific immune responses. Human tumor cells cultured in three dimensions display increased pro-angiogenic capacities and resistance to interferons, chemotherapeutic agents or irradiation, as compared with cells cultured in two-dimensional (2D) monolayers. Tumor cells cultured in three dimensions were also shown to be characterized by defective immune recognition by cytotoxic T lymphocytes (CTLs) specific for tumor-associated antigens (TAAs) and by a capacity to inhibit CTL proliferation and dendritic cell (DC) functions. Downregulation of human leukocyte antigen (HLA) or TAA expression and high production of lactic acid might play a role in the elicitation of these effects. Here, we propose that growth in 3D architectures might provide new insights into tumor immunology and could represent an integral missing component in pathophysiological tumor immune escape mechanisms.

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Sialic acids in human health and disease.

Publication Date: 2008 Aug PMID: 18606570
Authors: Varki, A.
Journal: Trends Mol Med

The surfaces of all vertebrate cells are decorated with a dense and complex array of sugar chains, which are mostly attached to proteins and lipids. Most soluble secreted proteins are also similarly decorated with such glycans. Sialic acids are a diverse family of sugar units with a nine-carbon backbone that are typically found attached to the outermost ends of these chains. Given their location and ubiquitous distribution, sialic acids can mediate or modulate a wide variety of physiological and pathological processes. This review considers some examples of their established and newly emerging roles in aspects of human physiology and disease.

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The moonlighting enzyme CD13: old and new functions to target.

Publication Date: 2008 Aug PMID: 18603472
Authors: Mina-Osorio, P.
Journal: Trends Mol Med

Aminopeptidase N (CD13) is a widely expressed ectoenzyme with functions that do not always depend on its enzymatic activity: an aspect that has been overlooked. Numerous CD13-targeting tools have been developed in the last few years. Several of them are already undergoing clinical trials, and there are promising reports on the effectiveness of others in animal models of disease. However, their efficacy might be obscured by their effects on unrecognized functions of CD13, resulting in unexpected complications. The purpose of this review is (i) to discuss the various functions ascribed to CD13 and the possible mechanisms behind them and (ii) to consider some of the questions that need to be answered to achieve a better understanding of the biological relevance of these functions, a more precise interpretation of the results obtained after their manipulation and a more rational design of CD13-targeting agents.

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