Breast cancer metastasis brain stem,co ed boarding schools in texas,preppers survival bag - How to DIY

Primary breast cancer cells metastasize through the blood vessels to various distant organs, preferentially, to the lung, liver and bones. Left Image: CAT SCan Brain Showing enhancing metastatic lesions from breast-cancer primary.
Jeffrey Dach MD is a physician and author of two books, Natural Medicine 101, and Bioidentical Hormones 101, both available on Amazon, or as a free e-book on his web sites. The New "Help": Community College of Philadelphia Exploits Low Wage Adjunct African American Faculty Posted by Linda D.
The effect of local therapy (surgery and radiation therapy) on the survival of patients with breast cancer has been debated for a long time.
In order for a cancer cell to spread, it must have the capacity to migrate and invade through the basement membrane and gain access to the vasculature or lymphatics from the primary site. Metastasis: Once the cancer cells go through the basement membrane of the breast duct they can colonize the blood and lymphatic vessels of the breast and migrate to other parts of the body.
Three theories of why cancers spread have been postulated as possible mechanisms of metastasis. The first one, postulated in the first half of the 20th century by Halsted, proposed that breast cancer begins as strictly a local disease and tumor cells spread over time in a contiguous manner away from the primary site through the lymphatics.
The second hypothesis, which was developed in the 1970’s, was called the systemic theory. Recent data supports the third hypothesis as there is evidence that mammographic screening reduces breast-cancer mortality. Si las celulas individuales fuesen conscientes de si mismas (?o seria mejor decir inconscientes…?) de la misma manera que los somos los humanos, probablemente tambien habrian inventado sus propias religiones para adorar a seres imaginarios y establecer unas reglas morales totalmente aleatorias. Os propongo un ejercicio de imaginacion para que especulemos sobre estos pecados teniendo en cuenta actividades reales que realizan las celulas en los seres vivos, lo cual nos servira como excusa para contar brevemente y de forma sencilla algunos conceptos interesantes relacionados con las celulas.
FECUNDACION o FERTILIZACION: es el proceso por el cual dos gametos o celulas sexuales se fusionan para crear una nueva celula llamada cigoto, que dara lugar a la formacion de un nuevo individuo con un genoma derivado de ambos progenitores.
CONJUGACION: La conjugacion bacteriana es el proceso de transferencia de informacion genetica desde una celula procariota donadora a otra receptora a traves de unas estructuras llamadas pili sexuales.
FAGOCITOSIS: La fagocitosis, es un tipo de endocitosis por el cual algunas celulas rodean con su membrana citoplasmatica a un antigeno, molecula o celula y lo introducen al interior celular. CANCER: El cancer es una enfermedad durante la cual el organismo produce un exceso de celulas malignas (conocidas como cancerigenas o cancerosas), con crecimiento y division mas alla de los limites normales, lo que implica la invasion del tejido circundante y, a veces, metastasis. CELULAS TUMORALES: Son las celulas que componen un tumor, en el sentido de cualquier bulto que se deba a un aumento en el numero de celulas, independientemente de que sean de caracter benigno o maligno. CNIDOCISTO o NEMATOCISTO: Los cnidocitos son unas celulas exclusivas de los Cnidarios, especialmente abundantes en los tentaculos y alrededor de la boca, que segregan una sustancia urticante y cuya funcion es tanto defensiva contra los posibles depredadores, como de ataque para capturar presas. Una persona envidiosa se encarga de divulgar a los cuatro vientos los defectos de la persona envidiada y se encargara de contar chismes a sus conocidos con la unica intencion de desprestigiar a la persona que le provoca el sentimiento de envidia. TOTIPOTENCIALIDAD: Una celula madre, stem cell o celula troncal, es una celula que tiene la capacidad de autorrenovarse mediante sucesivas divisiones mitoticas o bien de continuar la via de diferenciacion para la que esta programada y, por lo tanto, producir celulas de uno o mas tejidos maduros, distintos, funcionales y plenamente diferenciados en funcion de su grado de multipotencialidad o totipotencialidad. MITOSIS: Es un proceso que ocurre en el nucleo de las celulas eucarioticas y que consiste en el reparto equitativo del material hereditario, es decir, del ADN. 0 (0 Votos) Respondealejandro 25 febrero, 2011felicidades por el corpus del texto, ya te felicitaran mas, en realidad yo te escribo porque aunque soy ateo y todas las religiones me parecen un lastre para la dignidad humana creo que tu frase de que las reglas morales que construyeron las religiones son ARBITRARIAS es incorrecta. Sumamente original e interesante, ensena mucho sobre biologia celular de una manera muy divertida. Science, Technology and Medicine open access publisher.Publish, read and share novel research.
The Role of Adhesion Receptors in Melanoma Metastasis and Therapeutic Intervention Thereof Michael Alexander1, 2, 3 and Gerd Bendas3[1] Department of Genomics, LIFE & BRAIN Center GmbH, University of Bonn, Bonn, Germany[2] Institute of Human Genetics, University of Bonn, Bonn, Germany[3] Pharmaceutical Institute, Department of Pharmaceutical Chemistry II,University of Bonn, Bonn, Germany1.
GenisZym is made from high purity genistein (purity 40%) and EGCG (purity 94% ) fermented with a natural, proprietary process.
When cell divide, the ends of the DNA, called telomeres, shorten after every cell division. In addition to inhibiting the synthesis of the telomerase enzyme, genistein also inactivates previously synthesized telomerase enzymes. Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. EGCG (epigallocatechin-3- gallate) from green tea is a great antidote to the cancer-causing effect by synthetic or bio-identical estrogen. Green tea is high in the EGCG which helps prevent the body’s cells from becoming damaged and prematurely aged. Unfortunately both dietary genistein and EGCG in supplement form didn’t help cancers at all due to extremely low solubility and bioavailability. Improved screening and increased use of early local-regional treatment (surgery and radiation) and adjuvant treatment (chemotherapy, hormonal therapy, and trastuzumab) have been associated with a marked reduction in mortality associated with breast cancer. This theory arose in view of numerous cases of distant metastases, despite adequate local control with local surgery. Some breast cancers will remain local throughout their course while others have already spread systemically when first detected.
Teniendo en cuenta que esto fuera asi, ?cuales serian entonces los siete pecados capitales de estas celulas humanizadas imaginarias? Esto se produce gracias a la emision de pseudopodos alrededor de la particula o microorganismo hasta englobarla completamente y formar alrededor de el una vesicula, llamada fagosoma, la cual fusionan posteriormente con lisosomas para degradar el elemento fagocitado. La metastasis es la propagacion a distancia, por via fundamentalmente linfatica o sanguinea, de las celulas originarias del cancer, y el crecimiento de nuevos tumores en los lugares de destino de dicha metastasis. Dicho sentimiento se puede manifestar contra uno mismo o contra los demas y entre sus multiples manifestaciones, tanto psiquicas como fisicas, podemos encontrar impaciencia, venganza, fanatismo, intolerancia, discriminacion, agresiones, homicidios e incluso genocidio.
El cnidocisto es un gran organulo caracteristico, el cnidocisto o nematocisto, que consta de un flagelo muy modificado, el cnidocilio que capta los estimulos que desencadenan la descarga. El chismorreo rapidamente se transmite, se distorsiona y se amplifica mientras pasa de boca en boca. Los neurotransmisores, como la noradrenalina y la acetilcolina son los encargados de excitar o inhibir la accion de la otra neurona. La potencialidad es por tanto la capacidad de dar origen a varios tipos celulares, incluso pudiendo una sola de estas celulas dar origen a millones de celulas, tejidos, organos, hasta incluso embriones.
Se pueden englobar en la soberbia tambien el orgullo, la altivez, la vanidad y la arrogancia. Normalmente concluye con la formacion de dos nucleos separados (cariocinesis), seguido de la particion del citoplasma (citocinesis), para formar dos celulas hijas.
Es obvio que las morales son contingentes, pero eso no implica su arbitrariedad, au contraire, son contingentes porque obedecen al tiempo y el espacio en que se generaron.
Domain architecture of the heterodimeric transmembrane domains which show how integrins are designed to act as bidirectional signalling machines.
Cellular signalling modes of integrins.The two ways of integrin signalling can be divided in “outside-in” (left) and “inside-out” (right) modes.
IntroductionThe metastatic spread of solid tumors is the most fatal complication in malignant diseases and the major cause of tumor-related mortality. Genistein, an isoflavone derivative related to coumarin, is found in soy products and holds great promise as a natural cancer preventative. HIF-1(hypoxia-inducible factor-1) negatively regulates mitochondrial bio-genesis and O2 consumption in cancer cells lacking the von Hippel-Lindau tumor suppressor (VHL). Studies have suggested that the combination of GENISTEIN and EGCG may also be beneficial by providing protection against certain types of cancers, including breast cancer. There are several pharmacokinetic studies about EGCG and genistein’s low solubility and bioavailability, which means that most of what we swallow goes directly into our gastrointestinal area and is expelled.
Halsted’s theory postulated aggressive local therapy and even justification for radical breast surgery. In the middle of the group we have those breast cancers that start locally and eventually develop metastases if left untreated. Thus, in some patients earlier diagnosis can prevent the development of distant metastases.
La ira celular la podemos encontrar en unas estructuras asesinas llamadas CNIDOCISTOS o NEMATOCISTOS, que podemos encontrar en unas celulas llamadas cnidocitos de los Cnidarios, es decir, polipos, corales anemonas y medusas. Tiene de una capsula invaginada de doble pared, un operculo que la cierra y el cnidocilio, que puede tener espinas, enrollado en su interior. Cuando el nematocisto es estimulado se produce la evaginacion del filamento que se clava en la piel de la victima o depredador e inyecta un veneno hemolitico o miolitico contenido en la capsula. Al contrario que ocurre en la avaricia, la envidia no se centra tanto en los bienes materiales, sino en la emulacion o deseo de poseer algun bien inmaterial que otro posee. El simil con las neuronas y sus sinapsis esta mas o menos claro, si consideramos estas como celulas chismosas, que tambien transmiten y amplifican la informacion, aunque por suerte no la distorsionan. En el mundo celular la correspondencia al pecado de la soberbia no podia ser otra que la MITOSIS, ese fantastico proceso en el que las celulas hacen copias exactas de si mismas, intentando no cometer errores al replicar su ADN, como si pensaran que ellas son las mejores, las mas perfectas, unicas en su cometido e insustituibles, si no es por copias identicas a ellas. La mitosis completa, que produce celulas geneticamente identicas, es el fundamento del crecimiento, de la reparacion de tejidos y de la reproduccion asexual. Nunca habia visto algo tan gracioso, en el buen sentido, por original y porque, bueno, tengo que admitir que me parece super gracioso la apoptosis y todo el mecanismo, porque lo puedes comparar como lavado de cerebro o algo asi por parte de las NK. The figure shows a section of the possible signalling cascades which lead to the activation of cellular survival proliferation and migration. This is of high relevance for malignant melanoma which are highly proliferating tumors with aggressive metastatic tendency.
Richmond, 2010Chemokines and chemokine receptors: new insights into cancer-related inflammation. There are a number of isoflavones in soy products, but research has shown that genistein is the most potent inhibitor of the growth and spread of cancerous cells.
In order to introduce pure EGCG and genistein into the blood via absorption and maximize the activity  in the body, you could use GenisZym. Bernard Fisher postulated the view that breast cancer is a systemic disease that can be divided in two groups: tumors that have the ability to spread to distant sites and those that lack this ability. Unfortunately, we generally do not know if metastases have already settled in by the time of diagnosis.
Also, recent evidence supports a link between local control and overall survival of breast cancer.
De esta manera, pueden esperar ser eficientemente englobadas por otras celulas mediante fagocitosis. Segun este enfoque, podemos relacionar la envidia con un proceso y una caracteristica celulares: la SINAPSIS y la TOTIPOTENCIALIDAD.
En cuanto a la totipotencialidad, hablamos de una caracteristica celular que hace que una determinada estirpe de celulas sea capaz de convertirse o dar lugar casi a cualquier otro tipo celular, lo que las convierte en las perfectas celulas envidiosas capaces no solo de imitar a las demas celulas, sino que transforman literalmente en ellas.
Las celulas en mitosis no conciben la variacion, no dejan opcion a la mutacion para que la evolucion trabaje sobre ellas, aunque siempre alguna se escapa. Aunque creo que no lo podemos interpretar todo como un credo, porque estas enfermedades pueden o no ser creadas por estos llamados pecados. The ligand binding site is provided by the N-terminal domain of the ?- and ?-integrin subunits (the ?-propeller and the ?A domain, respectively) which are assembled in most integrins by non-covalent interactions to form a “head”. In the case of “outside-in” signalling, binding of integrins to their extracellular ligands changes the conformation of the integrin and - because many of the ligands are multivalent - contributes to integrin clustering. The majority of melanoma cells tend to metastasize primary via the lymph system and secondary into different organs, most likely distant skin regions, liver, lungs, brain, and heart via hematogenous distribution, which is associated with bad prognosis.



Wang, et al.2007The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. Torri, et al.2007P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. In addition, genistein is a general tyrosine kinase inhibitor, which means it inhibits the activity of the growth promoting EGF and HER-2 receptors.
The enzyme telemerase repairs the damaged DNA, thereby increasing the lifespan of the cells.
That is why eating more fruits and vegetables, in whatever form, is a great way to prevent cancers.
We know that surgery, even in the early stages of breast cancer, does not cure every woman. If distant metastasis were destined to develop, such metastasis had already occurred at the time of diagnosis of the breast tumor. The higher the likelihood the tumor was diagnosed at its local stage the higher the likelihood that local therapy (surgery, radiation) will influence survival. La sinapsis se puede considerar como parte de la envidia celular si la encuadramos en los chismorreos que acompanan a cualquier gesto envidioso.
La soberbia de las vanidosas celulas les lleva a dividirse por mitosis para no rebajarse a cambiar y transformarse en otra cosa distinta.
The combination of these two events leads to intracellular signals that control cell polarity, cytoskeletal structure, gene expression, cell survival and proliferation. Podda, et al.2004Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Raso, et al.2005Selective antimetastatic effect of heparins in preclinical human melanoma models is based on inhibition of migration and microvascular arrest.
Bistrian, et al.2006The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Bendas, 2007Kinetic analysis of heparin and glucan sulfates binding to P-selectin and its impact on the general understanding of selectin inhibition. The AKT enzyme is responsible for the activation of aerobic glycolysis, the metabolic pathway which typifies cancer cell growth.
Extracts of green tea have been shown to prevent cancer in animals, and recently similar claims have been made about black tea. The higher the likelihood of metastases at the time of diagnosis the higher the likelihood of benefit from systemic therapy. During ‘inside–out’ signalling, an intracellular activator, such as talin or kindlins, binds to the ?-integrin tail, leading to conformational changes that result in increased affinity for extracellular ligands (integrin ‘activation’).
All true tea comes from the same plant species (Camellia sinensis), such as black tea, pu-erh tea, and oolong- tea, so they should contain the same amount of EGCG. Inside–out signalling controls adhesion strength and enables sufficiently strong interactions between integrins and ECM proteins to allow integrins to transmit the forces required for cell migration and ECM remodelling and assembly. Amirkhosravi, 2006Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low molecular-weight heparin, enoxaparin. Klerk, et al.2009Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung.
NF-kB stimulates the synthesis of VEGF(vascular endothelial growth factor), pro-inflammatory hormones and anti-apoptosis survival factors. Both modes of signalling are often closely linked; for example, integrin activation can increase ligand binding, resulting in outside–in signalling. An intensive and ongoing preclinical research provided essential insight and several postulated factors and mechanisms for the hematogenous dissemination, i.e. Borsig, 2006L-selectin facilitation of metastasis involves temporal induction of fut7-dependent ligands at sites of tumor cell arrest. It kills cancer cells on so many different fronts that it is difficult, if not impossible, to keep abreast of new scientific developments. The PSI-domain (plexin, semaphorin and integrin) is at the N terminus of the ?-integrin subunit, but is joined by disulfide bonds to more C-terminal residues. The only thing keeping these cells alive is their over expression of the enzyme telomerase. The activation of the PTEN gene by low level of genistein inhibits AKT signaling and the activation of the telomerase enzyme. Genistein blocked the TNF(tumor necrosis factor) induced NF-kB activation in human volunteers and significantly enhances the anti-cancer effectiveness of chemo drugs.
The remaining C-terminal extracellular domains of the ?- and ?-subunit comprise two long ‘legs’ which are anchored in the PM.
P- and L-selectin, members of a family of carbohydrate binding adhesion receptors are regarded as functional key players in the contact formation of tumor cells with platelets and leukocytes, thus facilitating microemboli formation and accelerating metastatic dissemination. Once the ends of the DNA shorten to a prescribed length, the cells will die by programmed cell death.
The low affinity state of the integrin for its ligands is maintained by non-covalent interactions between the ?- and ?-integrin transmembrane and cytoplasmic domains.
The antimetastatic activities of heparin, confirmed by a number of prospective clinical trials, are to a large extent ascribed to the inhibition of these two selectins. At high concentrations, it can kill cancer and leukemia cells in probably 50 different ways.
Besides the important role of selectins, integrins as ubiquitary cell adhesion receptors are also involved in the mediation of manifold adhesive interactions in the metastasis of tumor cells. Integrins bind ligands of the extracellular matrix (ECM), such as fibronectin, collagen, laminin and vitronectin to stabilize cell attachment with the surrounding tissues or to mediate migration in the metastatic cascade. Furthermore, integrins mediate cellular contacts of the tumor cells to platelets, leukocytes, and endothelium.
However, in contrast to the selectins, the integrin function has hardly been considered as target for antimetastatic approaches. Integrins possess important tasks in cell signalling that can be summarized as defining the cellular shape, mobility, invasion and cell cycle regulation. The regulation of these processes via contribution of the actin and microtubule cytoskeletons is well known to be controlled by Rho-GTPases (Ras homologue; guanosintriphosphatases), which belong to the superfamily of Ras-GTPases (Rat adeno sarcoma).
GTPases of the Ras-superfamily are important for cell proliferation, metastasis, migration, apoptosis, gene expression and multiple other functions in the cell.
Since the integrin signalling is also cross-linked to the function of GTPases, a therapeutic influence on the GTPase activity could be a novel and attractive approach to control integrin bindings. Recent data on the treatment of melanoma cells with lysophosphatidylcholine (LysoPC) referred to reduced integrin functions, which might be related to reduced GTPase signalling. This book chapter will deal with the molecular function of adhesion receptors in the process of hematogenous metastasis of melanoma cells and the therapeutic potential and prospects to interfere with adhesion receptor activity as an antimetastatic approach. The focus was put on the integrins, which will be explained with their functions, abilities and connections to other indispensable proteins, such as cytoskeletal components in the context of cancer and metastasis.
Finally the hypothesis to influence the integrin functions in metastatic cascade at a signalling level will be introduced and discussed as an interesting novel target for antimetastatic approaches.2. The course of the metastatic cascade Tumor cell metastasis is a complex cascade which consists of various molecular events. Metastatic cells have to exit the primary tumor by a deregulation of the cellular contacts, have to migrate the basement membrane of the tumor, degrade the extracellular matrix and intravasate lymphatic vessels or local post capillary veins.
Once in the blood system, the tumor cells have to escape the immune surveillance and physical stress of the blood stream to finally seed at the vascular bed at distant organs.
This is the rate-limiting step of the metastatic cascade before they can extravasate and form metastases (Figure 1). Although these models do not completely recapitulate the natural processes of metastatic spread, the timely defined presence of tumor cells in the blood systems allows for characterization and evaluation of cellular contacts within the phase of hematogenous distribution. G., 2004)The massive interaction of tumor cells forming a platelet cloak is a vital strategy to evade the immune defense and was shown to correlate with metastatic progression. Furthermore, the recruitment of leukocytes to form microemboli is thought to support microvascular arrest at distant sites and contributes to activation of endothelial cells. However, cellular adhesion receptors play a pivotal role for this complex cellular communication.
The impact of selectins on the hematogenous tumor cell disseminationThe selectins, a family of carbohydrate binding proteins, represent the crucial importance linked with hematogenous metastasis (Laubli & Borsig, 2010).
It became evident that P-selectin, expressed by activated endothelial cells also contributes to the metastatic progression (Ludwig et al., 2004).
L-selectin, which is constitutively expressed by all types of leukocytes, supports the comprehension of leukocyte into the microemboli and vascular contact formation and activation (Laubli et al., 2006). Endothelial activation is associated with the upregulation of other adhesion receptors, such as E-selectin or the integrin ligand vascular cell adhesion molecule-1 (VCAM-1), which again advises to the inflammatory-like reaction (Auguste et al., 2007). Consequently, the competitive blocking of the selectin function appears as a promising therapeutic approach to interfere with the metastatic cascade.
The role of heparin for antimetastatic approachesThe evidence for those selectin-blocking approaches came indirectly from clinical efforts to treat cancer-associated thromboembolic events, which are frequent complications in malignant diseases.
Heparin, or low molecular weight heparin (LMWH) are the anticoagulant drug of choice in the clinical treatment or prophylactic treatment of cancer-associated thrombosis.
Based on the retrospective evaluation of clinical data, which referred to a survival benefit of heparin treated cancer patients, a number of prospective clinical trials have been lauchned (Zacharski & Lee, 2008). Animal experiments supported the assumption that heparin hardly affects the primary tumor but interferes with the process of metastasis. 2008) from which the inhibitory capacity of heparin towards P- and L-selectin binding should be highlighted here.Heparin as a highly sulfated, acidic polysaccharide has the ability to compete with the natural mucin-like selectin ligands. The capacity of heparin to interfere with P- and L-selectin binding has already been described in the early 90th (Skinner et al., 1991), but in the context of tumor cell metastasis the heparin effects as competitors of P- and L-selectins were accumulated during the last decade. Integrins as targets for heparinThe platelet integrin IIb IIIa also contributes to the bond formation between platelets and melanoma cells via fibronectin or vWF to melanoma integrins.
A recent study reported that heparin has also an inhibitory capacity to this binding (Zhang et al., 2009). Thrombin, interacting with its receptor PAR-1 on melanoma cells (protease-activated receptors-1) has a strong impact for regulating this interaction. PAR-1, which is predominantly overexpressed in malignant melanoma cells induces diverse procoagulant and metastatic events, such as matrix degradation, secretion of angiogenetic factors or integrin activation (Melnikova et al., 2008). Although these finding suggest that the inhibition of VLA-4 could be promising in the treatment of melanoma metastasis, and despite VLA-4 inhibition by antibodies or small molecules is a vital strategy to interfere with pathological inflammations, such approaches have not been described so far in the cancer field. Nevertheless, beside those approaches for a competitive blockade of integrin receptor function, the manifold signalling functions of integrins open a new way for a therapeutic interference, which will be discussed below. The biology of integrins in the context of cell adhesion processes and metastasisIn addition to the selectin-mediated cell adhesion processes in metastasis, the protein families of immunoglobulins (IGs), cadherins and integrins play important roles – in the case of malfunction - in the development and progression of melanoma metastasis. A switch of the cadherin molecules from E-cadherin to N-cadherin is responsible for the disassociation of melanoma cells from keratinocytes.
One of the most prominent examples that is frequently associated with the progression of melanoma is the integrin 41 (VLA-4) (Braeuer et al, 2011).
The general structure of integrinsThe integrins are large and complex transmembrane glycoproteins which act as adhesion receptor molecules that are responsible for the mediation of attachment and anchorage between cells or to the underlying extracellular matrix (ECM) (Morgan et al., 2007). In detail they span the plasma membrane and work alongside other proteins such as cadherins and selectins to mediate cell-cell and cell-matrix interaction and communication.


One important task of integrins is the binding of the cell surface and ECM components such as fibronectin, vitronectin, collagen, and laminin. That means the use of integrin-targeted reagents is not specific for all but for a few or one specific integrin. This provides additional mechanistic insights into the functions of integrin adhesion receptors. In addition, variants of some integrin subunits are formed by differential splicing, for example four variants of the beta-1 subunit exist (Hynes, 2002).
The pathway of extracellular binding of integrins to intracellular transformation of the binding is most often mediated by the cytoplasmic tail of the ?-subunit (Morgan et al., 2007). The integrin proteins act as receptors which are able to communicate between the ECM and the cell.
They also transport information from the status inside the cell to the extracellular space. Thus integrin tasks can be divided into two main functions: Attachment of the cell to the ECM and signal transduction from the ECM to the cell. Within the past decade it has become apparent that adhesion molecules such as integrins play an important role for the mediation of critical cytosolic signalling events in the cell (Stupack, 2007). Integrins act to regulate complex processes in cancer disease such as angiogenesis, tumor growth and metastasis (Hynes, 2002), and the signalling has a dramatic impact on cell proliferation, survival and motility. For this reason they have become attractive therapeutic targets for the development of pharmaceutical compounds. Figure 2.Domain architecture of the heterodimeric transmembrane domains which show how integrins are designed to act as bidirectional signalling machines. On one hand, integrins that ligate substrate-immobilized ligands typically transduce positive signals into the cell.
On the other hand, antagonized or unligated integrins promote negative signalling into the cell, which leads to cell cycle arrest or apoptosis. Thus, integrins constantly interrogate the local ECM and modulate cell behaviour accordingly. Typically, receptors inform a cell of the molecules in its environment and the cell evokes a response.
The integrins in the context of signal transduction processesThe mechanisms of integrin interaction at the cytoplasmic side are strongly connected to the regulation of GTPases.
For example, activated Rac1 and RhoA transduce signals to integrin activation via phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase 1? (PIP5K1?) (Tybulewicz & Henderson, 2009). Furthermore it is known that integrin signalling is inhibited by RhoH through an unknown mechanism. In this case, integrin signalling leads to the activation of the GEF ?PIX (PAK-interacting exchange factor-?) and the following activation of Rac1 and PAK (p21-activated kinase) (Tybulewicz & Henderson, 2009).
PAKs are well known to serve as targets for the small GTPases Cdc42 and Rac and they have been implicated in a wide range of biological activities, such as regulating the cell motility and morphology (PAK1), involvement in apoptotic processes (PAK2), or in the rapid cytoskeletal reorganization in dendritic spines (PAK3) or mediation of filopodia formation (PAK4). Integrin signalling works predominantly through the recruitment and activation of Src-family kinases (SFKs).
Most integrins recruit focal adhesion kinase (FAK) through their cytoplasmic domain of the ?-subunit (Guo & Giancotti, 2004).
From this important point of origin, several signal pathways influence the cell proliferation, survival and migration (Figure 4). Beside the interaction of integrins with SFKs mentioned before, some integrins are able to interact directly with SFKs via the cytoplasmic tail of their ?-subunits (Arias-Salgado et al., 2003).
This palmitoylation is required for the incorporation of the complete ?6?4 integrin in lipid rafts where the receptor is able to interact with SFKs that are similarly palmitoylated (Gagnoux-Palacios et al., 2003). The known pathways that integrins can activate through SFKs are sufficient for the induction of cell migration, invasion and proliferation or to confer some protection from apoptosis on cells. Disruption of raft integrity through depletion of membrane cholesterol with methyl-?-cyclodextrin (MbCD) completely disrupted ?4?1 cluster formation, implying that the lipid rafts are required for ?4 integrin clusters (Leitinger & Hogg, 2002).
These results hypothesize that the mechanism of membrane compartmentalization – as identified for the mentioned integrins – also operates in other integrin-signalling systems, which might be an explanation for several specific aspects of diverse integrins. Possible ways for pharmacological antimetastatic approaches by intervention with integrins on the plasma membrane and signalling levelThe integrins, especially the integrin VLA-4 has been for longer time in the interest as target for the design of small molecule competive inhibitors as potential antiinflammatory drugs (Singh et al, 2004).
Concerning the “non-competitive” influence on integrins, there basically exist two different ways for integrin modulation: An interference with the signal transduction at the cytoplasmatic site or an influence on the integrin compartmentalization at the plasma membrane.
As mentioned before the influence on integrins is mainly mediated via the cytoplasmatic tail of their ?-subunits which allows the inside-out signalling (Arias-Salgado et al., 2003).
In general, integrins essentially need the specific membrane positioning and membrane anchorage of signalling proteins like GTPases of the Ras-superfamily for their signalling processes. The distribution of Ras proteins is determined by different C-terminal lipid modifications. Several publications have pointed out the importance of Ras compartmentalization for signal transduction (Roy et al. This is in line with their palmitoylation status – two palmitoyl anchors for H-Ras and one palmitoyl anchor for N-Ras. Non-raft integrins are excluded from the rafts by cytoskeletal constraints and are no more able to perform signalling from raft microdomains (Leitinger & Hogg, 2002). Thus, the positioning of integrins inside or outside of rafts for their physical interaction with important signalling switches, such as GTPases or FAKs depends critically on the surrounding lipid composition. This study is based on earlier findings that empty liposomes consisting of saturated phosphatidylcholine (PC) displayed strong antimetastatic effects in a murine pancreatic mice model (Graeser et al., 2009). In order to follow this hypothesis, the authors incubated murine melanoma B16.F10 cells with physiological and increased concentrations of saturated LysoPC. The melanoma cells fastly removed the LysoPC from the medium which was accompanied by a radical shift in tumor cell membrane fatty acid composition towards saturated fatty acids.
Electron microscopic images suggested that the changed membrane composition leads to a strong increase in number and size of filopodial-like membrane protrusions. The functional basis for antimetastatic effects of LysoPC became exposed by investigating the adhesion receptor binding. As mentioned before, melanoma cells make use of their integrin VLA-4 binding the endothelial ligand VCAM-1 for vascular arrest in the metastatic cascade. LysoPC incubation affected crucially the VLA-4 activity in a concentration dependent manner, although the expression levels of this integrin were not changed. Exceeding the physiological LysoPC concentration, the melanoma cells lost their ability for VCAM-1 binding. Furthermore, even though the treated cells exhibited a remarkably augmented number of protrusions, the cell motility on fibronectin as essential requirement for distinct steps of metastasis, e.g. In addition, the interaction with platelets via P-selectin was also strongly diminished, which is a further factor for reduced metastasis. These in vitro findings were totally reflected in a syngenic intravenous lung-invasion model. Using ex vivo-treated B16.F10 cells, LysoPC concentrations above the threshold (450 µM) resulted in significantly reduced metastasis-like lesions in lung tissue.
The search for the molecular basis of these promising data is ongoing yet, but might lead to some preliminary postulations. On the one hand, biophysical aspects of membrane properties and their change by the saturated lipids can be discussed to affect integrin function.
On the other hand, an interference of LysoPC with the integrin signalling at the level of GTPases can be assumed.
Referring to the first assumption, a balance between saturated and unsaturated fatty acids is a fundamental biophysical determinant of membrane fluidity (Mansilla et al., 2008). This strongly indicates that the addition of exogenous fully hydrogenated LysoPC and the subsequent change of membrane composition might have a clear impact on the deregulation of these factors. Since the integrin function is dependent on several aspects of membrane compartmentation (as described before), a reduced VLA-4 function could result from changes in e.g. In addition, to the reduced gene expression of GTPases, we also identified that several integrin subunits (ITGA4, ITGA2 and ITGB1) are reduced in transcription by LysoPC exposition in a concentration-dependent manner (Alexander M.
Thus, one can assume interplay between the LysoPC incubation and the altered adhesion, membrane morphology and gene expression of the examined melanoma cells.The exact signal pathway that is affected by LysoPC exposition has to be investigated in future analyses due to the fact that not only one or a few defined signal pathways are triggering the adhesion process via integrins (Figure 4).
DUSP1 displays a rather broad specificity for inactivation of the ERK, p38 and JNK MAP kinases (Keyse, 2008). In addition, DUSP1 has detectable binding to ERK in vivo and is suggested to act as a positive activator of ERK in EGFR-mutant lung cancer cell lines independent of the ability to bind to ERK (Britson et al., 2009). Recent findings support the involvement of DUSPs in cancer progression and resistance (Bermundez et al., 2010) due to the fact that abnormalities in MAPK signalling have important consequences for processes critical to the development and progression of human cancer.
LysoPC exhibit a comparable chemical structure to the experimental anticancer drugs miltefosine and edelfosine (Figure 5). The treatment of cancer cells with those alkylphosphocholines (APCs), which are able to incorporate into specific membrane compartments can disturb the well balanced and organized lipid network and thus influence the signalling of associated proteins.
Since LysoPC possess a remarkably rapid uptake in the membranes of cancer cells, a comparable cellular mechanism by the critical alteration of the integrity and functionality of specific membrane microdomains could be hypothesized for LysoPC with regard to the global gene expression data. Although LysoPC possesses an evident similarity in chemical structure compared to the APCs, LysoPC seems to activate different signalling pathways.
Edelfosine was tested as a pharmaceutical compound against prostate cancer (Berdel et al., 1981), human brain tumors, lung tumors and other cancer types (Berdel et al. In a multiple myeloma animal model, oral administration of edelfosine showed a potent in vivo anti-myeloma activity and the drug accumulated preferentially in the tumor (Mollinedo et al., 2010).
These data suggest that edelfosine incorporation in lipid rafts leads to a redistribution of sterols from the plasma membrane (Zaremberg et al., 2005).
The redistribution of a major lipid raft component - they consist of cholesterol, glycolipids und sphingolipids - is likely to alter the biophysical properties of the lipid raft microdomain with putative important consequences for cell fate, due to the fact that the association of raft-targeted proteins is strongly assumed to be altered. Presently it remains open whether the antimetastatic effects and the serious affect on integrin activity by LysoPC are in line or on a comparable mechanistic level with the APC membrane effects. Future studies will provide insight into the hypotheses on membrane effects and the consequences for integrin localization and signalling.
However, the non-competitive influence on the integrin activity by changing the lipid microenvironment appears as an interesting approach to interfere with integrin function in tumor cell metastasis.6. ConclusionThe mortality rate of melanoma diseases is to a great extent related to the high tendency to form metastases via the lymph and blood system. An increasing insight into the molecular mechanisms of hematogenous metastasis offers new therapeutic options to interfere with the metastatic spread. Cellular adhesion receptors appear as attractive targets in that context, since adhesion molecules mediate several key events to allow the tumor cells the survival in the blood system and the settlement in the vascular bed of distant organs. For a competitive blockade of the adhesion receptor function, heparin or non-anticoagulative heparin products possess most promises, since heparin is clinically accepted as anticoagulant and numerous preclinical data confirm the capacity of heparin to interfere with the selectins and selected integrins.
A recent example is given by studies using LysoPC to melanoma cells, which drastically reduced the binding capacity of the integrin VLA-4 and thus, metastatic rate in mice. Although the exact molecular mechanisms are not fully elucidated, this might open new potential therapeutic options to reduce metastasis by interfering with adhesion molecules at the signalling level.



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