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Plant-derived natural products are significant resources for drug discovery and development including appreciable potentials in preventing and managing oxidative stress, making them promising candidates in cancer and other disease therapeutics. Their effects have been linked to phytochemicals such as phenolic compounds and their antioxidant activities. The abundance and complexity of these bio-constituents highlight the need for well-defined in vitro characterization and quantification of the plant extracts/preparations that can translate to in vivo effects and hopefully to clinical use. This review article seeks to provide relevant information about the applicability of cell-based assays in assessing anti-cytotoxicity of phytochemicals considering several traditional and current methods.
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Antioxidantes/toxicidade , Antioxidantes/uso terapêutico , Compostos Fitoquímicos/toxicidade , Compostos Fitoquímicos/uso terapêutico , Animais , Humanos , Estresse Oxidativo , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Testes de ToxicidadeRESUMO
INTRODUCTION: Neck pain presents a tremendous physical and financial burden. This study compared the efficacy of the complementary and alternative medical treatments of integrative muscular movement technique (IMMT) and Swedish massage on neck pain in women of occupation age, the largest demographic group with neck pain. METHODS: A total of 38 women were assigned to IMMT (n=28) or Swedish massage (n=10) in a blinded manner. Both groups received eight 30-minute treatments over 4 weeks. Cervical range of motion (ROM) in flexion, extension, sidebending, and rotation was measured before and after treatment. Each patient's pain was assessed by using an analogue pain scale of 0-10. RESULTS: Compared with the Swedish massage group, patients receiving IMMT experienced a significant increase in ROM in cervical flexion (p<0.001), extension (p<0.001), sidebending (p<0.05), and rotation (p<0.001). Absolute change in pain for IMMT was -1.75 units compared with -0.3 units for Swedish massage (p<0.05). CONCLUSION: Patients receiving the IMMT demonstrated significantly improved cervical ROM in every movement measured compared with Swedish massage. Inclusion of the IMMT in a treatment regimen for chronic neck pain may lead to decreased pain and increased cervical ROM. These positive effects of the IMMT intervention may have a role in enhancing functional outcomes in patients with neck pain.
Assuntos
Vértebras Cervicais , Dor Crônica/terapia , Movimento , Cervicalgia/terapia , Pescoço/patologia , Amplitude de Movimento Articular , Terapia de Tecidos Moles , Adulto , Terapia por Exercício , Feminino , Humanos , Massagem , Pessoa de Meia-Idade , Medição da Dor , Projetos Piloto , Rotação , Resultado do Tratamento , Adulto JovemRESUMO
TGF-ß, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-ß observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-ß-driven regulation of cell homeostasis. Analysis of the overall system model yields quantitative insight into how cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumour suppressor role of TGF-ß unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-ß is an effect of cancer cell phenotypic progression (specifically, acquired TGF-ß resistance), not the cause. We are thus able to explain precisely why the clinically observed correlation between elevated TGF-ß levels and poor prognosis is in fact consistent with TGF-ß's original (and unchanged) role as a tumour suppressor.
Assuntos
Transformação Celular Neoplásica/metabolismo , Retroalimentação Fisiológica , Modelos Biológicos , Neoplasias/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Simulação por Computador , HumanosRESUMO
BACKGROUND: Neck pain is a generalized condition resulting from a complex etiology with presentation of a wide variety of symptoms. Neck pain is most often accompanied by decreased range of motion (ROM), muscle and joint stiffness, and limitations in functional capabilities. This condition may result in significant personal and societal burden. PURPOSE: We evaluated the effectiveness of a novel massage therapy intervention by following the treatment regimen and outcomes of two patients experiencing chronic neck pain. PARTICIPANTS: Two patients (46 and 53 years old) experienced chronic (>5 years) neck pain. Both patients reported pain, limited ROM, and muscle and joint stiffness. Additionally, the first patient reported a lack of sleep, and both patients stated their pain interfered with their quality of life and activities of daily living. INTERVENTION: Patients received the Integrative Muscular Movement Technique (IMMT) intervention approximately twice a week for a total of eight treatments, each approximately 20 minutes in duration. RESULTS: Both patients experienced a reduction in pain and an increase in cervical ROM in flexion, extension, rotation, and sidebending. The first patient also reported an increased ability to sleep. Both patients reported an increased ability to perform activities of daily living, including work-related responsibilities. CONCLUSIONS: For the two patients included in this report, therapist observations and patient reports indicate that inclusion of the IMMT treatment in a treatment regimen for chronic neck pain may lead to decreased pain and increased cervical ROM. These positive effects of the IMMT intervention may have a role in enhancing functional outcomes of these patients.
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A reduction in progenitor cell populations that help preserve vascular continuity and induce vascularization may accentuate endothelial cell apoptosis and dysfunction, ultimately contributing to organ failure and increased cardiovascular disease in chronic kidney disease (CKD). We hypothesized that CD45+ myeloid and CD34+ hematopoietic circulating progenitor cell (CPC) subpopulations would be reduced, peripheral blood mononuclear cell (PBMNC) colony-forming units (CFU) would be impaired, and flow-mediated dilation (FMD) would be impaired in patients with moderate-to-severe CKD as compared with healthy controls. Eleven moderate-to-severe CKD patients (mean estimated glomerular filtration rate [eGFR]: 36 ± 5) and 14 healthy controls were studied; blood was drawn and FMD was assessed by brachial artery FMD. CPCs were quantified via flow cytometry, and isolated PBMNCs were cultured for the colony-forming assay. CKD patients had significantly impaired FMD; lower CD34+, CD34+/KDR+, CD34+/CD45- and CD34+/KDR+/CD45- hematopoietic CPCs; lower CD45+, CD45+/KDR+, CD34+/CD45+ and CD34+/KDR+/CD45+ myeloid CPCs; and impaired CFUs as compared with healthy controls. Regression analysis revealed that CD34+, CD34+/KDR+ and CD34+/CD45- hematopoietic CPCs were associated positively with eGFR and negatively with blood urea nitrogen and serum creatinine. The CD45+/KDR+ myeloid CPCs also were associated positively with eGFR and negatively with serum creatinine. CD34+ hematopoietic CPCs and CD45+/KDR+ as well as CD34+/CD45+ myeloid CPCs were associated positively with FMD. In conclusion, myeloid and hematopoietic CPCs are reduced and associated with renal function as well as FMD in CKD. Therefore, reductions in CPCs may be a potential mechanism by which vascular integrity is compromised, increasing cardiovascular disease risk and contributing to renal disease progression in CKD.
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Células-Tronco Hematopoéticas/fisiologia , Falência Renal Crônica/fisiopatologia , Vasodilatação/fisiologia , Estudos de Casos e Controles , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Feminino , Citometria de Fluxo , Taxa de Filtração Glomerular , Humanos , Contagem de Leucócitos , Leucócitos Mononucleares/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Immobilized recombinant perlecan domain I (PlnDI) binds and modulates the activity of heparin-binding growth factors, in vitro. However, activities for PlnDI, in solution, have not been reported. In this study, we assessed the ability of soluble forms to modulate vascular endothelial growth factor-165 (VEGF165) enhanced capillary tube-like formation, and VEGF receptor-2 phosphorylation of human bone marrow endothelial cells, in vitro. RESULTS: In solution, PlnDI binds VEGF165 in a heparan sulfate and pH dependent manner. Capillary tube-like formation is enhanced by exogenous PlnDI; however, PlnDI/VEGF165 mixtures combine to enhance formation beyond that stimulated by either PlnDI or VEGF165 alone. PlnDI also stimulates VEGF receptor-2 phosphorylation, and mixtures of PlnDI/VEGF165 reduce the time required for peak VEGF receptor-2 phosphorylation (Tyr-951), and increase Akt phosphorylation. PlnDI binds both immobilized neuropilin-1 and VEGF receptor-2, but has a greater affinity for neuropilin-1. PlnDI binding to neuropilin-1, but not to VEGF receptor-2 is dependent upon the heparan sulfate chains adorning PlnDI. Interestingly, the presence of VEGF165 but not VEGF121 significantly enhances PlnDI binding to Neuropilin-1 and VEGF receptor-2. CONCLUSIONS: Our observations suggest soluble forms of PlnDI are biologically active. Moreover, PlnDI heparan sulfate chains alone or together with VEGF165 can enhance VEGFR-2 signaling and angiogenic events, in vitro. We propose PlnDI liberated during basement membrane or extracellular matrix turnover may have similar activities, in vivo.
Assuntos
Células da Medula Óssea/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Proteoglicanas de Heparan Sulfato/química , Proteoglicanas de Heparan Sulfato/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/citologia , Proteoglicanas de Heparan Sulfato/isolamento & purificação , Proteoglicanas de Heparan Sulfato/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Estrutura Terciária de Proteína , Transdução de Sinais/efeitos dos fármacos , SolubilidadeRESUMO
Chemokines and their corresponding receptor interactions have been shown to be involved in prostate cancer (PCa) progression and organ-specific metastasis. We have recently shown that PCa cell lines and primary prostate tumors express CXCR5, which correlates with PCa grade. In this study, we present the first evidence that CXCL13, the only ligand for CXCR5, and IL-6 were significantly elevated in PCa patient serum compared to serum from subjects with benign prostatic hyperplasia (BPH), or high-grade prostatic intraepithelial neoplasia (HGPIN) as well as normal healthy donors (NHD). Serum CXCL13 levels significantly (p<0.0001) correlated with serum prostate-specific antigen (PSA), whereas serum IL-6 levels significantly (p<0.0003) correlated with CXCL13 serum levels. CXCL13 was found to be a better predictor of PCa than PSA. CXCL13 was highly expressed by human bone marrow endothelial (HBME) cells and osteoblasts (OBs), but not osteoclasts (OCs), following treatment with physiologically relevant levels of interleukin-6 (IL-6). We further demonstrate that CXCL13, produced by IL-6-treated HBME cells, was able to induce PCa cell invasion in a CXCR5-dependent manner. CXCL13-mediated PCa cell adhesion to HBME cells and alpha(v)beta(3)-integrin clustering was abrogated by CXCR5 blockade. These results demonstrate that the CXCL13-CXCR5 axis is significantly associated with PCa progression.
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Adesão Celular/fisiologia , Quimiocina CXCL13/sangue , Integrinas/metabolismo , Invasividade Neoplásica/patologia , Neoplasias da Próstata/sangue , Biomarcadores Tumorais/sangue , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-6/metabolismo , Masculino , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Neoplasia Prostática Intraepitelial/sangue , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologia , Receptores CXCR5/metabolismo , Células Estromais/metabolismoRESUMO
Transforming growth factor beta (TGF-beta) signaling, which regulates multiple cellular processes including proliferation, apoptosis, and differentiation, plays an important but incompletely understood role in normal and cancerous tissues. For instance, although TGF-beta functions as a tumor suppressor in the premalignant stages of tumorigenesis, paradoxically, it also seems to act as a tumor promoter in advanced cancer leading to metastasis. The mechanisms by which TGF-beta elicits such diverse responses during cancer progression are still not entirely clear. As a first step toward understanding TGF-beta signaling quantitatively, we have developed a comprehensive, dynamic model of the canonical TGF-beta pathway via Smad transcription factors. By describing how an extracellular signal of the TGF-beta ligand is sensed by receptors and transmitted into the nucleus through intracellular Smad proteins, the model provides quantitative insight into how TGF-beta-induced responses are modulated and regulated. Subsequent model analysis shows that mechanisms associated with Smad activation by ligand-activated receptor, nuclear complex formation among Smad proteins, and inactivation of ligand-activated Smad (e.g., degradation, dephosphorylation) may be critical for regulating TGF-beta-targeted functional responses. The model was also used to predict dynamic characteristics of the Smad-mediated pathway in abnormal cells, from which we generated four testable hypotheses regarding potential mechanisms by which TGF-beta's tumor-suppressive roles may appear to morph into tumor-promotion during cancer progression.
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Modelos Biológicos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Transporte Ativo do Núcleo Celular , Algoritmos , Núcleo Celular/metabolismo , Expressão Gênica , Análise dos Mínimos Quadrados , Ligantes , Mutação , Neoplasias/metabolismo , Fosforilação , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad/metabolismoAssuntos
Neoplasias/patologia , Animais , Humanos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/metabolismoRESUMO
An unbiased cDNA expression phage library derived from bone-marrow endothelial cells was used to identify novel surface adhesion molecules that might participate in metastasis. Herein we report that reticulocalbin 1 (RCN1) is a cell surface-associated protein on both endothelial (EC) and prostate cancer (PCa) cell lines. RCN1 is an H/KDEL protein with six EF-hand, calcium-binding motifs, found in the endoplasmic reticulum. Our data indicate that RCN1 also is expressed on the cell surface of several endothelial cell lines, including human dermal microvascular endothelial cells (HDMVECs), bone marrow endothelial cells (BMEC), and transformed human bone marrow endothelial cells (TrHBMEC). While RCN1 protein levels were highest in lysates from HDMVEC, this difference was not statistically significant compared BMEC and TrHBMEC. Given preferential adhesion of PCa to bone-marrow EC, these data suggest that RCN1 is unlikely to account for the preferential metastasis of PCa to bone. In addition, there was not a statistically significant difference in total RCN1 protein expression among the PCa cell lines. RCN1 also was expressed on the surface of several PCa cell lines, including those of the LNCaP human PCa progression model and the highly metastatic PC-3 cell line. Interestingly, RCN1 expression on the cell surface was upregulated by tumor necrosis factor alpha treatment of bone-marrow endothelial cells. Taken together, we show cell surface localization of RCN1 that has not been described previously for either PCa or BMEC and that the surface expression on BMEC is regulated by pro-inflammatory TNF-alpha.
Assuntos
Osso e Ossos/citologia , Proteínas de Ligação ao Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Neoplasias da Próstata/patologia , Fator de Necrose Tumoral alfa/farmacologia , Western Blotting , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular , Membrana Celular/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Microscopia Confocal , Biblioteca de Peptídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We present statistical details for estimating an in vitro 50% inhibitory concentration (IC(50)), based on several models for continuous response data fit to bone-marrow endothelial cell lines replicated in vehicle and at several dose increments. Nonlinear models are fit via maximum likelihood assuming normal errors, and primary attention is given to exponential, Gompertz, and scaled logistic dose-response curves that admit increasing or decreasing monotonic and sigmoidal patterns. Careful consideration is given to dose axis scaling, comparative model fit via mean squared error and graphical assessment, analogues to weighted least squares analysis to address heterogeneity of variance across doses, and potential hormetic effects. Standard error estimation is discussed in detail, highlighting the advantage of reparameterizing dose-response models directly in terms of IC(50). Specific results for two cell lines are provided, along with a sample commercial software-based program for implementing a selection of the methods discussed.
Assuntos
Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Dinâmica não Linear , Projetos de Pesquisa , Humanos , Funções Verossimilhança , Modelos Logísticos , Modelos EstatísticosRESUMO
BACKGROUND: The Rho GTPases comprise one of the eight subfamilies of the Ras superfamily of monomeric GTP-binding proteins and are involved in cytoskeletal organization. Previously, using a dominant negative construct, we demonstrated a role for RhoC GTPase in conferring invasive capabilities to PC-3 human prostate cancer cells. Further, we demonstrated that inactivation of RhoC led to morphological changes commensurate with epithelial to mesenchymal transition (EMT) and was accompanied by increased random, linear motility and decreased directed migration and invasion. EMT was related positively to sustained expression and activity of Rac GTPase. In the current study we analyze the individual roles of RhoA, RhoC and Rac1 GTPases in PC-3 cell directed migration, invasion and tumor cell diapedesis across a human bone marrow endothelial cell layer in vitro. RESULTS: Use of specific shRNA directed against RhoA, RhoC or Rac1 GTPases demonstrated a role for each protein in maintaining cell morphology. Furthermore, we demonstrate that RhoC expression and activation is required for directed migration and invasion, while Rac1 expression and activation is required for tumor cell diapedesis. Inhibition of RhoA expression produced a slight increase in invasion and tumor cell diapedesis. CONCLUSIONS: Individual Rho GTPases are required for critical aspects of migration, invasion and tumor cell diapedesis. These data suggest that coordinated activation of individual Rho proteins is required for cells to successfully complete the extravasation process; a key step in distant metastasis.
Assuntos
Movimento Celular/fisiologia , Invasividade Neoplásica/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Proteínas rho de Ligação ao GTP/metabolismo , Western Blotting , Linhagem Celular Tumoral , Imunofluorescência , Humanos , Masculino , Microscopia Confocal , Pseudópodes/ultraestruturaRESUMO
In order for cancer cells to successfully colonize a metastatic site, they must detach from the primary tumor using extracellular matrix-degrading proteases, intravasate and survive in the circulation, evade the immune response, and extravasate the vasculature to invade the target tissue parenchyma, where metastatic foci are established. Though many of the steps of metastasis are widely studied, the precise cellular interactions and molecular alterations associated with extravasation are unknown, and further study is needed to elucidate the mechanisms inherent to this process. Studies of leukocytes localized to inflamed tissue during the immune response may be used to elucidate the process of cancer extravasation, since leukocyte diapedesis through the vasculature involves critical adhesive interactions with endothelial cells, and both leukocytes and cancer cells express similar surface receptors capable of binding endothelial adhesion molecules. Thus, leukocyte extravasation during the inflammatory response has provided a model for transendothelial migration (TEM) of cancer cells. Leukocyte extravasation is characterized by a process whereby rolling mediated by cytokine-activated endothelial selectins is followed by firmer adhesions with beta1 and beta2 integrin subunits to an activated endothelium and subsequent diapedesis, which most likely involves activation of Rho GTPases, regulators of cytoskeletal rearrangements and motility. It is controversial whether such selectin-mediated rolling is necessary for TEM of cancer cells. However, it has been established that similar stable adhesions between tumor and endothelial cells precede cancer cell transmigration through the endothelium. Additionally, there is support for the preferential attachment of tumor cells to the endothelium and, accordingly, site-specific metastasis of cancer cells. Rho GTPases are critical to TEM of cancer cells as well, and some progress has been made in understanding the specific roles of the Rho GTPase family, though much is still unknown. As the mechanisms of cancer TEM are elucidated, new approaches to study and target metastasis may be utilized and developed.
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Metástase Neoplásica , Células Neoplásicas Circulantes , Animais , Adesão Celular , Moléculas de Adesão Celular/fisiologia , Endotélio Vascular/fisiologia , Humanos , Leucócitos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Selectinas/fisiologia , Proteínas rho de Ligação ao GTP/fisiologiaRESUMO
Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed almost exclusively in prostatic epithelial cells. Expression of PSMA is elevated in prostate cancer, with levels closely correlated with disease grade. Although the highest levels of PSMA expression are associated with high-grade, hormone-refractory and metastatic prostate cancer, the significance of elevated PSMA expression in advanced prostate cancer has yet to be fully elucidated. We provide evidence that prostatic carcinoma cells expressing PSMA exhibit reduced motility and increased attachment when grown on a bone marrow matrix substrate. This phenomenon occurs via activation of focal adhesion kinase and provides the first evidence of a link between PSMA expression and prostate cancer metastasis to the bone.
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Antígenos de Superfície/metabolismo , Neoplasias Ósseas/secundário , Adesão Celular , Movimento Celular , Glutamato Carboxipeptidase II/metabolismo , Neoplasias da Próstata/patologia , Actinas/análise , Antígenos de Superfície/análise , Medula Óssea/metabolismo , Matriz Óssea/metabolismo , Neoplasias Ósseas/química , Neoplasias Ósseas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Glutamato Carboxipeptidase II/análise , Humanos , Masculino , Fosforilação , Neoplasias da Próstata/química , Neoplasias da Próstata/metabolismo , Pseudópodes/química , Células Tumorais Cultivadas , Tirosina/metabolismoRESUMO
BACKGROUND: Stromal cell-derived factor-1 (SDF-1 or CXCL12) and CXCR4 are key elements in the metastasis of prostate cancer cells to bone--but the mechanisms as to how it localizes to the marrow remains unclear. METHODS: Prostate cancer cell lines were stimulated with SDF-1 and evaluated for alterations in the expression of adhesion molecules using microarrays, FACs, and Western blotting to identify alpha(v)beta(3) receptors. Cell-cell adhesion and invasion assays were used to verify that activation of the receptor is responsive to SDF-1. RESULTS: We demonstrate that SDF-1 transiently regulates the number and affinity of alpha(v)beta(3) receptors by prostate cancer cells to enhance their metastatic behavior by increasing adhesiveness and invasiveness. SDF-1 transiently increased the expression of beta(3) receptor subunit and increased its phosphorylation in metastatic but not nonmetastatic cells. CONCLUSIONS: The transition from a locally invasive phenotype to a metastatic phenotype may be primed by the elevated expression of alpha(v)beta(3) receptors. Activation and increased expression of alpha(v)beta(3) within SDF-1-rich organs may participate in metastatic localization.
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Quimiocinas CXC/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Integrina alfaVbeta3/biossíntese , Integrina alfaVbeta3/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/fisiologia , Masculino , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fenótipo , Fosforilação , Neoplasias da Próstata/genética , Ligação Proteica/genética , Ligação Proteica/fisiologia , Células Tumorais CultivadasRESUMO
Microvessel density is a prognostic factor for many cancers, including prostate. For this reason, several studies and therapeutic approaches that target the tumor microvasculature have been attempted. Thalidomide has long been recognized as an antiangiogenic molecule. Recently, this drug has regained favor as an anticancer agent and is in clinical trial for multiple myeloma and prostate cancer, among others. This article will briefly review the proposed mechanisms of action for thalidomide, discuss why these activities are of therapeutic value in diseases currently undergoing clinical trials, and summarize the current status of clinical trials for prostate cancer. The focus will be predominantly on the relationship of thalidomide to angiogenesis, as well as on the future and potential value of thalidomide-inspired structural derivatives.
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Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Neovascularização Patológica , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Talidomida/farmacologia , Talidomida/uso terapêutico , Ensaios Clínicos como Assunto , Esquema de Medicação , Humanos , Masculino , PrognósticoRESUMO
Prostate cancer (PCa) is no exception to the multi-step process of metastasis. As PCa progresses, changes occur within the microenvironments of both the malignant cells and their targeted site of metastasis, enabling the necessary responses that result in successful translocation. The majority of patients with progressing prostate cancers develop skeletal metastases. Despite advancing efforts in early detection and management, there remains no effective, long-term cure for metastatic PCa. Therefore, the elucidation of the mechanism of PCa metastasis and preferential establishment of lesions in bone is an intensive area of investigation that promises to generate new targets for therapeutic intervention. This review will survey what is currently know concerning PCa interaction with the extracellular matrix (ECM) and the roles of factors within the tumor and ECM microenvironments that contribute to metastasis. These will be discussed within the context of changes in expression and functional heterodimerization patterns of integrins, changes in ECM expression and reorganization by proteases facilitating invasion. In this context we also provide a brief summary of how growth factors (GFs), cytokines and regulatory signaling pathways favor PCa metastasis to bone.
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Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/secundário , Animais , Humanos , Masculino , Proteínas de Neoplasias/metabolismoRESUMO
Prostate cancer metastasis to bone may be mediated by preferential proliferation of these cells in the bone's microenvironment. We hypothesize that this preferential proliferation is mediated by bone-associated growth factors (GFs) and cytokines. To test our hypothesis, human prostate cancer cells, derived from both soft tissue (LNCaP, DuCaP, DU145) and bone metastases (PC-3, VCaP, MDA-2a, MDA-2b), were treated with bone-associated GFs and cytokines (PDGF, IGF-1, TGF-beta, EGF, bFGF, TNF-alpha, IL-1, and IL-6) for 48 h, and their growth responses were compared. The responses of soft tissue-derived prostate cancer cell lines to bone GFs and cytokines were variable. LNCaP cell growth was stimulated by IGF-1 but was inhibited by TNF-alpha. DU145 cell growth was stimulated with EGF. Prostate cancer cell lines derived from bone metastases also responded variably to bone GFs and cytokines. IL-1 stimulated the growth of MDA-2a and 2b cell lines in a dose-dependent manner. PDGF and bFGF both demonstrated variable effects on bone-derived prostate cancer cell lines. TNF-alpha inhibited proliferation of the VCaP cells. These findings demonstrate that human prostate cancer cell lines derived from bone metastases may not respond preferentially to bone-associated GFs and cytokines.
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Neoplasias Ósseas/metabolismo , Citocinas/metabolismo , Substâncias de Crescimento/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Tecidos Moles/metabolismo , Neoplasias Ósseas/secundário , Divisão Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-1/metabolismo , Masculino , Metástase Neoplásica , Neoplasias de Tecidos Moles/secundário , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Prostate carcinoma (PC) frequently metastasizes to bone, where it causes significant morbidity and mortality. Stromal elements in the primary and metastatic target organs are important mediators of tumor cell intravasation, chemoattraction, adhesion to target organ microvascular endothelium, extravasation, and growth at the metastatic site. METHODS: The role of stromal factors in bone metastasis was determined with a cyclic DNA microarray comparison of a bone-derived cell PC cell line with a soft tissue-derived cell PC cell line and by evaluating the effects of selected stromal components on PC cell chemotaxis, cell adhesion to human bone marrow endothelium (HBME), and PC cell growth. RESULTS: The authors demonstrate that PC cells express protease-activated receptor 1 (PAR1; thrombin receptor), and its expression is up-regulated in PC compared with normal prostate tissue. In addition, this overexpression was very pronounced in bone-derived PC cell lines (VCaP and PC-3) compared with soft tissue PC cell lines (DUCaP, DU145, and LNCaP). The authors report that bone stromal factors, including stromal cell-derived factor 1 (SDF-1) and collagen Type I peptides, are chemoattractants for PC cells, and they demonstrate that some of these factors (e.g., extracellular matrix components, transforming growth factor beta, bone morphogenic proteins [BMPs], and SDF-1) significantly alter PC-HBME interaction in vitro. Finally, stromal factors, such as BMPs, can regulate the proliferation of PC cells in vitro. CONCLUSIONS: Soluble and insoluble elements of the stroma are involved in multiple steps of PC metastasis to bone. The authors hypothesize that PAR1 may play a central role in prostate tumorigenesis.