The metastatic cascade in prostate cancer

Arya, Manit; Bott, Simon; Shergill, Iqbal; Ahmed, Hashim U.; Williamson, Magali; Patel, Hiten

doi:10.1016/j.suronc.2006.10.002

Cited by 102 publications

(83 citation statements)

References 102 publications

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“…Thus, we generated a pool of PC3 cells in which EphA2 is stably knocked down (EphA2-silenced PC3 cells) with respect to control cells (wtPC3 cells), as indicated by Western blot and flow cytometry analyses ( Fig. 1A and B) The long route of prostate cancer cells to metastasize a distant organ is composed of a series of sequential steps (19,20), involving entry into the systemic vasculature through the activation of transendothelial migration, sustain of cell survival, homing of cancer cells to the target tissue, adhesion to the new localization and growth of the colony to generate metastases. To understand the importance of EphA2 expression to produce successful metastases, we analyzed EphA2 involvement in each step of the metastatic progression.…”

Section: Role Of Epha2 In Proliferation Adhesion and Survival Of Prmentioning

confidence: 99%

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

Taddei

Parri

Angelucci

et al. 2011

Molecular Cancer Research

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EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 in tumor progression is still debated. In melanoma, EphA2 has been reported to affect cell migration and invasiveness allowing cells to move by a proteolysis-independent strategy, commonly referred as amoeboid motility. With the aim to understand the role of EphA2 in prostate cancer metastatic spreading, we stably silenced EphA2 expression in a model of aggressive metastatic prostate carcinoma. Our results show that EphA2 drives the metastatic program of prostate carcinoma, although its involvement greatly differs among metastatic steps. Indeed, EphA2 expression (i) greatly affects prostate carcinoma cell motility style, guiding an amoeboid movement based on Rho-mediated cell rounding and independent from metalloprotases, (ii) is ineffective on transendothelial migration, adhesion onto extracellular matrix proteins, and on resistance to anoikis, (iii) regulates clonogenic potential of prostate carcinoma, thereby increasing anchorage-independent growth and self-renewal, prostasphere formation, tumor onset, dissemination to bone, and growth of metastatic colonies. Our finding indicate that EphA2-overexpressing prostate carcinoma cells gain an invasive benefit from their amoeboid motility style to escape from primary tumors and then, enhancing their clonogenic potential successfully target bone and grow metastases, thereby acknowledging EphA2 as a target for antimetastatic therapy of aggressive prostate cancers. Mol Cancer Res; 9(2); 149-60. Ó2011 AACR.

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Section: Role Of Epha2 In Proliferation Adhesion and Survival Of Prmentioning

confidence: 99%

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

Taddei

Parri

Angelucci

et al. 2011

Molecular Cancer Research

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“…In order to develop therapies, we need to better understand the cellular and molecular basis of clinical and phenotypic effects that convert tumor cells to metastases. Major cellular events involved in tumor metastasis are relaxed proliferation controls, diminished cell-cell adhesion, altered cell interaction with extracellular matrix (ECM), increased activity of stromal fibroblasts and immune cells (Arya et al, 2006), increased hypoxia and nutritional deprivation, and production of an adequate blood supply (angiogenesis), entrance into (intravasation) and exit from (extravasation) blood or lymph, and implantation and proliferation at metastatic sites. Metastasis is an inefficient process because many tumor cells die (Weiss, 1990).…”

Section: The Drives and Operatives Of Metastasis Continuummentioning

confidence: 99%

Metastasis and AKT activation

Shen

Qiao

Pardee

2008

Journal Cellular Physiology

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Metastasis, responsible for 90% of cancer patient deaths, is an inefficient process because many tumor cells die. The survival of metastatic tumor cells should be considered as a critical therapeutic target. This review provides a new perspective regarding the role of AKT in tumor survival, and the rationale to target AKT in anti-metastasis therapies.J. Cell. Physiol. 218: 451-454, 2009. ß 2008 Wiley-Liss, Inc. The Drives and Operatives of Metastasis ContinuumMetastasis is the spread of cancer cells from their primary location to other parts of the body. Once cancer becomes metastatic, it cannot be effectively treated by surgical and radiation therapies. Metastasis is the predominant cause of cancer-related mortality. In order to develop therapies, we need to better understand the cellular and molecular basis of clinical and phenotypic effects that convert tumor cells to metastases. Major cellular events involved in tumor metastasis are relaxed proliferation controls, diminished cell-cell adhesion, altered cell interaction with extracellular matrix (ECM), increased activity of stromal fibroblasts and immune cells (Arya et al., 2006), increased hypoxia and nutritional deprivation, and production of an adequate blood supply (angiogenesis), entrance into (intravasation) and exit from (extravasation) blood or lymph, and implantation and proliferation at metastatic sites. Metastasis is an inefficient process because many tumor cells die (Weiss, 1990). In fact, death can be triggered at every step: immune surveillance, disruption of cell-cell contacts, changes of the matrix ligands of the epithelial cell surface integrin receptors, lack of oxygen and nutrients, and physical trauma as tumor cells force their path of migration through the endothelial tissue barrier. Tumor cells must be equipped with at least three essential operatives that can evolve to overcome barriers posed by constantly changing microenviroment (Fig. 1A). One operative, by which malignant cells escape the surrounding matrix and become migratory and invasive, is to adopt the phenotypes of mesenchymal cells known as the epithelial-to-mesenchymal transition (EMT). A second mechanism must arise to resist apoptosis. A third stimulates neovascularization to sustain the local supply of oxygen and nutrients. The sustaining power of tumor cells driving them toward an open-ended continuum of metastatic operation is their unique mutator phenotype, which also confers increased plasticity of epigenetic regulation. At the center of metastatic drive is the combination of the tumor cells' limitless replicative potential and their increased ability to survive.One of the key tumor survival mechanisms is the AKT signaling pathway (Franke et al., 1995). Three homologous AKT isoforms (AKT1, AKT2, and AKT3) are members of the AGC kinase family (Woodgett, 2005). The biological and biochemical characteristics of AKTs have been extensively reviewed. Briefly, in response to survival signals, activated phosphatidylinositol 3-OH kinase (PI3K) phosphorylates phosphatidylinosito...

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“…It is a multistep process, and the steps are similar in all tumors. Mobilization of tumor cells is an important step in metastasis (3). Ion channels regulate, and stimulate numerous behavioral changes in cells that are associated with cancer and metastasis, including cell movement (elongation and lateral motility) (4,5), migration, galvanotaxis (6) and invasion (7,8).…”

Section: Introductionmentioning

confidence: 99%

Effects of Hedera helix L. extracts on rat prostate cancer cell proliferation and motility

Aktaş

Altun

2016

Oncology Letters

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Abstract. Hedera helix L., a member of Araliaceae family, has antiproliferative, cytotoxic, antimicrobial, antifungal, antiprotozoal and anti-inflammatory effects, and is used in cosmetics. The aim of the present study was to investigate the effect of treatment with extracts of leaves and unripened fruits of H. helix on rat prostate cancer cell lines with markedly different metastatic potentials: Mat-LyLu cells (strongly metastatic) and AT-2 cells (weakly metastatic). The effects of the extracts on cell kinetics and migration were determined. Tetrodotoxin was used to block the voltage-gated sodium channels (VGSCs) associated specifically with Mat-LyLu cells. Cell proliferation was detected spectrophotometrically using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. The mitotic index was determined using the Feulgen staining method. Lateral motility was quantified by wound-healing assays. The results of the present study demonstrated that cell kinetics (proliferation and mitotic activity) and motility were inhibited by ethanolic leaf extract of H. helix. The ethanolic extract of H. helix fruit suppressed Mat-LyLu cell migration, with no effect on proliferation. The opposite effects were observed in AT-2 cells; migration was not affected but proliferation was inhibited. In conclusion, the ethanolic fruit extract of H. helix may inhibit the cell migration of Mat-LyLu cells by blocking VGSCs. However, the effect of ethanolic leaf extract of H. helix treatment on the lateral motility of the cancer cells is unclear. IntroductionProstate cancer is the second most common cause of cancer-associated mortality among men worldwide (1). By the time prostate cancer is diagnosed, metastasis has occurred in the majority of men, as early prostate cancer has no symptoms. Metastatic diseases are a significant public health problem affecting cancer patients and their families (2). Metastasis occurs when malignant cells leave the primary tumor, migrate via the circulatory system, localize in distant areas and lead to the development of secondary tumors. It is a multistep process, and the steps are similar in all tumors. Mobilization of tumor cells is an important step in metastasis (3). Ion channels regulate, and stimulate numerous behavioral changes in cells that are associated with cancer and metastasis, including cell movement (elongation and lateral motility) (4,5), migration, galvanotaxis (6) and invasion (7,8). A number of in vitro (9-11) and in vivo (12) studies performed using tetrodotoxin (TTX), which specifically blocks voltage-gated sodium channels (VGSCs) (13), have suggested that the plasma membrane of prostate cancer cells may gain a more excitable phenotype due to increased VGSC expression, and thus malignancy is able to progress. Bennett et al (11) demonstrated that VGSC expression was 'necessary' and 'enough' for the invasiveness of prostate cancer cells. Prostate cancer tends to invade the bones, lungs and lymph nodes (14). Combating metastasis formation and growth are important for succ...

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The metastatic cascade in prostate cancer

Cited by 102 publications

References 102 publications

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells

Metastasis and AKT activation

Effects of Hedera helix L. extracts on rat prostate cancer cell proliferation and motility

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