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Tumor Microenvironment (tumor + microenvironment)
Selected AbstractsTumor microenvironment in head and neck squamous cell carcinomas: Predictive value and clinical relevance of hypoxic markers.HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 6 2007A review Abstract Background. Hypoxia and tumor cell proliferation are important factors determining the treatment response of squamous cell carcinomas of the head and neck. Successful approaches have been developed to counteract these resistance mechanisms although usually at the cost of increased short- and long-term side effects. To provide the best attainable quality of life for individual patients and the head and neck cancer patient population as a whole, it is of increasing importance that tools be developed that allow a better selection of patients for these intensified treatments. Methods. A literature review was performed with special focus on the predictive value and clinical relevance of endogenous hypoxia-related markers. Results. New methods for qualitative and quantitative assessment of functional microenvironmental parameters such as hypoxia, proliferation, and vasculature have identified several candidate markers for future use in predictive assays. Hypoxia-related markers include hypoxia inducible factor (HIF)-1,, carbonic anhydrase IX, glucose transporters, erythropoietin receptor, osteopontin, and others. Although several of these markers and combinations of markers are associated with treatment outcome, their clinical value as predictive factors remains to be established. Conclusions: A number of markers and marker profiles have emerged that may have potential as a predictive assay. Validation of these candidate assays requires testing in prospective trials comparing standard treatment against experimental treatments targeting the related microregional constituent. © 2007 Wiley Periodicals, Inc. Head Neck, 2007 [source] pH-Activated Near-Infrared Fluorescence Nanoprobe Imaging Tumors by Sensing the Acidic MicroenvironmentADVANCED FUNCTIONAL MATERIALS, Issue 14 2010Cong Li Abstract Imaging tumors in their early stages is crucial to increase the surviving rate of cancer patients. Currently most fluorescence probes visualize the neoplasia by targeting the tumor-associated receptor over-expressed on the cancer cell membrane. However, the expression level of these receptors in vivo is hard to predict, which limits their clinical translation. Furthermore, the signal output of these receptor-targeting probes usually stays at a high level, which leads to a strong background signal in normal tissue due to non-specific binding. In contrast to receptors, characteristics of the tumor microenvironment , such as acidosis , are pervasive in almost all solid tumors and can be easily accessed. In this work, a novel biodegradable nanoprobe InNP1 that demonstrates pH-activated near-infrared (NIR) fluorescence in both human glioblastoma U87MG cancer cells in vitro and the subcutaneous U87MG tumor xenografts in vivo is developed. Bio-distribution, in vivo optical imaging, and autoradiography studies demonstrate that the pH-activated NIR fluorescence is the dominant factor responsible for the high tumor/normal tissue (T/N) ratio of InNP1 in vivo. Overall, the work provides a nanoprobe prototype to visualize the solid tumor in vivo with high sensitivity and minimal systemic toxicity by sensing the tumor acidic microenvironment. [source] Cooperative expression of junctional adhesion molecule-C and -B supports growth and invasion of gliomaGLIA, Issue 5 2010Mirna Tenan Abstract Brain invasion is a biological hallmark of glioma that contributes to its aggressiveness and limits the potential of surgery and irradiation. Deregulated expression of adhesion molecules on glioma cells is thought to contribute to this process. Junctional adhesion molecules (JAMs) include several IgSF members involved in leukocyte trafficking, angiogenesis, and cell polarity. They are expressed mainly by endothelial cells, white blood cells, and platelets. Here, we report JAM-C expression by human gliomas, but not by their normal cellular counterpart. This expression correlates with the expression of genes involved in cytoskeleton remodeling and cell migration. These genes, identified by a transcriptomic approach, include poliovirus receptor and cystein-rich 61, both known to promote glioma invasion, as well as actin filament associated protein, a c-Src binding partner. Gliomas also aberrantly express JAM-B, a high affinity JAM-C ligand. Their interaction activates the c-Src proto-oncogene, a central upstream molecule in the pathways regulating cell migration and invasion. In the tumor microenvironment, this co-expression may thus promote glioma invasion through paracrine stimuli from both tumor cells and endothelial cells. Accordingly, JAM-C/B blocking antibodies impair in vivo glioma growth and invasion, highlighting the potential of JAM-C and JAM-B as new targets for the treatment of human gliomas. © 2009 Wiley-Liss, Inc. [source] pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidityINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Angelo De Milito Abstract Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg,1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients. [source] Biological indicators of prognosis in Ewing's sarcoma: An emerging role for lectin galactoside-binding soluble 3 binding protein (LGALS3BP)INTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Diana Zambelli Abstract Starting from an experimental model that accounts for the 2 most important adverse processes to successful therapy of Ewing's sarcoma (EWS), chemoresistance and the presence of metastasis at the time of diagnosis, we defined a molecular signature of potential prognostic value. Functional annotation of differentially regulated genes revealed 3 major networks related to cell cycle, cell-to-cell interactions and cellular development. The prognostic impact of 8 genes, representative of these 3 networks, was validated in 56 EWS patients. High mRNA expression levels of HINT1, IFITM2, LGALS3BP, STOML2 and c-MYC were associated with reduced risk to death and lower risk to develop metastasis. At multivariate analysis, LGALS3BP, a matricellular protein with a role in tumor progression and metastasis, was the most important predictor of event-free survival and overall survival. The association between LGALS3BP and prognosis was confirmed at protein level, when expression of the molecule was determined in tumor tissues but not in serum, indicating a role for the protein at local tumor microenvironment. Engineered enhancement of LGALS3BP expression in EWS cells resulted in inhibition of anchorage independent cell growth and reduction of cell migration and metastasis. Silencing of LGALS3BP expression reverted cell behavior with respect to in vitro parameters, thus providing further functional validation of genetic data obtained in clinical samples. Thus, we propose LGALS3BP as a novel reliable indicator of prognosis, and we offer genetic signatures to the scientific communities for cross-validation and meta-analysis, which are indispensable tools for a rare tumor such as EWS. [source] Silencing of hSlo potassium channels in human osteosarcoma cells promotes tumorigenesisINTERNATIONAL JOURNAL OF CANCER, Issue 2 2008Béatrice Cambien Abstract Potassium channels, the most diverse superfamily of ion channels, have recently emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large conductance Ca2+ -activated K+ channels, often referred to as BK channels, are at the crossroads of several tumor-associated processes such as cell proliferation, survival, secretion and migration. Despite the high BK channel expression in osteosarcoma (OS), their function has not yet been investigated in this malignant bone pathology. Here, using stable RNA interference to reduce the expression of hSlo, the human pore-forming ,-subunit of the BK channel, in human Cal72 OS cells, we show that BK channels play a functional role in carcinogenesis. Our results reveal for the first time that BK channels exhibit antitumoral properties in OS in vivo and affect the tumor microenvironment through the modulation of both chemokine expression and leukocyte infiltration. © 2008 Wiley-Liss, Inc. [source] IL-1, induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3, untranslated region: Involvement of divergent RNA-binding factors HuR, KSRP and TIAR,INTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Esther A. Suswam Abstract IL-8 plays an integral role in promoting the malignant phenotype in breast cancer, and its production is directly influenced by inflammatory cytokines in the tumor microenvironment. Here, we show that activation of IL-1, receptors on malignant HS578t and MDA-MB-231 breast cancer cells strongly induces IL-8 expression and that RNA stabilization is persistently activated at least 12,24 hr after stimulation. SB 203580 and rapamycin reversed the RNA stabilization effect of IL-1, in a dose-dependent manner, suggesting involvement of the p38/MAP kinase and mTOR pathways. A luciferase reporter assay indicated that the stabilization effect was dependent on cis elements in the 3,-untranslated region (UTR) of the IL-8 transcript. By UV cross-linking, we identified multiple cellular factors that interact with the IL-8 3,UTR, ranging 34,76 kDa. Immunoprecipitation analysis indicated that HuR, KSRP and TIAR bound to one or more loci in the 3,UTR. While the cross-linking patterns were similar, quantitative immunoprecipitation of native IL-8 RNA from IL-1,-stimulated cytoplasmic extract revealed a 20-fold greater association of transcript with the stabilizing factor HuR vs. the destabilizing factor KSRP. In conclusion, IL-1, is a potent cytokine stimulus for IL-8 RNA stabilization in breast cancer cells, possibly by enhanced binding of cytoplasmic HuR to the 3,UTR. Published 2004 Wiley-Liss, Inc. [source] Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and sezary syndrome)INTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Arnaud Cirée Abstract Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T cells. In mice, we have demonstrated that, depending on the model, IL-17 may act as a tumor growth-promoting or -inhibiting factor. In order to address the relevance of these models in human tumors, we look for the natural expression and activity of IL-17 in mycosis fungoides (MF) and Sezary syndrome (SS). These cutaneous T-cell lymphomas were selected because they are usually CD3+ CD4+ CD45RO+, a phenotype similar to nontransformed T cells producing IL-17. We show that in vitro activated malignant T cells derived from MF or SS patients express IL-17 mRNA and secrete this cytokine. However, IL-17 does not act in vitro as a growth factor for MF or SS cell lines. In addition, 5 out of 10 MF/SS biopsies expressed IL-17 mRNA, while this cytokine was not detected in normal skin. IL-17 was not observed in the biopsies derived from 2 patients initially identified as MF, whereas an upregulation of this cytokine was clearly demonstrated during progression of the disease in these patients. An association between IL-17 expression and polymorphonuclear neutrophil infiltration was also recorded in this group of MF/SS patients. A more detailed analysis of 2 patients with a pustular form of MF and SS revealed that IL-17 may participate in the recruitment of polymorphonuclear neutrophils via a paracrine mechanism involving keratinocyte-released IL-8. This study is the first report demonstrating that some human tumor cells could express IL-17, a cytokine that represents an early event in the development of the inflammatory reaction within the tumor microenvironment, a process that may influence tumor phenotype and growth. © 2004 Wiley-Liss, Inc. [source] Tumor-infiltrating lymphocytes derived from human renal cell carcinoma: Clonal analysis of its characteristicsINTERNATIONAL JOURNAL OF UROLOGY, Issue 3 2008Tomoyuki Shimabukuro Aim: To assess the characteristics of activated tumor-infiltrating lymphocytes (TIL), we report the isolation, growth response, and functional analysis of a CD4 - CD8+ TIL-clone derived from human renal cell carcinoma (RCC). Methods: Bulk TILs were expanded from a human RCC and the lymphocytes were separated into a CD8+ enriched population. Subsequently, using the limiting dilution technique, a TIL clone was established and its growth response, phenotype and cytotoxic activity were analyzed. Results: A clone, T16-13, by day 94 numbering 1 × 107 cells, was harvested and characterized as a CD4 - CD8+ clone. On day 144, the cytotoxic activity of this clone against the autologous tumor was relatively high (2.3 ± 0.7 LU30/106 cells). Meanwhile, against allogeneic renal tumors, there was no cytotoxic activity (,0.1 LU30/106 cells). Conclusions: A TIL clone possessing modest autologous tumor-specific cytotoxicity can be isolated from human RCC. The characteristics analysis of various TIL clones may provide a better understanding of an RCC tumor microenvironment and may help to establish new modalities for the treatment of patients with metastatic kidney cancer. [source] Conquering cancer through discovery researchIUBMB LIFE, Issue 9 2010William C. S. Cho Abstract Cancer is a leading cause of death worldwide. Cancer research improves our understanding of cancer biology, which leads to the discoveries of novel detection approaches and effective therapies for cancer. Translational cancer medicine changes essential science breakthroughs to the practice of medicine and uses clinical result to supply back into basic research. This article covers some studies in the field of translational cancer medicine including the identification of 319 driver genes and the 12 core cancer pathways, the use of MammaPrint in breast cancer, the development of OncoMap, the progress in genome-wide association studies, as well as the generation of microRNA networks in cancer and leukemia. Apart from cancer genome, cancer stem cells, immune and tumor microenvironment are also discussed. In addition, some innovations in translational cancer medicine are introduced. A number of targeted agents have been developed, such as the histone deacetylases inhibitors, poly(ADP-ribose) polymerase inhibitors, anti-mammalian target of rapamycin agents, and PI3K pathway inhibitors. There are also reports of the results from some important clinical trials, including the STAR P-2 trial, NeoBIG program, and BATTLE trial. This review focuses on discussions that emphasize the marriage between curiosity-driven basic research and patient care-focused clinical investigations. With highlights on the most up-to-date molecular, cellular, clinical, and therapeutic cancer research findings, this article tends to provide a wealth of insights into better understanding of the complexity of cancer. © 2010 IUBMB IUBMB Life, 62(9): 655,659, 2010 [source] Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growthJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2002Jack Lawler Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that influences cellular phenotype and the structure of the extracellular matrix. These effects are important components of the tissue remodeling that is associated with angiogenesis and neoplasia. The genetic mutations in oncogenes and tumor suppressor genes that occur within tumor cells are frequently associated with decreased expression of TSP-1. However, the TSP-1 that is produced by stromal fibroblasts, endothelial cells and immune cells suppresses tumor progression. TSP-1 inhibits angiogenesis through direct effects on endothelial cell migration and survival and through indirect effects on growth factor mobilization. TSP-1 that is present in the tumor microenvironment also acts to suppress tumor cell growth through activation of transforming growth factor , in those tumor cells that are responsive to TGF,. In this review, the molecular basis for the role of TSP-1 in the inhibition of tumor growth and angiogenesis is summarized. [source] Real time non-invasive imaging of receptor,ligand interactions in vivoJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2003Paul Winnard Abstract Non-invasive longitudinal detection and evaluation of gene expression in living animals can provide investigators with an understanding of the ontogeny of a gene's biological function(s). Currently, mouse model systems are used to optimize magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and optical imaging modalities to detect gene expression and protein function. These molecular imaging strategies are being developed to assess tumor growth and the tumor microenvironment. In addition, pre-labeling of progenitor cells can provide invaluable information about the developmental lineage of stem cells both in organogenesis and tumorigenesis. The feasibility of this approach has been extensively tested by targeting of endogenous tumor cell receptors with labeled ligand (or ligand analog) reporters and targeting enzymes with labeled substrate (or substrate analog). We will primarily discuss MRI, PET, and SPECT imaging of cell surface receptors and the feasibility of non-invasive imaging of gene expression using the tumor microenvironment (e.g., hypoxia) as a conditional regulator of gene expression. © 2003 Wiley-Liss, Inc. [source] miR-20b modulates VEGF expression by targeting HIF-1, and STAT3 in MCF-7 breast cancer cells,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Sandra Cascio MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of different genes, including genes involved in cancer progression. A functional link between hypoxia, a key feature of the tumor microenvironment, and miRNA expression has been documented. We investigated whether and how miR-20b can regulate the expression of vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells under normoxic and hypoxia-mimicking conditions (CoCl2 exposure). Using immunoblotting, ELISA, and quantitative real-time PCR, we demonstrated that miR-20b decreased VEGF protein levels at 4 and 24,h following CoCl2 treatment, and VEGF mRNA at 4,h of treatment. In addition, miR-20b reduced VEGF protein expression in untreated cells. Next, we investigated the molecular mechanism by which pre-miR-20b can affect VEGF transcription, focusing on hypoxia inducible factor 1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), transcriptional inducers of VEGF and putative targets of miR-20b. Downregulation of VEGF mRNA by miR-20b under a 4,h of CoCl2 treatment was associated with reduced levels of nuclear HIF-1, subunit and STAT3. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-1,, but not STAT3, was recruited to the VEGF promoter following the 4,h of CoCl2 treatment. This effect was inhibited by transfection of cells with pre-miR-20b. In addition, using siRNA knockdown, we demonstrated that the presence of STAT3 is necessary for CoCl2 -mediated HIF-1, nuclear accumulation and recruitment on VEGF promoter. In summary, this report demonstrates, for the first time, that the VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner. J. Cell. Physiol. 224:242,249, 2010 © 2010 Wiley-Liss, Inc. [source] Molecular targets: Tissue and tumor microenvironment and metastasis postersJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue S1 2009Article first published online: 17 JUN 200 First page of article [source] Double-Blind Placebo-Controlled Trial of Adjuvant Pamidronate with Palliative Radiotherapy and Intravenous Doxorubicin for Canine Appendicular Osteosarcoma Bone PainJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2009T.M. Fan Background: Canine osteosarcoma (OSA) causes focal malignant osteolysis leading to severe pain. Despite the documented efficacy of radiotherapy or IV aminobisphosphonates for managing cancer bone pain, their potential combined therapeutic value has not been reported in OSA-bearing dogs. Hypothesis: Pamidronate combined with standardized palliative therapy will improve pain control and bone biologic effects in OSA-bearing dogs. Animals: Fifty dogs with appendicular OSA treated with standardized palliative therapy and either pamidronate or sterile saline. Methods: Randomized, prospective, double-blinded, placebo-controlled study. Treatment responses for dogs receiving standardized palliative therapy with (n = 26) or without (n = 24) adjuvant pamidronate were serially evaluated for changes in subjective pain scores, urine N-telopeptide (NTx) excretion, primary tumor relative bone mineral density (rBMD), and computerized pressure platform gait analysis. Results: Median duration of subjective pain relief for dogs treated with adjuvant pamidronate or placebo was 76 and 75 days, respectively (P= .39). Forty percent (20/50; pamidronate [11/26] and placebo [9/24]) of dogs experienced durable analgesia, defined by pain alleviation ,112 days. For patients achieving durable pain control, dogs treated with pamidronate achieved greater reductions in NTx excretion and larger increases in rBMD compared with placebo controls. Changes in peak vertical force assessed by computerized pressure platform gait analysis correlated with pain alleviation in OSA-bearing dogs. Conclusions and Clinical Importance: Combining pamidronate with standardized palliative therapy is safe, but does not clearly improve pain alleviation. However, in dogs achieving durable pain control, adjuvant pamidronate appears to decrease focal bone resorption in the local tumor microenvironment. [source] Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applicationsNMR IN BIOMEDICINE, Issue 5 2004Bernard Gallez Abstract This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed. Copyright © 2004 John Wiley & Sons, Ltd. [source] Quantitative analysis of the secretome of TGF-, signaling-deficient mammary fibroblastsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 13 2010Baogang J. Xu Abstract Transforming growth factor , (TGF-,) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-, type II receptor (T,RII) in stromal cells is associated with increased tumor metastasis and shorter patient survival. In this study, SILAC quantitative proteomics was used to identify differentially externalized proteins in the conditioned media from the mammary fibroblasts with or without intact T,RII. Over 1000 proteins were identified and their relative differential levels were quantified. Immunoassays were used to further validate identification and quantification of the proteomic results. Differential expression was detected for various extracellular proteins, including proteases and their inhibitors, growth factors, cytokines, and extracellular matrix proteins. CXCL10, a cytokine found to be up-regulated in the T,RII knockout mammary fibroblasts, is shown to directly stimulate breast tumor cell proliferation and migration. Overall, this study revealed hundreds of specific extracellular protein changes modulated by deletion of T,RII in mammary fibroblasts, which may play important roles in the tumor microenvironment. These results warrant further investigation into the effects of inhibiting the TGF-, signaling pathway in fibroblasts because systemic inhibition of TGF-, signaling pathways is being considered as a potential cancer therapy. [source] Glycosaminoglycan-binding cytokines as tumor markersPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 16 2008Takashi Muramatsu Dr. Abstract A significant proportion of cytokines bind to glycosaminoglycans such as heparin. Glycosaminoglycans are involved in signaling, stabilization and/or storage of these cytokines. Typical examples of glycosaminoglycan-binding cytokines are basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), VEGF-C, hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), midkine, and pleiotrophin. All are present in the tumor microenvironment and promote tumor growth, tumor invasion and/or tumor angiogenesis. Serum or plasma levels of glycosaminoglycan-binding cytokines are frequently elevated in patients with various malignant tumors. High levels of these cytokines are usually correlated with the occurrence of metastasis and a poor prognosis. The mode of elevation of individual glycosaminoglycan-binding cytokines in patients with malignant tumors is summarized here. Further studies, especially with multiple cytokines, are expected to make assays clinically useful for both early detection and prognostic prediction. [source] Quantitative proteomes and in vivo secretomes of progressive and regressive UV-induced fibrosarcoma tumor cells: Mimicking tumor microenvironment using a dermis-based cell-trapped system linked to tissue chamberPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 24 2007Yang Shi Abstract The alterations of tumor proteome and/or in vivo secretome created by host-tumor cell interaction may be crucial factors for tumors to undergo progression or regression in a host system. Two UV-induced fibrosarcoma tumor cell lines (UV-2237 progressive cells and UV-2240 regressive cells) were used as models to address this issue. Hundreds of proteins including in vivo secretome have been identified and quantified via an isotope-coded protein label (ICPL) in conjunction with high-throughput NanoLC-LTQ MS analysis. A newly designed technology using a dermis-based cell-trapped system was employed to encapsulate and grow 3-D tumor cells. A tissue chamber inserted with a tumor cell-trapped dermis was implanted into mice to mimic the tumor microenvironment. The in vivo secretome created by host-tumor interaction was characterized from samples collected from tissue chamber fluids via ICPL labeling mass spectrometric analysis. Twenty-five proteins including 14-3-3 proteins, heat shock proteins, profilin-1, and a fragment of complement C3 with differential expression in proteomes of UV-2237 and UV-2240 cells were revealed. Three secreted proteins including myeloperoxidase, alpha-2-macroglobulin, and a vitamin D-binding protein have different abundances in the in vivo secretome in response to UV-2237 and UV-2240 cells. Differential tumor proteomes and in vivo secretome were thus accentuated as potential therapeutic targets to control tumor growth. [source] REVIEW ARTICLE: RCAS1, MT, and Vimentin as Potential Markers of Tumor Microenvironment RemodelingAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2010Magdalena Dutsch-Wicherek Citation Dutsch-Wicherek M. RCAS1, MT, and vimentin as potential markers of tumor microenvironment remodeling. Am J Reprod Immunol 2010; 63: 181,188 A tumor stimulates the remodeling of its microenvironment for its own survival. To protect its own growth and induce angiogenesis, the tumor changes the structure of extracellular matrix and the function of existing cells; it thus chemo-attracts immune system cells altering their function. In our study, we discuss the potential markers of tumor microenvironment remodeling. For instance, RCAS1 is a protein responsible for tumor escape from host immunologic surveillance that additionally seems to be involved in the remodeling of the microenvironment. Another protein, metallothionein, which is both anti-apoptotic and pro-proliferative, is also responsible for modulating the response of immune system cells. Most likely, the expression of this protein by the fibroblasts of tumor microenvironment is related to the remodeled phenotype of these cells because of the tumor influence on cancer-associated fibroblasts. Lastly, vimentin is a protein that would appear to be the marker for the mesenchymal transition of cells from the epithelial phenotype. These cells seem to acquire the mesenchymal phenotype to migrate so that they can facilitate the development of metastases. Interestingly, the expression of vimentin has also been observed in the tumor microenvironment as well and may serve as a marker of a remodeled stroma in the process of facilitating tumor spread. [source] Low COX2 in tumor and upregulation in stroma mark laryngeal squamous cell carcinoma progressionTHE LARYNGOSCOPE, Issue 9 2009Konstantinos Kourelis MD Abstract Objectives/Hypothesis: Invasive squamous cell carcinomas (SCC) of the larynx, like most solid tumors, are surrounded by a reactive stroma, in which cancer associated fibroblasts (CAFs) are the predominant cell type. This mesenchymal reaction may affect cancer progression multiply. The proinflammatory enzyme cyclooxygenase-2 (COX-2) has been correlated with head and neck cancer. This study aims to explore the impact of epithelial and stromal COX-2 expression on SCC behavior. Study Design: Retrospective case review study performed in a tertiary health center institution. Methods: Double immunohistochemistry of COX-2 and the CAF marker ,-smooth muscle actin (,-SMA) was utilized in 97 laryngeal cancer patients. Follow-up data were collected in 52 cases. Results: Low COX-2 immunostaining in cancer cells was associated with advanced grade (P = .044) and shorter recurrence-free period (P = .035). CAF expression was positively correlated with the grade of the infiltrating tumor (P = .030). Conclusions: In laryngeal SCCs, COX-2 may exert its deleterious effect by alterations in the tumor microenvironment. CAF-derived, COX-2-mediated paracrine influences on malignant cells possibly facilitate cancer progression. Overlooking the stromal remodeling could account for unsuccessful treatments of epithelial neoplasms. Laryngoscope, 2009 [source] Cytotoxicity and antiangiogenesis by fibroblast growth factor 2,targeted Ad-TK cancer gene therapy,THE LARYNGOSCOPE, Issue 4 2009Koichiro Saito MD Abstract Objectives: Human head and neck squamous cell carcinoma (HNSCC) in addition to lung, skin, ovarian, and other cancers overexpress fibroblast growth factor (FGF) receptors on both individual tumor cells and endothelial cells within the tumor microenvironment. The purpose of this study was to investigate whether FGF2-targeted gene therapy could redirect adenoviral vectors encoding the herpes simplex virus thymidine kinase gene (Ad-TK) to FGF receptors on tumor and endothelial cells with the intent of improving both the efficiency of transgene expression and the antitumor response. Study Design and Methods: An Ad-TK vector consisting of a conjugate of FGF2 linked to a Fab, fragment against the adenoviral knob region was directly delivered to human HNSCC xenograft tumors in nude mice, which were subsequently dosed with ganciclovir. Tumor specimens were assessed for herpes simplex virus thymidine kinase (HSV- tk) transgene mRNA expression, FGF1/2 receptor expression, terminal deoxynucleotidyl transferase biotin,deoxy uridine triphosphate nick end labeling assay for apoptosis, CD31 immunohistochemistry to estimate tumor microvessel density, and tumor volume change. Results: FGF2-retargeted Ad-TK gene therapy demonstrated significant increases in both HSV- tk mRNA expression and cellular apoptosis levels, and a significant decrease in tumor volume size compared with all other groups. Furthermore, microvessel density was significantly lower in the FGF2-retargeted Ad-TK group, indicating a strong antiangiogenesis effect. Conclusions: These data suggest that FGF2-retargeted Ad-TK produces a combination of expected direct antitumor cytotoxicity and a newly reported antiangiogenesis effect that could prove promising as a novel therapeutic approach in the treatment of FGF receptor,expressing cancers. Laryngoscope, 2009 [source] A novel communication role for CYP17A1 in the progression of castration-resistant prostate cancerTHE PROSTATE, Issue 9 2009Jennifer A. Locke Abstract BACKGROUND CYP17A1 is currently a target for total androgen blockade in advanced prostate cancer (CaP) patients. After castration, or removal of testicular androgens, CYP17A1 can act as a rate-limiting enzyme in androgen synthesis from cholesterol or other adrenal precursors within the tumor microenvironment ultimately contributing to disease progression. Herein we provide evidence that CYP17A1 could also be a mediator of cell-to-cell communication within the CaP tumor microenvironment. METHODS CYP17A1 expression was evaluated by immunohistochemical analysis of human tumor sections and Western blot analysis of CaP patients' serum and exosome isolates. CYP17A1 activity assays were conducted in human serum (and positive control human liver and kidney microsomes) using progesterone as a precursor and an LC-MS endpoint. RESULTS These studies revealed that the expression pattern of CYP17A1 is typical of a secretory protein as it is localized to the luminal pole of the cells in exocrine secretory mode. CYP17A1 is expressed in human serum and in fact is elevated in the serum of CaP patients as compared to healthy controls. Serum CYP17A1 activity could not be confirmed, however, verification of CYP17A1 expression in exosomes suggests a role in cell-to-cell communication within the tumor microenvironment. CONCLUSIONS CYP17A1 is a crucial enzyme for de novo androgen synthesis within the tumor microenvironment after removal of testicular androgens by castration. We provide evidence for a novel role for CYP17A1 in serum and further reiterate the importance of targeting this enzyme in CaP progression. Prostate 69: 928,937, 2009. © 2009 Wiley-Liss, Inc. [source] Expression of non-mast cell histidine decarboxylase in tumor-associated microvessels in human esophageal squamous cell carcinomas,APMIS, Issue 12 2008ZHENFENG LI Histamine is produced by mast cells and many other types of cells. The role of histamine released from mast cells in promoting tumor angiogenesis has been intensively studied; however, the role of non-mast cell histamine in regulating tumor angiogenesis has been largely ignored. In this study, tissue specimen sections from 43 patients with esophageal squamous cell carcinoma (ESCC) and normal esophageal biopsies from 17 heath individuals obtained from a high incidence area of north China were used to assess changes in microvessel density (MVD) and non-mast cell L-histidine decarboxylase (HDC) (the only rate-limiting enzyme that catalyzes the formation of histamine from L-histidine) expression in the tumor microenvironment by immunohistochemistry (IHC). In addition, the cellular characterization of non-mast cell HDC-positive cells in microvessels was examined by double IHC combined with HDC/CD34 and HDC/PCNA antibodies. These IHC analyses revealed a significantly increased HDC-positive MVD in ESCC as compared with normal controls, which accounted for ,61% of CD34-labeled general MVD in ESCC. Furthermore, IHC in serial sections and double IHC showed that most of these HDC-positive cells were CD34-positive endothelial cells in microvessels with an increased proliferative capacity. Thus, our results suggest that non-mast cell histamine expressed in endothelial cells of microvessels could be an additional cellular source and might play a role in regulating angiogenesis in ESCC. [source] Cellular interactions in the vascular niche: implications in the regulation of tumor dormancy,APMIS, Issue 7-8 2008ELENA FAVARO Angiogenesis plays an established role in the promotion of growth of dormant micrometastasis, because blood vessels deliver oxygen and nutrients to the tumor microenvironment. In addition to this feeding function, however, there is accumulating evidence suggesting that endothelial cells,and perhaps other cellular components of the microenvironment,could communicate both positive and negative signals to tumor cells. This cross-talk between heterogeneous cell types could turn out to be important in the regulation of cancer cell behavior. Normal cells recruited during the angiogenic process, or attracted to future sites of metastasis by soluble products released by cancer cells, have been shown to create a niche favorable to tumor cell proliferation and survival. In addition, following an exogenous angiogenic spike, as may occur during inflammation, the same mechanisms could lead to re-activation of poorly angiogenic tumor cells seeded into tissues. In this review, we discuss the possible implications of this hypothesis for our understanding of the phenomenon of tumor dormancy. [source] Dendritic cell infiltration pattern along the colorectal adenoma-carcinoma sequence,APMIS, Issue 6 2008APING YUAN We have previously reported that the dendritic cell (DC) functional index cytokine interleukin-12 was significantly decreased in colorectal carcinoma (CRC) tissues. In this study, the DC infiltration pattern and the density of mature DCs (mDCs; labeled by anti-CD83 and anti-CD208) and immature DCs (iDCs; labeled by anti-CD1,) were characterized using immunohistochemistry (IHC) in tissue samples from 23 patients with CRC, 33 patients with colorectal adenoma (CRA), and 19 healthy controls. In addition, the DC function inhibitor cyclooxygenase-2 (COX-2) and the downstream signal molecule prostaglandin E2 (PGE2) and related receptors EP2/EP4 were measured by quantitative real-time PCR and double immunofluorescence staining. The IHC analyses revealed changed densities of mDCs and iDCs in the tumor microenvironment; in CRA and CRC, the density of mDCs was decreased, but the density of iDCs was gradually increased. Furthermore, the distribution patterns of DCs were also altered. In CRA, mDCs were abundantly distributed in the subepithelial stroma of the adenomatous mass. In CRC, the distribution of mDCs in the tumor stroma was not homogeneous, and mDCs residing in the stroma at invading edges were more frequently found compared with in the intratumoral stroma (P<0.05). Increased iDCs were found in the intratumoral mass in CRC, and some infiltrated into the malignant epithelium. By quantitative real-time PCR, a gradually increased level of COX-2 mRNA was demonstrated in the local tissues along the adenoma-carcinoma sequence, and double immunofluorescence staining showed a colocalization of PGE2 receptors EP2/EP4 with mDCs in the stroma of CRC. In conclusion, our current findings revealed an altered DC infiltration pattern along the adenoma-carcinoma sequence; gradually increased COX-2 expression might contribute to the DC functional defect. [source] Characterization of bone marrow T cells in monoclonal gammopathy of undetermined significance, multiple myeloma, and plasma cell leukemia demonstrates increased infiltration by cytotoxic/Th1 T cells demonstrating a squed TCR-V, repertoireCANCER, Issue 6 2006Martin Pérez-Andres M.D. Abstract BACKGROUND The majority of studies published to date regarding the role of the bone marrow (BM) microenvironment in the pathogenesis of monoclonal gammopathies (MG) have focused on the interaction between stroma cells and plasma cells, whereas information concerning the lymphocytes infiltrating the tumor microenvironment is scanty. METHODS The authors measured the distribution, TCR-V, repertoire, immunophenotype, and functional characteristics of different subsets of BM T lymphocytes from 61 nontreated patients with MG (30 patients with MG of undetermined significance [MGUS], 27 patients with multiple myeloma [MM], and 4 patients with plasma cell leukemia [PCL]). RESULTS The authors found a significantly increased rate of BM infiltration by T cells in all patient groups, at the expense of CD4+CD8, and CD4,CD8, T lymphocytes and both CD4+CD28, and CD8+CD28, cytotoxic/effector T cell subsets, and associated with TCR-V, expansions in both CD4+ and CD8+ BM T cells in the majority of patients with MGUS, MM, and PCL. Moreover, the percentage of T cells secreting interferon (IFN)-, was found to be increased (P , 0.05) both in CD4+ and CD8+ T cells in MGUS and MM patients, and a higher plasma concentration of IFN-, was found in patients with MM. It is interesting to note that a positive correlation was noted between the proportion of CD28, and both the percentage of IFN-,,secreting cells and the proportion of expanded TCR-V, lymphocytes within the total BM CD4+ T cells. CONCLUSIONS The results of the current study demonstrated an increased infiltration of BM by T cells associated with frequent TCR-V, expansions and a more prominent cytotoxic/Th1 phenotype in all the patient groups studied. Cancer 2006. © 2006 American Cancer Society. [source] Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironmentCANCER SCIENCE, Issue 4 2010Marco Tafani The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1, (HIF-1,) and nuclear factor-kappa B (NF-,B). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1, (SDF-1,) increased invasion and migration of hypoxic MCF-7 cells. Inhibition of HIF-1, by chetomin and NF-,B by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF-7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser-capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF-1, and NF-,B and up-regulation of IR, CXCR4, estrogen receptor , (ER,), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF-7 cells acquire a pro-inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF-1,, NF-,B, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. (Cancer Sci 2010; 101: 1014,1023) [source] Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxiaCANCER SCIENCE, Issue 8 2009Shinae Kizaka-Kondoh A tumor-specific microenvironment is characterized by hypoxia, in which oxygen tension is considerably lower than in normal tissues. The hypoxic status of various solid tumors has been attributed as an indicator of adverse prognosis due to tumor progression toward a more malignant phenotype with increased metastatic potential and resistance to treatment. Various exogenous and endogenous markers for hypoxia are currently available and studied in relation to each other, tumor architecture, and tumor microenvironment. Over the last few decades, various methods have been suggested to assess the level of oxygenation in solid tumors. Among them, nitroimidazole compounds have provided promising information on tumor hypoxia. To quantify the extent of hypoxia requires that nitroimidazole binding be primarily dependent on oxygen concentration as well as nitroreductase levels in the tumor cells. Furthermore, recent progress in molecular biology has highlighted a transcription factor, hypoxia-inducible factor (HIF)-1, whose activity is induced by hypoxia. HIF-1 plays a central role in malignant progression by inducing the expression of various genes, whose functions are strongly associated with malignant alteration of the entire tumor. The cellular changes induced by HIF-1 are extremely important therapeutic targets of cancer therapy, particularly in the therapy against refractory cancers. In this review, we will discuss the significance of pimonidazole and HIF-1 as exogenous and endogenous hypoxia markers, respectively, as well as their evaluation and imaging of tumor hypoxia. (Cancer Sci 2009) [source] From tumor lymphangiogenesis to lymphvascular nicheCANCER SCIENCE, Issue 6 2009Satoshi Hirakawa Metastasis in sentinel lymph nodes indicates the initial spread of tumors from a primary site. The recent discovery of tumor-associated growth of lymphatic vessels clarified that tumor lymphangiogenesis actively promotes enhanced draining/sentinel lymph node metastasis. Studies of experimental carcinogenesis have further established that tumors continue to induce lymphangiogenesis in metastatic foci such as draining lymph nodes. Lymphangiogenesis within draining lymph nodes probably contributes to enhanced distant lymph node and distant organ metastases. Lymph node lymphangiogenesis has recently been identified in several human malignancies, such as cutaneous malignant melanoma. Tumor-associated lymphangiogenesis thus has potential significance not only at the primary site, but also in lymph nodes. Primary tumors induce new lymphatic vessel growth in draining lymph nodes before metastasis. The remarkable enlargement of sinusoidal lymphatic endothelium might facilitate tumor cell transport to the lymph nodes, and potentially contribute to the migration, residence, and/or survival of metastatic tumor cancer stem cells by inducing a specific tumor microenvironment. Therefore, the novel concept of ,lymphvascular niche' is proposed herein to explain lymphatic network expansion. This concept might help to improve understanding of the molecular mechanism of lymph node metastasis, and change therapeutic approaches to treating cancer metastasis. (Cancer Sci 2009; 100: 983,989) [source] | ||||||||||||||||||||||||||||||||||