Alan Wells

..Hence, we identify here a new pathway helping to govern cell motility, with PLC signaling playing a role in activation of PKCdelta to promote the acute phase of EGF-induced MLC activation...

..In this context, the cellular phenotype will also be discussed because the modes of migration are dictated by quantitative and physical aspects of the cell motility machinery...

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..The present review looks at the effect of and downstream signaling of various growth factors on proliferation and survival in MSCs...

..Finally, we will describe a new mode of discerning the balance between epithelioid and mesenchymal movement...

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..Furthermore, this pathologist must be steeped in the skills required for lifelong learning and adaptation...

..The phosphorylation of m-calpain by ERK and PKA by growth factors and chemokines, respectively, act in cells to regulate the enzyme only indirectly by controlling its redistribution...

..This work extends the signaling paradigm of EGFL repeat being presented in a restricted fashion as part of the extracellular matrix...

..These studies establish a pathophysiologic role for CXCR3 and its ligand during wound repair...

..This approach has obvious implications for cell therapeutics and tissue engineering of hollow visceral organs such as blood vessels...

..Herein, a number of key molecules whose expression levels are interrelated, including both EGFR and uPAR, are required but none are sufficient in the absence of other keys molecules in promoting tumor progression...

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..Our findings suggest that melanoma-derived TNCEGFL exert a role in melanoma invasion by modulating ROCK signaling and cell migration...

..All these results support the hypothesis that myopodin functions as a tumor suppressor gene to limit the growth and to inhibit the metastasis of cancer cells...

..Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness...

..Thus, we conclude that PKCdelta inhibition can limit migration and invasion of prostate cancer cells...

..While often considered 'stop' signals for adherent cells, CXCR3-binding chemokines have recently been correlated positively with cancer progression though the molecular basis remains unclear...

..These results suggest that EGF regulates the actin binding activity of ACTN4 by inducing tyrosyl-directed phosphorylation...

..The biological efficacy of, and spectrum of action of, agents used in treatment of breast cancer are important issues in therapy planning...

..These suggest that the major determinant of healing versus scarring lies with the nature of the matrix. These findings have intriguing implications for rational cellular interventions aimed at promoting wound healing via cell therapy...

..It also circumvents current limitations in assays to assess early events in metastasis, and provides new approaches to study molecular events during tumor progression...

..Interestingly, ACTN4 is phosphorylated upon growth factor stimulation, and this loosens its interaction with actin...

..In summary, this study uncovers a unique biological consequence of profilin1-phosphoinositide interaction, thus providing direct evidence of profilin1's regulation of cell migration independent of its actin-related activity...

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..Our findings for the first time highlight a possible mechanism of how reduced expression of a pro-migratory molecule like Pfn1 could actually promote motility of breast cancer cells...

..Herein we describe methods that measure the overall motility and its parameters as well as the biophysical processes extension, de-adhesion/retraction, and contraction...

..These results demonstrate that one interventional target for limiting invasion is not necessarily an individual motility pathway but rather cell migration per se...

..To investigate hepatocyte growth factor (HGF) primed fibroblasts and decorin application on skin and vocal fold fibroblasts in vitro and in vivo in rabbit vocal fold scar model...

..Thus, the blunted migratory response to EGF noted in keloid fibroblasts appears due to limited activation of two important biochemical switches for cell motility...

..This transient interaction with the receptor on the cell surface is in marked contrast to other EGFR ligands which cause EGFR transit through, and signaling from intracellular locales in addition to cell surface signaling...

..This is the first direct evidence for an extracellular signaling mechanism through CXCR3 that causes the dissociation of newly formed blood vessels followed by cell death...

..The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis...

..Tethered EGF can also be utilized to direct MSC towards osteogenic lineage both in vitro and in vivo...

..This is also the first demonstration of differential activation of the two ubiquitous calpain isoforms in the same cell by different signals...

..Taken together, these results strongly suggest that epigenetic activation of calpain plays an important role in the invasion of human prostate cancer and that it can be targeted to reduce tumor progression...

..We provide a model framework for further studies into this emerging class of signals...

..Tumors expressed higher levels of phosphorylated PLCgamma-1 compared with normal adjacent mucosa (P = 0.05). Thus, PLCgamma-1 may mediate invasion and metastasis downstream of EGFR in HNSCC...

..We conclude that IP-9 is a key ligand in the CXCR3 signaling system for wound repair, promoting re-epithelialization and modulating the maturation of the superficial dermis...

..These findings may provide mechanistic insights underlying at least some of the tumor-suppressive properties of Pfn1...

..These studies further establish the emerging signaling network that involves the CXCR3 chemokine receptor and its ligands as a key regulator of wound repair...

..We conclude that NO-induced motility in osteoclasts requires regulated Ca(2+) release, which activates mu-calpain. This occurs via the Ins(1,4,5)P(3)R1...

..These represent novel and potentially selective targets for drug development. Future advances in the imaging of tumors in animals and ex vivo organ culture systems should provide additional new targets...

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..These preclinical studies show that the anti-microbial polymer gel not only supports but also accelerates healing of bacterially contaminated wounds...

..We conclude that Cdc42 controls cell polarity, likely in part, through its binding to active PLCgamma...

..Expression of CSR1 in PC3 cell xenografts produced a dramatic reduction (>8-fold) in tumor size, rate of invasion (0 versus 31%), and mortality (13 versus 100%). The present findings suggest that CSR1 is a potent tumor sup-pressor gene...

..These findings indicate that EGF receptor activation provides survival response against staurosporine-induced apoptosis through signal pathways of PI3K and Rac, which then may prevent the activation of caspase-3...

..Increased levels of EPO and EPOR in lymph node metastases as compared to primary tumors from HNSCC patients further support the role of EPO/EPOR in HNSCC disease progression and metastasis...

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..This provides a means by which late wound repair signals limit the angiogenesis driven early in the wound response process...

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..These data support a model in which, near senescence, dermal fibroblasts become resistant to EGFR-mediated stimuli by a combination of receptor downregulation and increased signal attenuation...

..These data also provide proof that malignant tumor cells, derived from a diverse number of human solid tumors, can be isolated and grown in primary cell culture...

..We also report for the first time that a few tumor-related genes are overexpressed in keloid fibroblasts...

..Together, these experimental data demonstrate that Pfn1 regulates VEC migration, invasion and capillary morphogenesis through its interaction with both actin and proline-rich ligands...

..Armed with this knowledge, the precise roles of calpains in inflammation, wound repair and tumor progression can be ascertained and offer novel therapeutic targets...

..This concordance demonstrates the value of SOCs for conducting proteomic investigations of the melanoma microenvironment...

..This provides for a model whereby redifferentiated basal keratinocytes could limit fibroblast repopulation of the dermis underlying healed wounds while simultaneously promoting re-epithelialization of the remaining provisional wound...

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..This is particularly true of the inducers of scar formation. Here, we present a hypothesis that it is the matrix itself that is a primary driver of scar, rather than being simply the result of other cellular dysregulations...

..Together these data suggest a model of PIP(2) hydrolysis at the leading edge causing a localized release of PIP(2)-binding proteins-particularly gelsolin-that drives cytoskeletal rearrangement and protrusion...

..Cell-cell communication was maintained in serum starvation, which may model response to acute injury, but was sensitive to TNFs. These inflammatory agents mediated selective, reversible removal of connexin43 from cell processes...

..These data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by PKA...

..These findings suggest that EGFR ligands could be used for ex vivo expansion and direction of BMMSCs...

..There are precedents for all three scenarios, but which one proves true will define the window of opportunity for regulating cell migration...

..One possible mechanism was suggested by LHRH receptors triggering phospholipase-C (PLC) to activate protein kinase C (PKC) because PKC activation limits EGFR tyrosine kinase activity by phosphorylating EGFR at threonine 654...

..This has focused attention on initiators of signaling cascades that regulate tumor migration. In this effort, one molecule, phospholipase C-gamma 1 (PLCgamma), has been shown to function as a key molecular switch...

..These data suggest that wound healing studies incorporating transgene expression can utilize tet-on/tet-off regulation of gene expression without interference from doxycycline...

..For chemosensitivity and resistance assays to be clinically useful in predicting patient outcome, they should require small amounts of tissue and be highly reproducible and reliable...

..In conclusion, silver ions can serve dual functions of catalyzing gelation and providing anti-microbial properties to a biocompatible polymer...

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..Studies of the multiple roles of the glycoprotein hormone receptors are likely to uncover novel endocrine functions and axes, and highlight the potential of these receptors as novel therapeutic targets...

..These in vitro responses compare favorably to published in vivo clinical response rates. The current study serves to demonstrate how an in vitro predictive assay can be used as a surrogate for clinical therapeutic challenge...

..Countervailing processes that down-regulate calpain activation can, accordingly, direct the transition of cell function from locomotion to matrix contraction...

..In short, we demonstrate a salutary action of the CA extract on wound healing, and suggest that this may be due to mitogenic and motogenic promotion of dermal fibroblasts...

..Disclosure of potential conflicts of interest is found at the end of this article...

..Thus, in our mammary epithelial cell system, migration and proliferation are differentially sensitive to the mode of EGF ligand presentation...

..This curriculum is presented as a potentially helpful outline for use by pathology residency training programs...

..The purpose of this study was to investigate the efficacy of combined inhibition of c-Src and PLCgamma-1 in the abrogation of HNSCC invasion...

..This curriculum is presented as a potentially helpful outline for use by pathology residency training programs...

..Our findings have thus identified key signals downstream of EGFR, which integrate in a complex manner to generate and transmit contractile forces to yield matrix deformation...

..This curriculum is presented as a potentially helpful outline for use by pathology residency training programs...

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..Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments...

..m-80k-EGFP alone was not active, but with 21k or 28k subunits was active in both cell types. The EGFP domain was partially cleaved during expression, releasing an active m-80k/21k calpain...

..we conclude that decision tree methodology may facilitate elucidation of signal-response cascade relationships and generate experimentally testable predictions, which can be used as directions for future experiments...

..This will enable the design of'smart scaffolds for cell and tissue engineering directing the synthesis of both the matrix and the vascular bed that is reauired to sunnort tissue function. ..

..These studies will define molecular bases for spatial restriction of receptor signaling and resultant biophysical responses, offering promise for design of 'smart' scaffolds for tissue engineering to support tissue function. ..

..These studies will define molecular bases for spatial restriction of receptor signaling and resultant biophysical responses, offering promise for design of 'smart'scaffolds for tissue engineering to support tissue function. ..

..These investigations will define key extracellular and intracellular molecules that are potential targets for rationally designed interventions to promote normal wound healing and limit scarring. ..

..These studies will define molecular bases for spatial restriction of receptor signaling and resultant biophysical responses, offering promise for design of 'smart'scaffolds for tissue engineering to support tissue function. ..

..The completion of these investigations will yield a model of dermal skin repair in which key extracellular and intracellular molecules are identified that can be targeted to either increase healing or limit scarring. ..

..That decreased wound healing in aging is, in part, due to decreased motility response of fibroblasts secondary to decreased signal transduction of the motility pathway. ..

..Understanding the delicate balance of these molecular mechanisms is important for rationally designing interventions to achieve normal wound healing. ..

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