Interactions between normal and transformed epithelial cells: Their contributions to tumourigenesis

During the initial stages of carcinogenesis, neoplastic transformation occurs in single epithelial cells and the transformed cells proliferate while being surrounded by normal epithelia. In Drosophila, normal and transformed epithelial cells compete with each other for survival, a process called cell competition. However, it was not known whether comparable phenomena also occur in mammals. Recently, several reports have shown that the interaction between normal and transformed epithelial cells causes various phenomena in mammals. For example, with elaborate cell culture systems that express oncoproteins or knockdown tumour suppressor proteins in an inducible manner, certain types of transformed cells have been shown to be apically eliminated from normal epithelial layers in an apoptosis-dependent or -independent manner. During the process of apical extrusion, various signalling pathways are modulated in transformed cells located within the normal epithelium, indicating that the presence of surrounding normal epithelial cells affects the behaviour and fate of transformed cells. Recent studies in mice have also shown that normal and transformed cells can compete with each other for survival during several processes such as liver regeneration. In this review, we will introduce these recent publications on interactions between normal and transformed mammalian epithelial cells. Furthermore, we will discuss how these studies can potentially lead to identification of biomarkers for precancerous cells and to invention of novel types of cancer prevention and treatment.     

Optimized methods for imaging membrane nanotubes between T cells and trafficking of HIV-1

A wide variety of cell types, including immune cells, have been observed to frequently interact via transient, long-distance membrane connections [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. However, considerable heterogeneity in their structure, mode of formation and functional properties has emerged, suggesting the existence of distinct subclasses [18], [19], [20], [21]. Open-ended tunneling nanotubes allow for the trafficking of cytoplasmic material, e.g. endocytic vesicles, or the transmission of calcium signals [1], [8]. Closed-ended membrane nanotubes do not seamlessly connect the cytoplasm between two interacting cells and a junction exists within the nanotube or where the nanotube meets a cell body [4], [5], [7]. Recent live cell imaging suggested that membrane nanotubes between T cells could present a novel route for HIV-1 transmission [7], [22]. Here, we describe detailed protocols for observing membrane nanotubes and HIV-1 trafficking by live cell fluorescence microscopy.     

Molecular architecture of mouse activating NKR-P1 receptors

Receptors belonging to NKR-P1 family and their specific Clr ligands form an alternative missing self recognition system critical in immunity against tumors and viruses, elimination of tumor cells subjected to genotoxic stress, activation of T cell dependent immune response, and hypertension. The three-dimensional structure of the extracellular domain of the mouse natural killer (NK) cell receptor mNKR-P1Aex has been determined by X-ray diffraction. The core of the C-type lectin domain (CTLD) is homologous to the other CTLD receptors whereas one quarter of the domain forms an extended loop interacting tightly with a neighboring loop in the crystal. This domain swapping mechanism results in a compact interaction interface. A second dimerization interface resembles the known arrangement of other CTLD NK receptors. A functional dimeric form of the receptor is suggested, with the loop, evolutionarily conserved within this family, proposed to participate in interactions with ligands.     

Organic nutrient uptake by mycorrhizal fungi enhances ecosystem carbon storage: a model-based assessment

Understanding the factors that drive soil carbon (C) accumulation is of fundamental importance given their potential to mitigate climate change. Much research has focused on the relationship between plant traits and C sequestration, but no studies to date have quantitatively considered traits of their mycorrhizal symbionts. Here, we use a modelling approach to assess the contribution of an important mycorrhizal fungal trait, organic nutrient uptake, to soil C accumulation. We show that organic nutrient uptake can significantly increase soil C storage, and that it has a greater effect under nutrient-limited conditions. The main mechanism behind this was an increase in plant C fixation and subsequent increased C inputs to soil through mycorrhizal fungi. Reduced decomposition due to increased nutrient limitation of saprotrophs also played a role. Our results indicate that direct uptake of nutrients from organic pools by mycorrhizal fungi could have a significant effect on ecosystem C cycling and storage.     

The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile

Nosocomial infections are increasingly being recognised as a major patient safety issue. The modern hospital environment and associated health care practices have provided a niche for the rapid evolution of microbial pathogens that are well adapted to surviving and proliferating in this setting, after which they can infect susceptible patients. This is clearly the case for bacterial pathogens such as Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Enterococcus (VRE) species, both of which have acquired resistance to antimicrobial agents as well as enhanced survival and virulence properties that present serious therapeutic dilemmas for treating physicians. It has recently become apparent that the spore-forming bacterium Clostridium difficile also falls within this category. Since 2000, there has been a striking increase in C. difficile nosocomial infections worldwide, predominantly due to the emergence of epidemic or hypervirulent isolates that appear to possess extended antibiotic resistance and virulence properties. Various hypotheses have been proposed for the emergence of these strains, and for their persistence and increased virulence, but supportive experimental data are lacking. Here we describe a genetic approach using isogenic strains to identify a factor linked to the development of hypervirulence in C. difficile. This study provides evidence that a naturally occurring mutation in a negative regulator of toxin production, the anti-sigma factor TcdC, is an important factor in the development of hypervirulence in epidemic C. difficile isolates, presumably because the mutation leads to significantly increased toxin production, a contentious hypothesis until now. These results have important implications for C. difficile pathogenesis and virulence since they suggest that strains carrying a similar mutation have the inherent potential to develop a hypervirulent phenotype.