Plasticity of tumor cell migration: acquisition of new properties or return to the past?

During tumor development cancer cells pass through several stages when cell morphology and migration abilities change remarkably. These stages are named epithelial-mesenchymal and mesenchymal-amoeboid transitions. The molecular mechanisms underlying cell motility are changing during these transitions. As result of transitions the cells acquire new characteristics and modes of motility. Cell migration becomes more independent from the environmental conditions, and thus cell dissemination becomes more aggressive, which leads to formation of distant metastases. In this review we discuss the characteristics of each of the transitions, cell morphology, and the specificity of cellular structures responsible for different modes of cell motility as well as molecular mechanisms regulating each transition.     

Huntington’s disease: the coming of age

Huntington’s disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells. The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.     

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Mesenchymal stromal cells(MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC hominghas been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.     

Should I stay or should I go?: Shedding of RPTPs in cancer cells switches signals from stabilizing cell-cell adhesion to driving cell migration

Dissolution of cell-cell adhesive contacts and increased cell-extracellular matrix adhesion are hallmarks of the migratory and invasive phenotype of cancer cells. These changes are facilitated by growth factor binding to receptor protein tyrosine kinases (RTKs). In normal cells, cell-cell adhesion molecules (CAMs), including some receptor protein tyrosine phosphatases (RPTPs), antagonize RTK signaling by promoting adhesion over migration. In cancer, RTK signaling is constitutive due to mutated or amplified RTKs, which leads to growth factor independence or autonomy. An alternative route for a tumor cell to achieve autonomy is to inactivate cell-cell CAMs such as RPTPs. RPTPs directly mediate cell adhesion and regulate both cadherin-dependent adhesion and signaling. In addition, RPTPs antagonize RTK signaling by dephosphorylating molecules activated following ligand binding. Both RPTPs and cadherins are downregulated in tumor cells by cleavage at the cell surface. This results in shedding of the extracellular, adhesive segment and displacement of the intracellular segment, altering its subcellular localization and access to substrates or binding partners. In this commentary we discuss the signals that are altered following RPTP and cadherin cleavage to promote cell migration. Tumor cells both step on the gas (RTKs) and disconnect the brakes (RPTPs and cadherins) during their invasive and metastatic journey.Key words: receptor protein tyrosine kinase, receptor-like protein tyrosine phosphatase, cadherins, cell adhesion, signal transduction, phospholipase C gamma, protein kinase C, catenins, IQGAP1 protein, regulated intramembrane proteolysis     

A phenomenological model for chemico-mechanically induced cell shape changes during migration and cell–cell contacts

A phenomenological model for the evolution of shape transition of cells is considered. These transitions are determined by the emission of growth-factors, as well as mechanical interaction if cells are subjected to hard impingement. The originality of this model necessitates a formal treatment of the mathematical model, as well as the presentation of elementary cases in order to illustrate the consistence of the model. We will also show some small-scale relevant applications.     

APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration

Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3β (GSK-3β). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-β (TGFβ) and is known to inhibit various TGFβ-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGFβ stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3β kinases to facilitate local TGFβ/p38-dependent inactivation of GSK-3β, accumulation of β-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGFβ type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGFβ.     

Regulation of acetohydroxy acid synthase in Corynebacterium glutamicum during fermentation of α-ketobutyrate to l-isoleucine

Summary Corynebacterium glutamicum ATCC 13 032 produces 13 g/l l-isoleucine from 200 mM -ketobutyrate as a synthetic precursor. In fed batch cultures up to 19 g/l l-isoleucine is formed. For optimal conversion the addition of 0.3 mM l-valine plus 0.3 mM l-leucine to the fermentation medium is required. The affinity constants for the acetohydroxy acid synthase (AHAS) were determined. (This enzyme directs the flow of -ketobutyrate plus pyruvate towards l-isoleucine and that of two moles of pyruvate to l-valine and l-leucine, respectively.) For -ketobutyrate the K _m is 4.8×10^-3 M, and V _max 0.58 U/mg, for pyruvate the K _m is 8.4×10^-3 M, and V _max 0.37 U/mg. Due to these characteristics the presence of high -ketobutyrate concentrations apparently results in a l-valine, l-leucine deficiency. This in turn leads to a derepression of the AHAS synthesis from 0.03 U/mg to 0.29 U/mg and high l-isoleucine production is favoured. The derepression of the AHAS synthesis induced by the l-valine, l-leucine shortage was directly proven with a l-valine, l-leucine, l-isoleucine auxotrophic mutant where the starvation of each amino acid resulted in an increased AHAS level. This is in accordance with the fact that only one AHAS enzyme could be verified by chromatographic and electrophoretic separations as being responsible for the synthesis of all three branched-chain amino-acids.     

Regulation of activin's access to the cell: why is mother nature such a control freak?

Activin A is a pluripotent growth factor with important roles in development, erythropoiesis and the local regulation of many tissues. At the post-translational level, the amount of activin A produced by cells may be modulated through the diversion of activin A subunits into the formation of inhibin or other activins containing heterodimeric forms. Once assembled, activin interacts with various low- and high-affinity binding proteins, such as follistatin and alpha(2)-macroglobulin, that have consequences for receptor availability. In common with other TGFbeta family members, activin signals through pairs of type I and II receptor kinases and the Smad intracellular signalling cascade. Other checkpoints have been identified such as the recently identified pseudoreceptor, BAMBI. These emerging findings point to a tightly coordinated regulation of the exposure of a cell or tissue to activin, consistent with the low amounts of this potent factor that are necessary to modulate cellular responses.     

Should I stay or should I go? Shedding of RPTPs in cancer cells switches signals from stabilizing cell-cell adhesion to driving cell migration

Dissolution of cell-cell adhesive contacts and increased cell-extracellular matrix adhesion are hallmarks of the migratory and invasive phenotype of cancer cells. These changes are facilitated by growth factor binding to receptor protein tyrosine kinases (RTKs). In normal cells, cell-cell adhesion molecules (CAMs), including some receptor protein tyrosine phosphatases (RPTPs), antagonize RTK signaling by promoting adhesion over migration. In cancer, RTK signaling is constitutive due to mutated or amplified RTKs, which leads to growth factor independence, or autonomy. An alternative route for a tumor cell to achieve autonomy is to inactivate cell-cell CAMs such as RPTPs. RPTPs directly mediate cell adhesion and regulate both cadherin-dependent adhesion and signaling. In addition, RPTPs antagonize RTK signaling by dephosphorylating molecules activated following ligand binding. Both RPTPs and cadherins are downregulated in tumor cells by cleavage at the cell surface. This results in shedding of the extracellular, adhesive segment and displacement of the intracellular segment, altering its subcellular localization and access to substrates or binding partners. In this commentary we discuss the signals that are altered following RPTP and cadherin cleavage to promote cell migration. Tumor cells both step on the gas (RTKs) and disconnect the brakes (RPTPs and cadherins) during their invasive and metastatic journey.     

FAK and paxillin: regulators of N-cadherin adhesion and inhibitors of cell migration?

FAK and paxillin are important components in integrin-regulated signaling. New evidence suggests that these two proteins function in crosstalk between cell-matrix and cell-cell adhesions. Further, new insight suggests that under some conditions these proteins inhibit cell migration, in contrast to their established roles in several cell systems as positive regulators of cell adhesion and migration.     

Differential regulation of chemotaxis: Role of Gβγ in chemokine receptor-induced cell migration

CC and CXC chemokine receptor signalling networks are regulated in different ways. Here we show that intracellular calcium release and cell migration occur independent of Gβγ activation in response to CCL3, whereas CXCL11 induced migration of activated T-lymphocytes depends on Gβγ activation. Treatment of a range of cell types with gallein, a pharmacological inhibitor of Gβγ signalling, did not result in a reduction in CCL3 induced cellular migration, but resulted in enhanced calcium mobilisation following chemokine stimulation. Inhibition of PI3 kinase (PI3K) and AKT, which are activated downstream of Gβγ, equally had no effect on calcium release and a minor effect on cell migration. Similarly, inhibition of ERK1/2 did not prevent CCL3 induced migration. Interestingly, Gβγ as well as PI3K activation is necessary for CXCL11 induced migration of activated T-cells. These data not only confirm a role for Gβγ signalling in CXCL11 induced migration, but also demonstrate that targeting Gβγ as a therapeutic target to prevent migration in inflammatory disease may not be beneficial, at least not for CCL3 induced migration. This highlights the distinct differences in the mechanisms on how CC- and CXC-receptors activate cellular migration.     

‘For her protection and benefit’: the regulation of marriage-related migration to the UK

This paper argues that a two-tier system has evolved dividing intra-UK/EU marriages from extra-UK/EU marriages. For the former, marriage is a contract between two individuals overseen by a facilitating state. For the latter, marriage has become more of a legal status defined and controlled by an intrusive and obstructive state. I argue that this divergence in legislating regulation is steeped in an ethnicized imagining of ‘Britishness’ whereby the more noticeably ‘other’ migrants (by skin colour or religion) are perceived as a threat to the national character. The conceptualization of women as legally ‘disabled’ citizens (1870 Naturalisation Act) for whom a state must act as responsible patriarch, is a fundamental part of this imagining of the nation. The paper therefore examines the social (gendered and ethnicized) assumptions and political aims embedded within the legislation.     

Quantity and quality of communication during parental deployment: Links to adolescents’ functioning

Using an online survey methodology, we examined individual differences in distance communication between 75 adolescents and their deployed parents and found substantial individual differences in both the quantity and quality of their communication. We also examined the statistical associations between these features of distance communication and adolescents’ functioning, including emotional reactions following communication, health-related quality of life, and externalizing and internalizing problems. The quantity of communication of deployed parents with their adolescents was not associated with adolescents’ functioning, but more positive and less controlling communication was statistically associated with adolescents’ higher functioning. Implications for theory, practice, and future research are discussed.     

Control of cell migration: a tumour suppressor function for p53?

Much remains to be learned about how cancer cells acquire the property of migration, a prerequisite for invasiveness and metastasis. Loss of p53 functions is assumed to be a crucial step in the development of many types of cancers, leading to dysregulation of cell cycle checkpoint controls and apoptosis. However, emerging evidence shows that the contribution of the tumour suppressor p53 to the control of tumorigenesis is not restricted to its well-known anti-proliferative activities, but is extended to other stages of cancer development, i.e. the modulation of cell migration. This interesting alternative function has been proposed in light of the effect of p53 on specific features of migrating cells, including cell spreading, establishment of cell polarization and the production of protrusions. The effects of p53 on cell motility are largely mediated through the regulation of Rho signalling, thereby controlling actin cytoskeletal organization. These recent studies connect the regulation of proliferation to the control of cell migration and define a new concept of p53 function as a tumour suppressor gene, suggesting that p53 might be involved in tumour invasion and metastasis. This review focuses on emerging data concerning the properties of p53 that contribute to its atypical role in the regulation of cell migration.     

IgM memory and Waldenström macroglobulinemia’s cell of origin

Waldenstr?m macroglobulinemia (WM) is a neoplasm of mature IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of hematopoietic bone marrow with malignant lymphoplasmacytic cells. WM remains incurable despite the development of new therapeutic options. Owing in large measure to having a low incidence, indolent clinical course and good long-term control with proper clinical management, WM has not been investigated as extensively as other B-lineage neoplasms. Major knowledge gaps in our understanding of the natural history of WM include the cell of origin. With that shortcoming in mind, here we discuss the significance of a specific gain-of-function mutation in the adapter protein, myeloid differentiation primary response 88 (MYD88), that occurs with near-complete penetrance in WM and suggests that tumor development is under strong selective pressure for elevated MYD88 signaling. This provides an intriguing link to IgM memory B-cells, which comprise two types of B-lymphocytes ( natural effector IgM⁺IgD⁺ cells and IgM^-only IgM⁺IgD^- cells ) that depend, in part, on MYD88 signaling and constitute intriguing candidates for WM’s cell of origin. We review the features and developmental history of IgM memory in greater depth and propose that WM may be derived from primitive innate-like B-cells ( marginal zone B-cells and B1 B-cells ) that feed the IgM memory compartment. We conclude with a model of MYD88-dependent tumor development in the mature B-cell lineage that considers two different ( convergent or divergent) oncogenesis pathways with respect to the cells of origin.     

Do you see what I mean? Corticospinal excitability during observation of culture-specific gestures

People all over the world use their hands to communicate expressively. Autonomous gestures, also known as emblems, are highly social in nature, and convey conventionalized meaning without accompanying speech. To study the neural bases of cross-cultural social communication, we used single pulse transcranial magnetic stimulation (TMS) to measure corticospinal excitability (CSE) during observation of culture-specific emblems. Foreign Nicaraguan and familiar American emblems as well as meaningless control gestures were performed by both a Euro-American and a Nicaraguan actor. Euro-American participants demonstrated higher CSE during observation of the American compared to the Nicaraguan actor. This motor resonance phenomenon may reflect ethnic and cultural ingroup familiarity effects. However, participants also demonstrated a nearly significant (p = 0.053) actor by emblem interaction whereby both Nicaraguan and American emblems performed by the American actor elicited similar CSE, whereas Nicaraguan emblems performed by the Nicaraguan actor yielded higher CSE than American emblems. The latter result cannot be interpreted simply as an effect of ethnic ingroup familiarity. Thus, a likely explanation of these findings is that motor resonance is modulated by interacting biological and cultural factors.