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At least 1,261 records · Page 70Linked to original sources
PubMed2004

Targeting the tumor and its microenvironment by a dual-function decoy Met receptor.

Met, the receptor for hepatocyte growth factor (HGF), is activated in human cancer by both ligand-dependent and -independent mechanisms. We engineered a soluble Met receptor (decoy Met) that interferes with both HGF binding to Met and Met homodimerization. By lentiviral vector technology, we achieved local or systemic delivery of decoy Met in mice. We provide evidence that in vivo expression of decoy Met (1) inhibits tumor cell proliferation and survival in a variety of human xenografts, (2) impairs tumor angiogenesis by preventing host vessel arborization, (3) suppresses or prevents the formation of spontaneous metastases, and (4) synergizes with radiotherapy in inducing tumor regression, without (5) affecting housekeeping physiological functions in the adult animal.

Angiogenesis Inhibitors↗
PubMed2004

Molecular characterization of the tumor microenvironment in breast cancer.

Here we describe the comprehensive gene expression profiles of each cell type composing normal breast tissue and in situ and invasive breast carcinomas using serial analysis of gene expression. Based on these data, we determined that extensive gene expression changes occur in all cell types during cancer progression and that a significant fraction of altered genes encode secreted proteins and receptors. Despite the dramatic gene expression changes in all cell types, genetic alterations were detected only in cancer epithelial cells. The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. Thus, chemokines may play a role in breast tumorigenesis by acting as paracrine factors.

Biomarkers, Tumor↗
PubMed2005

The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation.

Constitutive activation of Akt characterizes a high percentage of human melanomas and represents a poor prognostic factor of the disease. We show that Akt transforms melanocytes only in a hypoxic environment, which is found in normal skin. The synergy between Akt and hypoxia is HIF1alpha mediated. Inhibition of HIF1alpha decreases Akt transformation capacity in hypoxia and tumor growth in vivo, while overexpression of HIF1alpha allows anchorage-independent growth in normoxia and development of more aggressive tumors. Finally, we show that mTOR activity is necessary to maintain the transformed phenotype by sustaining HIF1alpha activity. Taken together, these findings demonstrate that Akt hyperactivation and HIF1alpha induction by normally occurring hypoxia in the skin significantly contribute to melanoma development.

Animals↗
PubMed2004

Immunosuppressive mechanisms in the microenvironment of malignant pleural effusions.

Malignant effusions in serous cavities constitute a unique milieu for direct contact of tumor cells with host lymphoid cells in a fluid phase. The aim of this study was to depict agents responsible for suppression of lymphoid cells with putative anti-tumor potential. Pleural effusions drawn from 44 (18 non-malignant and 26 malignant) patients were tested for selected cytokines--interleukin-10 (IL-10), transforming growth factor beta (TGF-beta1) and soluble Fas ligand (sFasL) and nuclear membrane proteins (NMPs) content by ELISA. TCR-zeta expression of T cells and TUNEL reaction for apoptosis were evaluated by three color flow cytometry. Both cytokine concentrations were found to be significantly elevated in malignant pleural effusions (MPE) as compared to non-malignant ones. It was also true for sFasL content. Moreover, NMPs corresponding to decoy cell fragments, were also heightened in MPE. Concentrations of NMPs correlated with the percent of apoptotic (TUNEL+) T CD3+ lymphocytes and inversely correlated with the percent of T cells. The low expression of TCR-zeta chain on T cells corresponded to high concentration of sFasL in MPE. In conclusion, the above data suggest that out of three suppression agents tested, only sFasL appears to show correlation with the downregulation of T cells in MPE.

Apoptosis↗
PubMed2006

[The PAI-1 swing: microenvironment and cancer cell migration].

Cancer is a complex and dynamic process caused by a cellular dysfunction leading to a whole organ or even organism vital perturbation. To better understand this process, we need to study each one of the levels involved, which allows the scale change, and to integrate this knowledge. A matricellular protein, PAI-1, is able to induce in vitro cell behaviour modifications, morphological changes, and to promote cell migration. PAI-1 influences the mesenchymo-amaeboid transition. This matricellular protein should be considered as a potential 'launcher' of the metastatic process acting at the molecular, cellular, tissular levels and, as a consequence, at the organism's level.

Cell Adhesion↗
PubMed2005

Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells.

OBJECTIVE: Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. MATERIALS AND METHODS: AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. RESULTS: Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14(-) AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14(-)-derived AML-DCs restored optimal interferon-gamma (IFN-gamma) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14(-) cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14(-)-derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-gamma, thus maintaining a Th1 cytokine profile. CONCLUSION: IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.

Adult↗
PubMed2006

The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Prognostication in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) based, in part, on ZAP-70 and CD38 expression, and to a lesser extent, on MUM1/IRF4 expression, is currently of great interest. The more aggressive type of CLL/SLL is reportedly characterized by neoplastic cells that are more responsive to B-cell signaling with proliferation centers (PCs), a potentially important site of neoplastic cell stimulation. To study the relationship of these markers to each other and to the pattern of PCs, immunohistochemical stains for ZAP-70 and MUM1/IRF4 were performed and the PC patterns assessed (where possible) in 29 tissue biopsies with CLL/SLL. CD38 expression was assessed in 18 cases using flow cytometry. Ten evaluable cases had a typical PC pattern and 16 an atypical pattern with larger or more confluent PCs and/or more numerous paraimmunoblasts/transformed cells. ZAP-70 was positive in 14 of 28 cases, including 3 with atypical PCs and enhanced PC staining. All 29 cases showed MUM1/IRF4 expression in PCs. Seven cases, none with atypical PC, also showed uniform positivity throughout, 14 showed weaker staining of surrounding lymphocytes, and 8 had PC staining only. CD38 was positive in 14 of 18 cases. The only significant association identified was between uniform MUM1/IRF4 positivity and typical PCs (P = .004). These findings highlight the complex interrelationship of prognostic markers in CLL/SLL and demonstrate potentially important microenvironmental variations in their expression. They support the hypothesis that PCs are a site for B-cell receptor signaling, which helps explain reported site-dependent antigenic variation in CLL/SLL, and suggest that PC morphology may correlate with other biological features.

ADP-ribosyl Cyclase 1↗
PubMed2005

Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy.

PURPOSE: To investigate the effect of arsenic trioxide, Trisenox (TNX), on primary cultures of endothelial cells and tumor tissue under varying pH and pO(2) environments and the effects of combined TNX and radiation therapy on experimental tumors. METHODS AND MATERIALS: Human dermal microvascular endothelial cells were cultured in vitro and exposed to TNX under various combinations of aerobic, hypoxic, neutral, or acidic conditions, and levels of activated JNK MAP kinase were assessed by Western blotting. FSaII fibrosarcoma cells grown in the hind limb of female C3H mice were used to study the effect of TNX on tumor blood perfusion and oxygenation. The tumor-growth delay after a single or fractionated irradiation with or without TNX treatment was assessed. RESULTS: A single intraperitoneal injection of 8 mg/kg TNX reduced the blood perfusion in FSaII tumors by 53% at 2 hours after injection. To increase the oxygenation of the tumor vasculature during TNX treatment, some animals were allowed to breathe carbogen (95% O(2)/5% CO(2)). Carbogen breathing alone for 2 hours reduced tumor perfusion by 33%. When carbogen breathing was begun immediately after TNX injection, no further reduction occurred in tumor blood perfusion at 2 hours after injection. In vitro, TNX exposure increased activity JNK MAP kinase preferentially in endothelial cells cultured in an acidic or hypoxic environment. In vivo, the median oxygenation in FSaII tumors measured at 3 or 5 days after TNX injection was found to be significantly elevated compared with control tumors. Subsequently, radiation-induced tumor-growth delay was synergistically increased when radiation and TNX injection were fractionated at 3-day or 5-day intervals. CONCLUSIONS: Trisenox has novel vascular-damaging properties, preferentially against endothelium in regions of low pH or pO(2), which leads to tumor cell death and enhancement of the response of tumors to radiotherapy.

Animals↗
PubMed2005

Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements.

PURPOSE: Interstitial fluid pressure (IFP) and oxygen (pO(2)) measurements are prognostic factors in cervical cancer. The purpose of this study was to determine the relationship between IFP and oxygenation and parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT). METHODS AND MATERIALS: Dynamic contrast-enhanced computed tomography was performed in 32 patients with cervical cancer before radiation therapy. Images were acquired during intravenous contrast injection at 1 per s for 120 s and 1 per 15 s for 60 s. DCE-CT was analyzed using CT Perfusion 3 software (GE Medical Systems) to derive tumor blood flow (BF), permeability surface area product, blood volume, and mean transit time. Further analysis was performed to obtain relative peak enhancement, residual enhancement at 3 min after contrast injection (RE), time to peak and initial slope. Nodal status and tumor size were assessed with MRI. From in vivo IFP (n = 31) and pO(2) (n = 31) tumor measurements median pO(2) (mO(2)), percentage measurements less than 5 mm Hg (HP5) and mean IFP values were calculated. RESULTS: There was a positive correlation between BF and mO(2) (r = 0.47, p = 0.007) and between RE and HP5 (r = 0.39, p = 0.03). There was no correlation between IFP and DCE-CT parameters. CONCLUSION: There is a moderately positive, correlation between tumor oxygenation and BF as well as RE and HP5. Further study is required to determine if DCE-CT parameters are useful predictors of tumor behavior in cervical cancer.

Extracellular Fluid↗
PubMed2005

Dependence of FDG uptake on tumor microenvironment.

PURPOSE: To investigate the factors affecting the (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in tumors at a microscopic level, by correlating it with tumor hypoxia, cellular proliferation, and blood perfusion. METHODS AND MATERIALS: Nude mice bearing Dunning prostate tumors (R3327-AT) were injected with (18)F-FDG and pimonidazole, bromodeoxyuridine, and, 1 min before sacrifice, with Hoechst 33342. Selected tumor sections were imaged by phosphor plate autoradiography, while adjacent sections were used to obtain the images of the spatial distribution of Hoechst 33342, pimonidazole, and bromodeoxyuridine. The images were co-registered and analyzed on a pixel-by-pixel basis. RESULTS: Statistical analysis of the data obtained from these tumors demonstrated that (18)F-FDG uptake was positively correlated with pimonidazole staining intensity in each data set studied. Correlation of FDG uptake with bromodeoxyuridine staining intensity was always negative. In addition, FDG uptake was always negatively correlated with the staining intensity of Hoechst 33342. CONCLUSIONS: For the Dunning prostate tumors studied, FDG uptake was always positively correlated with hypoxia and negatively correlated with both cellular proliferation and blood flow. Therefore, for the tumor model studied, higher FDG uptake is indicative of tumor hypoxia, but neither blood flow nor cellular proliferation.

Animals↗
PubMed2006

A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.

PURPOSE: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. METHODS AND MATERIALS: Thirty-one patients were accrued to a phase I-II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP(5)) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1-4.4 years). RESULTS: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, -4.6 mm Hg; p = 0.09; relative, -21%; p = 0.07), whereas HP(5) did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP(5) or IFP and response to treatment (p = 0.2, relative HP(5) change and p = 0.14, relative IFP change). CONCLUSIONS: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.

Adult↗
PubMed2004

The tumor microenvironment: CXCR4 is associated with distinct protein expression patterns in neuroblastoma cells.

In previous studies, we demonstrated that human neuroblastoma cells are equipped with the machinery to direct their homing to bone marrow. These tumor cells express the CXCR4 receptor for the bone marrow stroma-derived chemokine CXCL12 (SDF-1) and secrete the CXCL12 ligand. The present study was undertaken to explore possible differences in gene-expression patterns between neuroblastoma variants that over-express CXCR4 (designated STH cells) and those which express very little of this receptor (STL cells). The results of the study clearly indicate that these variants show a differential gene-expression profile. They differ in expression of some integrins such as VLA2, VLA3 and VLA6, of neuroendocrine-markers such as CD56 and synaptophysin, in the expression of c-kit and in the secretion of certain cytokines and growth factors such as TNFalpha, SDF-1, VEGF, IL-8, GM-CSF and IP-10. We hypothesize that these differences are due to an autocrine SDF-1alpha-CXCR4 axis.

CD56 Antigen↗
PubMed2003

NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity.

Although it is clear that natural killer (NK) cells have the ability to recognize and kill tumour cells in vitro, their potential as a highly effective treatment for tumours has not yet been realized in the clinical setting. Following activation, endogenous and adoptively transferred NK cells can be found in tumours. However, not all tumours are equally well-infiltrated, and many of the infiltrating cells do not make target-cell contact but rather reside in the tumour stroma. New insights into the migration of NK cells, their activation status and production of matrix-degrading proteases might help to overcome this localization defect, with implications for the treatment of human cancer.

Adoptive Transfer↗
PubMed2005

Immunobiology of muscle: advances in understanding an immunological microenvironment.

Skeletal muscle, which is the largest cellular compartment of the body, lacks detectable MHC expression under physiological conditions. Therefore, immune reactions triggered by, or directed against, muscle cells proceed along specific pathways. Recently, the expression and functioning of classical MHC, non-classical MHC, adhesion and co-stimulatory molecules have been shown to support the concept that muscle cells can act as facultative antigen-presenting cells and should be considered as active participants, rather than passive targets, of immune reactions. Here, we summarize current knowledge on the immunological capabilities of skeletal muscle cells and discuss how these characteristics might contribute to inflammatory muscle disorders, as well as therapeutic strategies, such as gene or myoblast transfer.

Antigen Presentation↗