Current Molecular Medicine - Volume 10, Issue 5, 2010

The bone marrow microenvironment houses haematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and their progeny, supports haematopoiesis, osteogenesis, osteoclastogenesis, and adipogenesis. It plays a key role in maintaining homeostatic production of erythroid, myeloid or lymphoid cells, appropriate bone mass and bone health throughout life. Through cell-cell adhesion and chemotactic axes, a reciprocal inter-dependent relationship exists between these two cell lineages. Following chemotherapy-induced myelosuppression observed in cancer patients, HSCs are induced to enter into the cell cycle in order to re-establish the damaged microenvironment. These cells not only have the capacity to mobilise to the peripheral blood, but the ability to repopulate the marrow cavity as required. However, depending on the dosage and length of chemotherapy treatment, complications in bone and bone marrow recovery occur. This may manifest as marrow haematopoietic depletion, high marrow fat content, reduced bone formation and aggravated osteoclastic bone resorption. Although the molecular and cellular mechanisms governing injured states of the marrow microenvironment are yet to be fully elucidated, many reports have demonstrated the CXCL12/CXCR4 axis plays an important role in regulating the two cell lineages. Their interaction maintains bone marrow homeostasis and orchestrates its regeneration following chemotherapy. This review explores movement of MSC and HSC, haematopoiesis, commitment of osteoblasts, osteoclasts, and adipocytes, as well as the major signalling pathways that regulate these cellular processes under chemotherapy-treated conditions. This review also discusses molecular targets that are being used clinically or are currently under investigation for preserving the bone marrow microenvironment during or enhancing recovery after chemotherapy.

One of the most intriguing enzymes of sphingolipid biology is acid sphingomyelinase (ASMase). In a phospholipase C reaction, ASMase catalyzes the cleavage of the phosphocholine head group of sphingomyelin to generate ceramide. Cumulative efforts of various laboratories over the past 40 years have placed ASMase and its product ceramide at the forefront of lipid research. Activation of the ASMase/ceramide pathway is a shared response to an ever-growing list of receptor and non-receptor mediated forms of cellular stress including: death ligands (TNFα, TRAIL, Fas ligand), cytokines (IL-1, IFNγ), radiation, pathogenic infections, cytotoxic agents and others. The strategic role of ASMase in lipid metabolism and cellular stress response has sparked interest in investigatig the molecular mechanisms underlying ASMase activation. In this article, we review the translational role of the ASMase/ceramide pathway and recent advances on its mechanisms of regulation.

When considered together, enterohepatic tumours, i.e., those affecting the liver, the biliary tree and gallbladder and the intestine, constitute the first cause of death due to cancer. Although in many cases surgery and radiotherapy are efficacious, these therapeutic strategies cannot always be implemented. Moreover, even when the removal of tumours is possible, pre- and post-operative pharmacological adjuvant regimens are often needed. However, one important limitation to the use of cytostatic drugs to treat enterohepatic tumours is that they generally exhibit marked refractivity to currently available pharmacological approaches. In addition, most of them increase their chemoresistance during treatment. In view of the high refractivity of these tumours to anti-cancer drugs and the existence of undesirable side effects, both of which are drawbacks in the available chemotherapy, several novel therapeutic approaches have been devised. The purpose of the present review is to offer some insight into the different types of strategies that have already been evaluated and incorporated into clinical practice, such as therapies based on the use of molecular targets, as well as into the approaches that are still under experimental development, such as the chemosensitization of cancer cells, genetic manipulation of tumour or host cells, and cell-specific enhancement of intracellular concentrations of the active agent by efficient targeting of pro-drugs or by using inhibitors of efflux pumps.

Inflammatory bowel diseases (IBD) are common inflammatory disorders of the gastrointestinal tract that include ulcerative colitis (UC) and Crohn's disease (CD). The incidences of IBD are high in North America and Europe, affecting as many as one in 500 people. These diseases are associated with high morbidity and mortality. Colorectal cancer risk is also increased in IBD, correlating with inflammation severity and duration. IBD are now recognized as complex multigenetic disorders involving at least 32 different risk loci. In 2007, two different autophagy-related genes, ATG16L1 (autophagy-related gene 16-like 1) and IRGM (immunity-related GTPase M) were shown to be specifically involved in CD susceptibility by three independent genome-wide association studies. Soon afterwards, more than forty studies confirmed the involvement of ATG16L1 and IRGM variants in CD susceptibility and gave new information on the importance of macroautophagy (hereafter referred to as autophagy) in the control of infection, inflammation, immunity and cancer. In this review, we discuss how such findings have undoubtedly changed our understanding of CD pathogenesis. A unifying autophagy model then emerges that may help in understanding the development of CD from bacterial infection, to inflammation and finally cancer. The Pandora's box is now open, releasing a wave of hope for new therapeutic strategies in treating Crohn's disease.

The discovery of miRNAs and the establishment of it's clinical links with multiple diseases have led to a paradigm shift in the drug development pipeline of major pharmaceutical companies and has given birth to several biotechnology enterprises revolving around these magic molecules. The miRNA profiling studies over the last few years have indicated implicit involvement of miRNAs in the pathobiology of cancer, diabetes, infectious diseases as well as cardiovascular, neurological and immune system disorders. This information is currently being translated into tools for diagnosis, prognosis and predicting response to treatment. In addition, active and vigorous investigations are ongoing in several laboratories across academia and industry to decipher the precise molecular functions and mechanism of action for key miRNAs with therapeutic potential. Knowledge gained from these efforts will surely pave the way for designing effective R&D strategies and will revolutionize the way we diagnose and treat various diseases. The present review attempts to track the evolutionary progression of microRNA research from it's early infancy years to its maturity into a dynamic field of drug discovery.

Long interspersed nuclear elements (LINEs) are mobile sequences shown to play a fundamental role in eukaryotic genome evolution. Recently, increasing interest has been directed at unveiling molecular mechanisms by which LINE-1 (L1), a ubiquitous member of this family, regulates gene expression and mammalian cell development, differentiation, and cancer. This mini review summarizes recent studies conducted to examine stress-induced L1 reactivation, with special attention given to the role of E2F/Rb transcription factors in epigenetic silencing of L1 and its potential role as a global modifier of chromatin structure and function. The last section focuses on the impact of histone deacetylase inhibitors in the regulation of gene function, chromatin structure, and cancer treatment through alterations in epigenetic signaling.