DNA tumour viruses promote tumour cell invasion and metastasis by deregulating the normal processes of cell adhesion and motility

Approximately 15-20% of global cancer incidence is causally linked to viral infection, yet the low incidence of cancers in healthy infected individuals suggests that malignant conversion of virus-infected cells occurs after a long period as a result of additional genetic modifications. There are four families of viruses that are now documented to be involved in the development of human cancers which include members of the polyomavirus, hepadnavirus, papillomavirus and herpesvirus families. Although a number of these viruses are implicated in the aetiology of lymphomas or leukaemias, the vast majority are associated with malignancies of epithelial cells. In epithelial tissues, several classes of proteins are involved in maintaining tissue architecture, including those that promote cell-cell adhesion, and others, which mediate cell-matrix interactions. Proteins representative of all classes are frequently altered in malignant tumour cells that possess invasive and metastatic properties. Malignant tumour cells acquire mechanisms to degrade basement membranes and invade the underlying tissue. Many viruses encode proteins which engage signalling pathways that affect one or more of these mechanisms. It is believed that activation of these processes by chronic viral infection can, under certain circumstances, promote tumour cell invasion and metastasis. This review will take a brief look at the current knowledge of viral-induced alterations in cell motility and invasiveness in the context of tumour invasion and metastasis.     

Managing genetic variation in tropical trees: linking knowledge with action in agroforestry ecosystems for improved conservation and enhanced livelihoods

Tree species in agroforestry ecosystems contribute to the livelihoods of rural communities and play an important role in the conservation of biodiversity. Unless agroforestry landscapes are productive, however, farmers will not maintain or enhance the range and quality of tree species in them, and both income opportunities and biodiversity will be lost. Productivity depends on both tree species diversity and genetic (intra-specific) variation, but research on the latter has until recently not received the recognition it deserves. Worse, when knowledge on tree genetic variation in agroforestry systems has become available, it has not generally been linked in any systematic way with management, indicating a disjunction between research and field-level practice. In this essay, we attempt to bridge this gap by considering three questions: why is genetic diversity important in tree species? What is our current state of knowledge about intra-specific variation in trees in agroforestry systems? And, finally, what practical interventions are possible to support the conservation of this diversity in agricultural landscapes, while enhancing farmers’ livelihoods? A wide genetic base in agroforestry trees is essential to prevent inbreeding depression and allow adaptation to changing environmental conditions and to altering markets for tree products. Recent evidence shows, however, that many species are subject to poor germplasm collection practice, occur at low densities in farmland, and are found in highly aggregated distributions, all of which observations raise concerns about productivity and sustainability. A range of germplasm-access based interventions is necessary to improve current management, including the enhancement of community seed- and seedling-exchange networks, and the development of locally based tree domestication activities. Equally necessary, but more difficult to address, is the development of markets that support genetic diversity in tropical tree species; we discuss approaches by which this may be undertaken.     

Nitric oxide protects cardiac sarcolemmal membrane enzyme function and ion active transport against ischemia-induced inactivation

Nitric oxide (NO.) generated from nitric oxide synthase (NOS) isoforms bound to cellular membranes may serve to modulate oxidative stresses in cardiac muscle and thereby regulate the function of key membrane-associated enzymes. Ischemia is known to inhibit the function of sarcolemmal enzymes, including the (Na+ + K+)-ATPase, but it is unknown whether concomitant injury to sarcolemma (SL)-associated NOS isoforms may contribute to this process by reducing the availability of locally generated NO. Here we report that nNOS, as well as eNOS (SL NOSs), are tightly associated with cardiac SL membranes in several different species. In isolated perfused rat hearts, global ischemia caused a time-dependent irreversible injury to cardiac SL NOSs and a disruption of SL NO. generation. Pretreatment with low concentrations of the NO. donor 1-hydroxy-2-oxo-3-(N-3-methyl-aminopropyl)-3-methyl-1-triazene (NOC-7) markedly protected both SL NOS and (Na+ + K+)-ATPase functions against ischemia-induced inactivation. Moreover, ischemia impaired SL Na+/K+ binding, and NOC-7 significantly prevented ischemic injury to the ion binding sites on (Na+ + K+)-ATPase. These novel findings indicate that NO. can protect cardiac SL NOSs and (Na+ + K+)-ATPase against ischemia-induced inactivation and suggest that locally generated NO. may serve to regulate SL Na+/K+ ion active transport in the heart.     

Some characteristics and antibiotic resistance of anaerobic bacteria from the ceca and colons of pigs fed chlortetracycline-containing and unmedicated diets.

Morphology and end product patterns were used to group 112 bacterial isolates from the ceca and colons of pigs fed unmedicated and chlortetracycline-containing diets. Most of the isolates (68%) were resistant to chlortetracycline (greater than 4 micrograms/ml). Chlortetracycline resistance was associated with all groups of anaerobic and facultative bacteria.     

Osmotic Regulation Is Required for Cancer Cell Survival under Solid Stress

For a solid tumor to grow, it must be able to support the compressive stress that is generated as it presses against the surrounding tissue. Although the literature suggests a role for the cytoskeleton in counteracting these stresses, there has been no systematic evaluation of which filaments are responsible or to what degree. Here, using a three-dimensional spheroid model, we show that cytoskeletal filaments do not actively support compressive loads in breast, ovarian, and prostate cancer. However, modulation of tonicity can induce alterations in spheroid size. We find that under compression, tumor cells actively efflux sodium to decrease their intracellular tonicity, and that this is reversible by blockade of sodium channel NHE1. Moreover, although polymerized actin does not actively support the compressive load, it is required for sodium efflux. Compression-induced cell death is increased by both sodium blockade and actin depolymerization, whereas increased actin polymerization offers protective effects and increases sodium efflux. Taken together, these results demonstrate that cancer cells modulate their tonicity to survive under compressive solid stress.     

Expression of actin mutants to study their roles in cardiomyopathy

Mutations in the human cardiac actin gene (ACTC) have been implicated in the development of hypertrophic or dilated cardiomyopathy in humans. To determine the molecular mechanism for the disease development, a system for the expression of mutant cardiac actin proteins that may be lethal to eukaryotic cells must be developed. Here, we explore some of the advantages and disadvantages of human ACTC expression in yeast and insect cells. We show that human ACTC is incapable of rescuing a yeast endogenous actin (ACT1)-knockout in yeast cells and that coexpression of human ACTC in yeast results in slower growth, making yeast an unsuitable expression system. However, we show that it is possible for yeast cells to express a polymerization-deficient ACTI mutant, thereby allowing us to examine the cell biology of this mutation in the future. Finally, mutant forms of human cardiac actin can be expressed in and purified from insect cells in a properly folded and functional form, permitting important characterization of the biochemical mechanisms responsible for cardiomyopathy development in humans. These studies allow for further research into the biochemical characteristics of previously untenable actin mutant proteins.     

Synthesis of myelin glycosphingolipids (galactosylceramide and galactosyl(3-O-sulfate)ceramide (sulfatide)) by cloned cell lines derived from mouse neurotumors

Clonal cell lines derived from both spontaneous and chemically induced rat and mouse brain tumors were screened for their ability to incorporate H232SO4 into galactosyl(3-O-sulfate)ceramide (sulfatide). High levels of 35SO4 incorporation into sulfatide were found only in two of the mouse cell lines studied (G26-20 and -24). Tumors produced by subcutaneous injection of these cell lines into C57BL/6 mice were also unique in that they contained high levels of both sulfatide and galactosylceramide. The synthesis of large amounts of sulfatide and galactosylceramide by a clonal cell line of neurological origin suggests that the original tumor was of oligodendrocyte or Schwann cell origin. In common with a large number of mouse and rat astrocyte cell strains and their derived tumors, these glial cells lacked the ability to synthesize gangliosides such as monosialotetraglycosylceramide and disialotetraglycosylceramide (as judged by analytical and [3H]GlcNH2 incorporation studies). This appears to be a unique characteristic of neuroblastoma-derived cell strains such as N18, NB2a, and NB41A.