Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive transfer of effector T cells has been used successfully to eliminate metastases in animal models. Because antitumor activity depends on the number of effector cells transferred, some human trials have used in vitro-repetitive activation and expansion techniques to increase cell number. We hypothesized that the prolonged culture period might contribute to the lack of human trial success by decreasing the potency of the effector T cells. Lymph nodes draining a progressively growing murine melanoma tumor transduced to secrete granulocyte/macrophage colony-stimulating factor were harvested and activated in vitro with anti-CD3 monoclonal antibody followed by expansion in IL-2 for a total of 5 days in culture. Some lymphocytes were reactivated and further expanded for a total of 9 days in culture. In vivo activity of the effector T cells was measured by the reduction in lung metastases and is shown to be dose dependent. The prolonged culture period resulted in nearly 3-fold more T cells but at least 8-fold less antitumor activity. This was accompanied by decreased secretion of the proinflammatory cytokine, IFN-gamma, and increased secretion of the anti-inflammatory cytokine, IL-10. Thus, although increased cell number is important to maximize the effectiveness of adoptive immunotherapy, some culture conditions may actually be counterproductive in that decreases in cell potency can outweigh the benefits of increased cell numbers. The T-cell cytokine secretion pattern predicts decreased effector cell function and may explain the decreased antitumor effect.
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PMID:Prolonged culture of vaccine-primed lymphocytes results in decreased antitumor killing and change in cytokine secretion. 1560 82

We have previously described the antitumor reactivity of tumor-draining lymph node (TDLN) cells after secondary activation with antibodies. In this report, we examined the effects of interleukin (IL)-12 and IL-18 on modulating the immune function of antibody-activated murine TDLN cells. TDLN cells were activated with anti-CD3/anti-CD28 monoclonal antibody followed by stimulation with IL-12 and/or IL-18. IL-18 in combination with IL-12 showed a synergistic effect in augmenting IFNgamma and granulocyte macrophage colony-stimulating factor secretion, whereas IL-18 alone had minimal effect. Concurrently, IL-18 prevented IL-12-stimulated TDLN cells from producing IL-10. The IL-12/IL-18-cultured TDLN cells therefore manifested cytokine responses skewed towards a Th1/Tc1 pattern. IL-12 and IL-18 stimulated CD4(+) TDLN cells and enhanced IFNgamma production by CD4(+) cells to a greater extent than by CD8(+) cells. Use of NF-kappaB p50(-/-) TDLN cells suggested the involvement of NF-kappaB in the IL-12/IL-18 polarization effect. Furthermore, a specific NF-kappaB inhibitor significantly suppressed IL-12/IL-18-induced IFNgamma secretion, thus confirming the requirement for NF-kappaB activation in IL-12/IL-18 signaling. In adoptive immunotherapy, IL-12- and IL-18-cultured TDLN cells infiltrated pulmonary tumor nodules and eradicated established tumor metastases more efficiently than T cells generated with IL-12 or IL-18 alone. Antibody depletion revealed that both CD4(+) and CD8(+) cells were involved in the tumor rejection induced by IL-12/IL-18-cultured TDLN cells. These studies indicate that IL-12 and IL-18 can be used to generate potent CD4(+) and CD8(+) antitumor effector cells by synergistically polarizing antibody-activated TDLN cells towards a Th1 and Tc1 phenotype.
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PMID:Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. 1570 8

Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that is expressed highly in many solid tumours often correlating with a poor prognosis. In this study, we investigated the expression of VEGF and its receptors in bone metastases from primary human breast tumours and further characterised its effects on osteoclasts in vitro. Breast cancer metastases to bone were immunohistochemically stained for VEGF, its receptors VEGFR1 and 2 (vascular endothelial growth factor receptor 1 and 2), demonstrating that breast cancer metastases express VEGF strongly and that surrounding osteoclasts express both VEGFR1 and VEGFR2. RAW 264.7 cells (mouse monocyte cell line) and human peripheral blood mononuclear cells (PBMCs) were cultured with VEGF, RANKL and M-CSF. VEGF and RANKL together induced differentiation of multinucleated, tartrate-resistant acid phophatase (TRAP)-positive cells in similar numbers to M-CSF and RANKL. The PBMCs were also able to significantly stimulate resorption of mineralised matrix after treatment with M-CSF with RANKL and VEGF with RANKL. We have shown that VEGF in the presence of RANKL supports PBMC differentiation into osteoclast-like cells, able to resorb substrate. Vascular endothelial growth factor may therefore play a role in physiological bone resorption and in pathological situations. Consequently, VEGF signalling may be a therapeutic target for osteoclast inhibition in conditions such as tumour osteolysis.
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PMID:Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. 1581 59

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

Sentinel lymph nodes are the first nodes to receive lymph from primary tumors and are the preferential site of initial metastases. Sentinel nodes show morphology changes that suggests immune modulation with reduced antigen-presenting dendritic cells, activated T lymphocytes, high endothelial venules and transvenular migration of T lymphocytes. Tumor cells generate down-regulatory molecules. We postulate that tumor-induced immune dysfunction facilitates establishment of nodal metastases. Nodal immune modulation can be reversed by granulocyte macrophage colony-stimulating factor (GMCSF), a finding with implications for future therapy to prevent or reverse these nodal metastases.
Cancer Metastasis Rev 2006 Jun
PMID:Experimental frontiers for clinical applications: novel approaches to understanding mechanisms of lymph node metastases in melanoma. 1877 12

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.
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PMID:Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. 1690 9

Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.
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PMID:Tumour-induced immune modulation of sentinel lymph nodes. 1693 51

A patient with recurrent breast cancer metastases following initial response to chemotherapy and hormonal maintenance was treated with a whole-cell tumor vaccine, resulting in a prompt objective complete remission of a lung lesion on computed tomography (CT) scans and near-complete regression of multiple breast lesions on magnetic resonance imaging (MRI). Three months after completion of the protocol, metastases were again found in the breast and lung, with new lesions in the brain and liver. Reinstitution of vaccine inoculation resulted in major regression of the brain and breast lesions, improvement in all other areas, and no indication of new lesions. Therapy consisted of inoculation of 20 x 10(6) SV-BR-1-GM cells, a unique breast cancer cell line transfected to release sargramostim (granulocyte macrophage colony-stimulating factor [GM-CSF]). Following lethal irradiation to 200 cGy, vaccine was injected intradermally in four divided doses to the back and thighs, every 2 weeks x 3, then every month x 3. Each treatment was preceded 48 hours earlier with low-dose cyclophosphamide 300 mg/m2 to abrogate regulatory T-cell activity. Interferon (IFN)-alpha, 20,000 IU, was injected into each inoculation site at 48 and 96 hours postinoculation to provide an additional "danger signal." The patient developed positive delayed-type hypersensitivity responses and also antibody reactivity to the vaccine cells.
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PMID:Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim. 1695 69

Patients with melanoma considered at high risk for recurrence or regional metastases often have to choose between adjuvant interferon therapy or enrolling in a clinical trial. High-dose interleukin-2 therapy has had limited success in producing durable responses in stage IV melanoma; this success has been offset by marked toxicity. High-dose interferon alpha therapy has consistently shown disease-free survival benefit in clinical trials but has marked toxicity. The overall survival benefit has been inconsistent and controversial. Treatment with granulocyte macrophage colony-stimulating factor has shown promise in early studies. Various cytokines have had some success in treating advanced stage melanoma but with marked toxicity. Cytokine therapy that is well-tolerated and consistently provides an overall survival benefit for high-risk melanoma patients has not been achieved. Cytokines will continue to have a role in therapy for advanced-stage melanoma, most likely in combination with other immunomodulatory therapy. The challenge is finding the right doses, frequency, combinations, and duration of treatment.
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PMID:Cytokine therapy in advanced melanoma. 1766 34

Microarray studies have yielded valuable information that can be used to determine a cancer patient's prognosis and allow for optimum treatment choices. Tumor profiling has also changed our perception of metastatic propensity. Genomic analyses clearly showed that a metastasis signature is encoded within the genome so that when a cancer develops, the likelihood of metastasis is high, whereas other cancers which do not have this genotype metastasize as a result of random mutations. It is certain however, that cells other than tumor cells contribute to the development of metastasis through their production of various pro-metastatic proteins. Here, we review the published metastasis profiling studies and the role of the host in metastasis. Collagen type I, CXCR4, CSF-1, OPN and RhoC are metastasis-associated genes for which evidence exists for a causal contribution to elements of the metastatic process. These genes are discussed in detail and represent excellent drug targets for anti-metastasis therapies.
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PMID:Molecular targets in metastasis: lessons from genomic approaches. 1787 24


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