Metastasis causes most cancer deaths, yet this process remains one of the most enigmatic aspects of the disease. Building on new mechanistic insights emerging from recent research, we offer our perspective on the metastatic process and reflect on possible paths of future exploration. We suggest that metastasis can be portrayed as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a metastatic lesion at that distant site. Although much remains to be learned about the second phase, we feel that an understanding of the first phase is now within sight, due in part to a better understanding of how cancer cell behavior can be modified by a cell-biological program called the epithelial-to-mesenchymal transition.

http://science.sciencemag.org/content/sci/331/6024/1559.full.pdf

A Perspective on Cancer Cell Metastasis

Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.

/pdf/growth-factors-matrices-and-forces-combine-and-control-stem-4daxw4e632.pdf

Growth Factors, Matrices, and Forces Combine and Control Stem Cells

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

Ageing as a risk factor for neurodegenerative disease.

One type of RNA editing converts adenosines to inosines (A-->I editing) in double-stranded RNA (dsRNA) substrates. A-->I RNA editing is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. A-->I RNA editing of protein-coding sequences of a limited number of mammalian genes results in recoding and subsequent alterations of their functions. However, A-->I RNA editing most frequently targets repetitive RNA sequences located within introns and 5' and 3' untranslated regions (UTRs). Although the biological significance of noncoding RNA editing remains largely unknown, several possibilities, including its role in the control of endogenous short interfering RNAs (esiRNAs), have been proposed. Furthermore, recent studies have revealed that the biogenesis and functions of certain microRNAs (miRNAs) are regulated by the editing of their precursors. Here, I review the recent findings that indicate new functions for A-->I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms.

/pdf/functions-and-regulation-of-rna-editing-by-adar-deaminases-1j7eq0l7wm.pdf

Functions and Regulation of RNA Editing by ADAR Deaminases

Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors--Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a--that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

Background 
Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.


Methods and Findings 
A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.


Conclusions 
This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

/pdf/donor-derived-brain-tumor-following-neural-stem-cell-1zi0hmywzy.pdf

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Metastatic tumours to the oral cavity – Pathogenesis and analysis of 673 cases

Polarization colors of various purified collagens were studied in fibers of similar thickness. Three different soluble collagens of type I, insoluble collagen type I, lathyritic collagen type I, two p-N-collagens type I, pepsin extract collagen type II, two soluble collagens type III, p-N-collagen type III, and soluble collagen type V were submitted to a routine histopathologic procedure of fixation, preparation of 5-microns-thick sections, staining with Picrosirius red and examination under crossed polars. Polarization colors were determined for thin fibers (0.8 micron or less) an thick fibers, (1.6-2.4 microns). Most thin fibers of collagens and p-N-collagens showed green to yellowish-green polarization colors with no marked differences between the various samples. Thick fibers of all p-N-collagens, lathyritic and normal 0.15 M NaCl-soluble collagens showed green to greenish-yellow polarization colors, while in all other collagens, polarization colors of longer wavelengths (from yellowish-orange to red) were observed. These data suggested that fiber thickness was not the only factor involved in determining the polarization colors of Picrosirius red-stained collagens. Tightly packed and presumably, better aligned collagen molecules showed polarization colors of longer wavelengths. Thus, packing of collagen molecules and not only fiber thickness plays a role in the pattern of polarization colors of Picrosirius red-stained collagens.

Are the polarization colors of picrosirius red-stained collagen determined only by the diameter of the fibers?

A review of the English language literature revealed 390 well-documented cases of metastatic lesions to the jawbones. Most metastatic lesions were diagnosed in patients in their fifth to seventh decade. The primary site differed between the genders: for women, it was the breast followed by the adrenal, colo-rectum, female genital organs and thyroid; for men, it was the lung, followed by the prostate, kidney, bone and adrenal. The most common location of the metastatic tumors was the mandible, with the molar area the most frequent site involved. In about 30% of cases the oral lesion was the first sign of the malignant disease. The present data are compared with those of metastatic tumors to the oral mucosa and a view on the possible pathogenesis is presented.

Metastatic tumors to the jawbones : analysis of 390 cases

A review of the English-language literature revealed 157 well-documented cases of metastatic lesions to the oral mucosa. Most (64%) were diagnosed in patients in their fifth to seventh decade. The frequency of the primary site differed between genders: for men it was the lung (35.5%) followed by the kidney (16%) and skin (15%); for women it was the breast (24%) followed by the genital organs (17%). The most common oral site was the gingiva and alveolar mucosa (54.8%) followed by the tongue (27.4%), and with much less frequency by the tonsil, palate, lip, buccal mucosa and floor of the mouth. Of the dentulous patients, 79% exhibited the metastatic tumor in the attached gingiva. The clinical appearance of the metastatic oral lesion in most cases resembled hyperplastic or reactive lesions.

Abraham Hirshberg

Papers

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Metastatic tumours to the oral cavity – Pathogenesis and analysis of 673 cases

Are the polarization colors of picrosirius red-stained collagen determined only by the diameter of the fibers?

Metastatic tumors to the jawbones : analysis of 390 cases

Metastases to the oral mucosa: analysis of 157 cases.