Cell competition and its implications for development and cancer

Cell competition is a struggle for existence between cells in heterogeneous tissues of multicellular organisms.Loser cells,which die during cell competition,are normally viable when grown only with other loser cells,but when mixed with winner cells,they are at a growth disadvantage and undergo apoptosis.Intriguingly,several recent studies have revealed that cells bearing mutant tumor-suppressor genes,which show overgrowth and tumorigenesis in a homotypic situation,are frequently eliminated,through cell competition,from tissues in which they are surrounded by wild-type cells.Here,we focus on the regulation of cellular competitiveness and the mechanism of cell competition as inferred from two different categories of mutant cells:(1) slower-growing cells and (2) structurally defective cells.We also discuss the possible role of cell competition as an intrinsic homeostasis system through which normal cells sense and remove aberrant cells,such as precancerous cells,to maintain the integrity and normal development of tissues and organs.     

RECKing MMP function: implications for cancer development

Cancer is a multistage process requiring progressive genetic and epigenetic changes in neoplastic and responding stromal cells. Many alterations that occur during the process of malignant progression are regulated by the matrix metalloproteinase (MMP) family of extracellular proteases and their endogenous inhibitors. Recent work has identified a new cell-surface inhibitor of MMPs - RECK. RECK regulates MMP-induced pericellular signaling cascades during embryogenesis and tumorigenesis. Homozygous loss of RECK results in embryonic lethality and attenuated tumor development in adults - thus providing further support for an efficacious role for protease inhibitors as anticancer therapeutics.     

Cell polarity in development and cancer

The development of cancer is a multistep process in which the DNA of a single cell accumulates mutations in genes that control essential cellular processes. Loss of cell-cell adhesion and cell polarity is commonly observed in advanced tumours and correlates well with their invasion into adjacent tissues and the formation of metastases. Growing evidence indicates that loss of cell-cell adhesion and cell polarity may also be important in early stages of cancer. The strongest hints in this direction come from studies on tumour suppressor genes in the fruitfly Drosophila melanogaster, which have revealed their importance in the control of apical-basal cell polarity.     

Intra-guild competition and its implications for one of the biggest terrestrial predators, Tyrannosaurus rex

Identifying tradeoffs between hunting and scavenging in an ecological context is important for understanding predatory guilds. In the past century, the feeding strategy of one of the largest and best-known terrestrial carnivores, Tyrannosaurus rex, has been the subject of much debate: was it an active predator or an obligate scavenger? Here we look at the feasibility of an adult T. rex being an obligate scavenger in the environmental conditions of Late Cretaceous North America, given the size distributions of sympatric herbivorous dinosaurs and likely competition with more abundant small-bodied theropods. We predict that nearly 50 per cent of herbivores would have been within a 55–85 kg range, and calculate based on expected encounter rates that carcasses from these individuals would have been quickly consumed by smaller theropods. Larger carcasses would have been very rare and heavily competed for, making them an unreliable food source. The potential carcass search rates of smaller theropods are predicted to be 14–60 times that of an adult T. rex. Our results suggest that T. rex and other extremely large carnivorous dinosaurs would have been unable to compete as obligate scavengers and would have primarily hunted large vertebrate prey, similar to many large mammalian carnivores in modern-day ecosystems.     

Cell wall biochemistry in Archaea and its phylogenetic implications

Cellularization of a precellular ancestral condition of life must have occured separately for each of the three domains of life resulting in a protoarchaeon, a protobacterium and a protocaryon. Accordingly, a first cell, ancestral to the three domains of life has never existed. This statement is based on a retrospective evaluation of the distribution patterns of membrane lipids and of cell wall polymers with their different chemical nature and modes of biosynthesis in a global phylogenetic tree based on 16S rRNA sequence comparison.Dedicated to Professor Peter Sitte on the occasion of his 65th birthday.     

固定化细胞技术及其应用研究进展

细胞固定技术是将具有特定生理功能的生物细胞用一定的方法进行固定,并以其作为生物催化剂加以利用的一门技术。相对于游离的单细胞,固定化细胞可简化生产工艺,降低生产成本。本文回顾了细胞固定技术在制备方法和载体材料等方面的研究进展,并总结了近几年来固定化细胞技术在新能源开发、食品加工及环境污染物处理中的应用,对其发展前景进行展望。     

Glycosylation and its implications in breast cancer

Introduction: For decades, the role of glycans and glycoproteins in the progression of breast cancer and other cancers have been evaluated. Through extensive studies focused on elucidating the biological functions of glycosylation, researchers have been able to implicate alterations in these functions to tumor formation and metastasis.

Areas covered: In this review, we summarize how changes in glycosylation are associated with tumorigenesis, with emphasis on breast cancers. An overview of the changes in N-linked and O-linked glycans associated with breast cancer tumors and biofluids are described. Recent advances in glycomics are emphasized in the context of continuing to decipher the glycosylation changes associated with breast cancer progression.

Expert opinion: While changes in glycosylation have been studied in breast cancer for many years, the clinical relevance of these studies has been limited. This reflects the inherent biological and clinical heterogeneity of breast cancers. Glycomics analysis lags behind the advances in genomics and proteomics, but new approaches are emerging. A summary of known glycosylation changes associated with breast cancer is necessary to implement new findings in the context of clinical outcomes and therapeutic strategies. A better understanding of the dynamics of tumor and immune glycosylation is critical to improving emerging immunotherapeutic treatments.     

Novel oncogene HCCR: its diagnostic and therapeutic implications for cancer

Identification of robust diagnostic and therapeutic target molecules for human malignancy is still an important issue. If we identify novel proteins which play a stem-line role for cellular transformation or aggravation of malignancy, it could give us a clue to diagnose a tumor in an earlier stage and to develop more reliable therapeutic tools. For this purpose, we have screened abnormally expressed genes in various human cancers by differential display RT-PCR. One of the overexpressed genes was a human cervical cancer oncogene (HCCR). HCCR was not only identified in cervical cancer tissues, but also found to be overexpressed in various human malignancies such as leukemia/lymphoma, breast, kidney, stomach, colon, liver and ovarian cancer. This molecule appeared to be a negative regulator of p53. In this paper, we discuss the biological functions of HCCR molecules and its implications for early diagnosis and future development of therapeutic devices of cancer.     

The Warburg effect and its cancer therapeutic implications

Increased aerobic glycolysis in cancer, a phenomenon known as the Warburg effect, has been observed in various tumor cells and represents a major biochemical alteration associated with malignant transformation. Although the exact molecular mechanisms underlying this metabolic change remain to be elucidated, the profound biochemical alteration in cancer cell energy metabolism provides exciting opportunities for the development of therapeutic strategies to preferentially kill cancer cells by targeting the glycolytic pathway. Several small molecules capable of inhibiting glycolysis in experimental systems have been shown to have promising anticancer activity in vitro and in vivo. This review article provides a brief summary of our current understanding of the Warburg effect, the underlying mechanisms, and its influence on the development of therapeutic strategies for cancer treatment.     

Subsite specificity of anthrax lethal factor and its implications for inhibitor development

The lethal factor of Bacillus anthracis is a major factor for lethality of anthrax infection by this bacterium. With the aid of the protective antigen, lethal factor gains excess to the cell cytosol where it manifests toxicity as a metalloprotease. For better understanding of its specificity, we have determined its residue preferences of 19 amino acids in six subsites (from P3 to P3′) as relative k_cat/K_m values (specificity constants). These results showed that lethal factor has a broad specificity with preference toward hydrophobic residues, but not charged or branched residues. The most preferred residues in these six subsites are, from P1 to P3′, Trp, Leu, Met, Tyr, Pro, and Leu. The result of residue preference was used to design new substrates with superior hydrolytic characteristics and inhibitors with high potency. For better use of the new findings for inhibitor design, we have modeled the most preferred residues in the active site of lethal factor. The observed interactions provide new insights to future inhibitor designs.     

The intensity of competition versus its importance: an overlooked distinction and some implications

The intensity of competition is a physiological concept, related directly to the well-being of individual organisms but only indirectly and conditionally to their fitness, and even more indirectly to the evolution of populations and the structure of communities. The importance of competition is primarily an ecological and evolutionary concept, related directly to the ecology and fitness of individuals but only indirectly to their physiological states. The intensity of competition is not necessarily correlated with the intensities of predation, disturbance, abiotic stress, or other ecological processes. The importance of competition is necessarily relative to the importances of other processes. Intensity refers primarily to the process of present competition, whereas importance refers primarily to the products of past competition. The distinction between the intensity and the importance of competition clarifies two long-standing ecological debates. Some ecologists have proposed that competition is greater in more stressful habitats, others the opposite, and still others that no such relationship exists. Evidence cited to refute or support these positions often confuses intensity and importance. Distinguishing between them focuses questions more sharply and indicates what sorts of new evidence should be sought. The more widely known debate over the prevalence of competition as an agent of community structure is a debate about the importance of competition, but evidence about the intensity of competition has often been used by both sides. We argue that intensity and importance need not be correlated, and so measurements of the intensity of competition are not directly relevant to this debate. This distinction also generates testable hypotheses and suggests directions for research. For example, we hypothesize that competition can be unimportant even if it is very intense: no such hypothesis is possible unless importance is distinguished from intensity. We discuss the application of these ideas to methods and theories used to study competition, ecological communities, and the evolution of competitive ability. We advocate a research approach that presumes multiple, interacting causes, including competition, affecting community structure, and we show how the distinction between intensity and importance helps to make this feasible.     

Cell death pathology: cross-talk with autophagy and its clinical implications

Autophagy is a self-digesting mechanism that cells adopt to respond to stressful stimuli. Morphologically, cells dying by autophagy show multiple cytoplasmic double-membraned vacuoles, and, if prolonged, autophagy can lead to cell death, “autophagic cell death”. Thus, autophagy can act both as a temporary protective mechanism during a brief stressful episode and be a mode of cell death in its own right. In this mini-review we focus on recent knowledge concerning the connection between autophagy and programmed cell death, evaluating their possible implications for therapy in pathologies like cancer and neurodegeneration.     

MicroRNA-regulated stress response in cancer and its clinical implications

The precise coordination of the different steps of DNA replication is critical for the maintenance of genome stability. We have probed the mechanisms coupling various components of the replication machinery and their response to polymerase stalling by inhibition of the DNA polymerases in living mammalian cells with aphidicolin. We observed little change in the behaviour of proteins involved in the initiation of DNA replication. In contrast, we detected a marked accumulation of the single stranded DNA binding factor RPA34 at sites of DNA replication. Finally, we demonstrate that proteins involved in the elongation step of DNA synthesis dissociate from replication foci in the presence of aphidicolin. Taken together, these data indicate that inhibition of processive DNA polymerases uncouples the initiation of DNA replication from subsequent elongation steps. We, therefore, propose that the replication machinery is made up of distinct functional sub-modules that allow a flexible and dynamic response to challenges during DNA replication.     

Ethnic differences in cytokine gene polymorphisms: potential implications for cancer development

Differences in incidence and outcome of cancer among ethnic groups may be explained by biological and/or socio-economic factors. Genetic variations that affect chronic inflammation, a potentially important risk factor for carcinogenesis, may differ across ethnic groups. Such differences may help explain cancer disparities among these groups. Single nucleotide polymorphisms (SNPs) within cytokine genes can affect cytokine levels and the degree of inflammation. Associations between cancer and some cytokine SNPs have been suggested. However, these have not been consistently replicated among populations, suggesting that SNP function may differ according to ethnicity, or that SNPs alone do not completely account for regulation of inflammation. We examined seven polymorphisms in African-American (n = 294) and Caucasian (n = 299) newborns in Louisiana: IL1B-511C > T, IL1B-31T > C, IL1B + 3954C > T, IL1RN*2, IL10-1082G > A, IL10-592C > A, and TNF-308G > A. African-American newborns had significantly higher frequencies of IL1B-511T, IL1B-31C, IL10-1082A and IL10-592A alleles and complete linkage equilibrium between IL1B + 3954 and IL1B-31. In contrast, IL1B + 3954T, IL1RN*2, and TNF-308A were more frequent in Caucasian newborns and exhibited strong linkage disequilibrium between IL1B + 3954 and IL1B-31. All allelic frequencies were significantly different between groups. We hypothesize that these dissimilarities may contribute to differences in the inflammatory response and cancer incidence and mortality between African-Americans and Caucasians in Louisiana.