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

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.
 ...
PMID:Clinical significance of CXCR3 and CXCR4 expression in primary melanoma. 1598 Dec 10

Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.
 ...
PMID:CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. 1612 70

The chemokine receptors CCR5 and CXCR4 serve as co-receptors for the human immunodeficiency virus 1 (HIV-1) and thus, are important cellular components during HIV-1 cell entry. In recent years, a new biological role for chemokine receptors has emerged in assisting the spread of primary tumors to distant secondary sites within the human body (metastasis). This review highlights some of the HIV-1 cell entry inhibitors (antagonists), which are currently in development and/or under evaluation in clinical trials, and discusses the therapeutic use of these new antagonists for the treatment of certain forms of metastatic cancer.
 ...
PMID:Killing two birds with one drug: a new application for HIV-1 cell entry inhibitors in the treatment of metastatic cancer. 1615 63

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.
 ...
PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

G protein-coupled receptors (GPCRs) play important roles in a variety of biological and pathological processes. They are considered among the most desirable targets for drug development. Recent studies have demonstrated that many GPCRs, such as endothelin receptors, chemokine receptors and lysophosphatidic acid receptors have been implicated in the tumorigenesis and metastasis of multiple human cancers. In this study, we conducted an in silico analysis of GPCR gene expression in primary human tumors by analyzing some publicly available gene expression profiling data. Statistical analysis was performed on eight microarray data sets of non-small cell lung cancer, breast cancer, prostate cancer, melanoma, gastric cancer and diffused large B cell lymphoma to identify GPCRs that are up-regulated in primary or metastatic cancer cells. Our analysis has demonstrated overexpression of several GPCRs in primary tumor cells, including chemokine receptors and protease-activated receptors that were shown to be important for tumorigenesis by previous studies. In addition, we have uncovered several GPCRs, such as neuropeptide receptors, adenosine A2B receptor, P2Y purinoceptor, calcium-sensing receptor and metabotropic glutamate receptors, that are expressed at a significantly higher level in some cancer tissue and may play a role in cancer progression. Analysis of cancer samples in different disease stages also suggests that some GPCRs, such as endothelin receptor A, may be involved in early tumor progression and others, such as CXCR4, may play a critical role in tumor invasion and metastasis. The present study demonstrates the value of publicly available microarray data as a resource to gain more understanding of cancer biology, to validate previous findings from in vitro experiments, and to identify potential novel anticancer targets and biomarkers.
 ...
PMID:Overexpression of G protein-coupled receptors in cancer cells: involvement in tumor progression. 1621 Dec 29

Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-kappaB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.
 ...
PMID:Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway. 1632 49

The support mechanisms that are involved in lymph-node metastasis of oral squamous cell carcinoma (OSCC) remain largely unknown. Recent studies have demonstrated that tumor cells express chemokine receptors and use chemokines to metastasize to the target organ in many malignancies in humans. In this study, we examined the expression and function of chemokines and their receptors in OSCC. The expression of chemokine receptors was assessed in eight OSCC cell lines. CXCR3 mRNA and protein were expressed in all the OSCC cell lines examined, while CXCR4 mRNA and protein were expressed only in HSC2, HSC3, and Ca9-22 cells. Treatment with the ligand for CXCR4, stromal cell-derived factor-1 (SDF-1), enhanced the motility and invasiveness of OSCC cells expressing CXCR4. However, the CXCR3 ligand, Mig, did not affect the migration or invasiveness of CXCR3-positive cells. We also evaluated the clinical significance of CXCR4 expression immunohistochemically. CXCR4 expression was detected in 27 (30%) of the 90 OSCC tissues tested, and was localized in the membrane and cytoplasm of cancer cells. There was a highly significant correlation between CXCR4 expression and lymph-node metastasis (P=0.0035). Collectively, these findings suggest that CXCR4 might be involved in the lymph-node metastasis of OSCC.
 ...
PMID:CXCR4 expression is associated with lymph-node metastasis of oral squamous cell carcinoma. 1632 80

Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.
 ...
PMID:Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. 1633 1

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.
 ...
PMID:Regulation of cancer cell migration and bone metastasis by RANKL. 1731 31

The major role of matrix metalloproteinases (MMPs) is for homeostatic regulation of the extracellular environment, not simply to degrade matrix as their name suggests. We designed and printed a dedicated, focused DNA microarray, the CLIP-CHIP, that enables the analysis of every human and murine protease, protease homologue and inhibitor on a system-wide basis in cancer. We have also developed novel proteomic approaches to identify cleaved substrates of proteases in complex milieu. Isotope coded affinity tag (ICAT) and iTRAQ labeling of conditioned medium proteins secreted by MDA-MB-231 breast carcinoma cells and Mmp2 -/- murine fibroblasts transfected with protease (MT1-MMP or active MMP-2) or their inactive mutant forms enabled quantitative proteomics to be performed. Comparison of the relative abundance ratios of identical peptides from the two samples identified proteins in the conditioned medium that may have been degraded (low ratios) and those that were shed from the cell membrane (high ratios). MS/MS was used to sequence and identify the potential substrates. These analyses have revealed a plethora of new bioactive substrates and biological roles for MMPs. Biochemical confirmation of cleavage of the potential substrates was performed and the cleavage sites identified by MALDI-TOF. In these studies we discovered and confirmed that CTGF, galectin-1, death receptor-6, HSP90alpha, procollagen C-proteinase enhancer protein, the chemokine fractalkine, and cystatin C were novel MT1-MMP or MMP-2 substrates. These sophisticated cellular control functions highlight new intervention points in multiple pathways to treat early stage cancer.
Cancer Metastasis Rev 2006 Mar
PMID:Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer. 1668 May 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>