Brucella: a Mr "Hide" converted into Dr Jekyll

Dr David Bruce (1855-1931) first identified the causative agent of brucellosis as a small Gram-negative alpha-Proteobacterium, which was later on called Brucella melitensis in his honor by Meyer and Shaw. Nowadays, four strains exhibit pathogenicity in humans with B. melitensis being the least host specific and also the most infectious for humans. The other strains are Brucella suis and Brucella abortus and more recently human cases being infected with Brucella cetaceae have been reported. Why such a reemerging disease is so difficult to fight, evidence shows that the pathogenic bacterium has developed strategies to hide from immune recognition.     

Acanthamoeba differentiation: a two-faced drama of Dr Jekyll and Mr Hyde

The ability of cyst-forming protists such as Acanthamoeba to escape death by transforming into a cyst form, that is resistant to harsh physiological, environmental and pharmacological conditions, has continued to pose a serious challenge to human and animal health. A complete understanding of the fundamental principles of genome evolution and biochemical pathways of cellular differentiation offers unprecedented opportunities to counter detrimental outcomes. Acanthamoeba can elude inhospitable conditions by forming cysts. Here we unravel the processes involved in the phenotypic switching of Acanthamoeba, which are critical in our efforts to find potential targets for chemotherapy.     

Playing Dr Jekyll and Mr Hyde: combined mechanisms of phase variation in bacteria

Phase variation is the adaptive process by which bacteria undergo frequent and reversible phenotypic changes resulting from genetic alterations in specific loci of their genomes. This process is crucial for the survival of pathogens and commensals in hostile and ever-changing host environments. Despite important differences in the molecular mechanisms that mediate and regulate phase variation, related strategies have evolved to generate high levels of genetic diversity through complex and combinatorial reshuffling of genetic information. Recent studies, supported by the emergence of global genomic approaches, have revealed that bacterial pathogens often use a combination of different mechanisms to vary the expression of a variety of biological functions, providing new insights into bacterial adaptation and virulence mechanisms. Recent advances in the understanding of the molecular mechanisms of phase variation are reviewed, and differences in these mechanisms outlined.     

Catalytic antibodies: balancing between Dr. Jekyll and Mr. Hyde

The immunoglobulin molecule is a perfect template for the de novo generation of biocatalytic functions. Catalytic antibodies, or abzymes, obtained by the structural mimicking of enzyme active sites have been shown to catalyze numerous chemical reactions. Natural enzyme analogs for some of these reactions have not yet been found or possibly do not exist at all. Nowadays, the dramatic breakthrough in antibody engineering and expression technologies has promoted a considerable expansion of immunoglobulin's medical applications and is offering abzymes a unique chance to become a promising source of high‐precision “catalytic vaccines.” At the same time, the discovery of natural abzymes on the background of autoimmune disease revealed their beneficial and pathogenic roles in the disease progression. Thus, the conflicting Dr. Jekyll and Mr. Hyde protective and destructive essences of catalytic antibodies should be carefully considered in the development of therapeutic abzyme applications.     

Dr. Jekyll and Mr. Hyde: A short history of anthrax

The anthrax letters crisis, following the discovery of a major bacterial warfare program in the USSR and the realization that Irak had been on the verge of using anthrax as a weapon during the first Gulf war, had the consequence of putting anthrax back on the agenda of scientists. Fortunately, although it was mostly unknown by the public before these events, it was far from unknown by microbiologists. Already mentioned in the bible as a disease of herbivores, it remained a major cause of death for animals all over the planet until the end of the 19th century, with occasional, sometimes extensive, contamination of human beings. The aetiological agent, Bacillus anthracis, was identified by French and German scientists in the 1860s and 1870s. This was the first time that a disease could be attributed to a specific microorganism. The discovery by Koch that this bacterium formed spores greatly contributed to the understanding of the disease epidemiology. Studies on the pathophysiology of anthrax led to the identification of two major virulence factors, the capsule, protecting the bacilli against phagocytosis, and a tripartite toxin. The latter consists of two toxins with a common component (protecting antigen, PA) that allows the binding to and penetration into cells of two enzymes, the oedema factor EF, a calmodulin dependent adenylate cyclase, and the lethal factor LF, a specific zinc metalloprotease. The primary targets of these toxins would seem to be cells of innate immunity that would otherwise impair multiplication of the bacilli. If detected early enough, B. anthracis infections can be stopped by using antibiotics such as ciprofloxacin. Infection of animals can be prevented by the administration of vaccines, the first of which was developed by Pasteur after an historical testing at Pouilly-le-Fort which marked the beginning of the science of vaccines.     

Acute pancreatitis: proteinase-activated receptor-2 as Dr. Jekyll and Mr. Hyde

"Proteinase-activated" receptor-2 (PAR-2) is a G protein-coupled transmembrane receptor with seven transmembrane domains activated by trypsin. It has been shown in the pancreatic tissue that PAR-2 is involved in duct/acinary cells secretion, arterial tonus regulation and capillary liquid content turnover under physiological conditions. These above mentioned structures play an important role during the development of acute pancreatitis and are profoundly influenced by a high concentration of trypsin enzyme after its secretion into the interstitial tissue from the basolateral aspect of acinar cells. Among the other factors, it is the increase of interstitial trypsin concentration followed rapidly by PAR-2 action on pancreatic vascular smooth muscle cells that initiates ischemic changes in pancreatic parenchyma and that finally leads to necrosis of the pancreas. Consequent reperfusion perpetuates changes leading to the acute pancreatitis development. On the contrary, PAR-2 action on both exocrine and duct structures seems to play locally a protective role during acute pancreatitis development. Moreover, PAR-2 action is not confined to the pancreas but it contributes to the systemic vascular endothelium and immune cell activation that triggers the systemic inflammatory response syndrome (SIRS) contributing to an early high mortality rate in severe disease.     

The brain microenvironment and cancer metastasis

The process of metastasis consists of a series of sequential, selective steps that few cells can complete. The outcome of cancer metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that are unique to one or another organ microenvironment. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion and survival. Many lung cancer, breast cancer, and melanoma patients develop fatal brain metastases that do not respond to therapy. The blood-brain barrier is intact in and around brain metastases that are smaller than 0.25 mm in diameter. Although the blood-brain barrier is leaky in larger metastases, the lesions are resistant to many chemotherapeutic drugs. Activated astrocytes surround and infiltrate brain metastases. The physiological role of astrocytes is to protect against neurotoxicity. Our current data demonstrate that activated astrocytes also protect tumor cells against chemotherapeutic drugs.     

The organ microenvironment and cancer metastasis

Primary neoplasms are biologically heterogeneous and the process of metastasis consists of a series of sequential, selective steps that few cells can complete. The outcome of cancer metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that are unique to one or another organ microenvironment. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion, and survival. Therapy of metastasis should therefore be targeted not only against tumor cells, but also against the host factors that contribute to and support the progressive growth and survival of metastatic cancer cells.     

Occupy tissue: The movement in cancer metastasis

The critical role of migration and invasion in cancer metastasis warrants new therapeutic approaches targeting the machinery regulating cell migration and invasion. While 2-dimensional (2D) models have helped identify a range of adhesion molecules, cytoskeletal components and regulators that are potentially important for cell migration, the use of models that better mimic the 3-dimensional (3D) environment has yielded new insights into the physiology of cell movement. For example, studying cells in 3D models has revealed that invading cancer cells may switch between heterogeneous invasion modes and thus evade pharmacological inhibition of invasion. Here we summarize published data in which the role of cell adhesion molecules in 2D vs. 3D migration have been directly compared and discuss mechanisms that regulate migration speed and persistence in 2D and 3D. Finally we discuss limits of 3D culture models to recapitulate the in vivo �situation.     

The role of lipids in cancer progression and metastasis

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The importance of regulatory ubiquitination in cancer and metastasis

Ubiquitination serves as a degradation mechanism of proteins, but is involved in additional cellular processes such as activation of NFκB inflammatory response and DNA damage repair. We highlight the E2 ubiquitin conjugating enzymes, E3 ubiquitin ligases and Deubiquitinases that support the metastasis of a plethora of cancers. E3 ubiquitin ligases also modulate pluripotent cancer stem cells attributed to chemotherapy resistance. We further describe mutations in E3 ubiquitin ligases that support tumor proliferation and adaptation to hypoxia. Thus, this review describes how tumors exploit members of the vast ubiquitin signaling pathways to support aberrant oncogenic signaling for survival and metastasis.     

The role of laminin in cancer invasion and metastasis

Laminin, a basement membrane glycoprotein, has been implicated in a number of stages in tumour invasion and metastasis. In addition to its roles in cell adhesion and migration, laminin may be important in mediating interactions of tumour cells with the immune system and have more subtle roles in controlling metastatic behaviour. Recent work on the prognostic significance of laminin and the possible role of the molecule in antimetastasis therapy will also be discussed.