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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastasis is the major cause of death for cancer patients with solid tumours, due mainly to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of metastasis is therefore essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies. Metastasis is an inefficient process, such that very few cells that leave a tumour successfully form macrometastases in distant sites. This suggests that only a small subset of cells can successfully navigate the metastatic cascade and eventually re-initiate tumour growth to form life-threatening metastases. Recently, there has been growing support for the cancer stem cell (CSC) hypothesis which stipulates that primary tumours are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. Classical properties of normal stem cells are strikingly reminiscent of the observed experimental and clinical behaviour of metastatic cancer cells, including an unlimited capacity for self renewal; the requirement for a specific 'niche' or microenvironment to grow; use of the stromal cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) axis for migration; enhanced resistance to apoptosis and an increased capacity for drug resistance. Therefore, in addition to playing a role in primary tumour formation, we believe that CSCs are also key players in the metastatic process. We will review the current evidence supporting this idea and discuss the potential implications of the CSC hypothesis with regards to experimental investigation and treatment of metastatic disease.
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PMID:Cancer stem cells: implications for the progression and treatment of metastatic disease. 1818 63

Cruciferous vegetables are thought to protect against numerous types of cancer. 3,3'-Diindolylmethane (DIM) is an acid-catalyzed product generated during the consumption of cruciferous vegetables and appears to be chemoprotective for breast cancer. The interaction between the chemokine receptor, CXCR4, and its unique ligand, CXCL12, is known to mediate the progression and metastasis of breast and other cancers. Organs to which these cancers metastasize secrete CXCL12, which binds to CXCR4 expressed on the surface of primary cancer cells. This process subsequently stimulates the invasive properties of the cancer cells and attracts them to the preferred organ sites of metastases. We have found that DIM down-regulates both CXCR4 and CXCL12 in MCF-7 and MDA-MB-231 breast cancer cells as well as in BG-1 ovarian cancer cells at the transcriptional level and in an estrogen-independent manner. We demonstrate that the potential of MDA-MB-231 and BG-1 cells for chemotaxis and invasion towards CXCL12, but not towards IL-6 or fetal bovine serum, respectively, is inhibited by DIM. Furthermore, we show that DIM down-regulates CXCR4 under hypoxia and CXCL12 under estradiol-inducing conditions. Our data suggest that one mechanism whereby DIM protects against breast, ovarian, and possibly other cancers is through the repression of CXCR4 and/or CXCL12, thereby lowering the invasive and metastatic potential of these cells.
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PMID:CXCR4 and CXCL12 down-regulation: a novel mechanism for the chemoprotection of 3,3'-diindolylmethane for breast and ovarian cancers. 1837 71

Chemokines and their cognate receptors have key functions in cell growth, survival, and tissue-specific homing of cells. While these functions first were identified in normal immune cells, cancer cells may co-opt chemokine receptor signaling to promote primary tumor growth and metastasis. Our knowledge of signaling by chemokines and chemokine receptors in cancer is lacking, particularly as this signaling occurs in vivo. New insights into chemokine receptor signaling in cancer are needed to understand molecular regulation of primary and metastatic disease and develop targeted therapies to improve patient survival. To meet this need, we have developed a molecular imaging reporter to investigate activation of CXCR4, a chemokine receptor that regulates tumor growth and metastasis in a variety of common cancers. The reporter system uses a firefly luciferase-based protein fragment complementation assay to detect interactions between CXCR4 and beta-arrestin molecules, a common early step in chemokine receptor signaling. In cell-based assays, incubation with the chemokine ligand CXCL12 (SDF-1) produced dose-dependent increases in bioluminescence with >7-fold induction above basal levels of association between these proteins. Reporter activation could be blocked with specific inhibitors of CXCR4 signaling. These reporters enabled in vivo imaging of CXCR4 activation and inhibition in living mice. Overall, this research establishes a new imaging reporter for probing CXCR4 signaling in cancer and other diseases regulated by this chemokine receptor.
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PMID:Imaging CXCR4 signaling with firefly luciferase complementation. 1853 83

Stromal derived factor-1 (SDF-1 or CXCL12) expressed by osteoblasts and endothelial cells, and its receptors CXCR4 and CXCR7/RDC1 are key molecular determinants in prostate cancer (PCa) metastasis. What drives PCa cells into the extravascular marrow space(s) once they make contact with the blood vessel endothelium, however remains unclear. Here, we evaluated whether degradation of CXCL12 facilitates PCa cell entry into the marrow cavity by locally lowering CXCL12 levels intravascularly. To explore this possibility, co-cultured conditioned media from PCa cells and endothelial cells were evaluated for their ability to degrade biotinylated CXCL12 (bCXCL12). Co-culture of PCa cells/endothelial cells resulted in greater digestion of CXCL12 than was achieved by either cell type alone, and this activity regulated invasion in vitro. The ability to degrade CXCL12 was not however observed in PCa and osteoblasts co-cultures. Fractionation and inhibitor studies suggested that the activity was CD26/dipeptidyl peptidase IV (DPPIV) and possibly other cysteine/serine proteases. By inhibiting CD26/DPPIV, invasion and metastasis of PCa cell lines were enhanced in in vitro and in vivo metastasis assays. Together, these data suggest that the degradation of CXCL12 by CD26/DPPIV may be involved in the metastatic cascades of PCa, and suggests that inhibition of CD26/DPPIV may be a trigger of PCa metastasis.
Clin Exp Metastasis 2008
PMID:CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12. 1856 94

The stromal-derived factor 1alpha (CXCL12)/chemokine receptor CXCR4 system plays an important role in the metastatic process of a variety of cancers, with CXCR4 frequently expressed by tumor cells homing to CXCL12-rich compartments. The current study evaluated a possible association of CXCR4 expression with lymph node metastasis in primary non-small cell lung cancer. CXCR4 expression levels were evaluated using immunohistology in 46 non-small cell lung cancer specimens of patients without or with lymph node involvement (N0 = 24, N1/N2/N3 = 22). Evaluation of immunostaining was performed semiquantitatively by visual assessment. Statistical analyses with multiple testing adjustments for confirmatory comparisons were performed to assess relevant parameters associated with lymph node metastases. In all samples of non-small cell lung cancer, tumor cells stained positively for cytoplasmic CXCR4. The intensity of the CXCR4 staining varied considerably between specimens: 2 (4%) tumors demonstrated weak cytoplasmic CXCR4, 22 (48%) intermediate, and 22 (48%) strong staining. Membranous staining was absent; however, nuclear staining of CXCR4 was observed in 5 non-small cell lung cancer samples. Statistical analyses of the association between presence of lymph node metastases and CXCR4 expression levels revealed that cytoplasmic CXCR4 expression was not associated with the presence of lymph node metastases. However, nuclear CXCR4 was significantly correlated with increasing lymph node stage (P = .008), linear-to-linear association. The association between aberrant expression of CXCR4 in the nucleus of non-small cell lung cancer and metastasis to lymph nodes points toward a potential tumor metastasis promoting function of nuclear CXCR4.
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PMID:Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis. 1870 Nov 33

The chemokine stromal cell-derived factor (SDF-1/CXCL12) and its specific receptor, CXCR4, have been implicated in the regulation of tumor growth and organ-specific spread. The aim of this study was to determine the expression of CXCL12 and CXCR4 in samples obtained from primary squamous cell carcinoma (SCC) of the oral cavity (OCSCC) and of the lip (LSCC) and in metastatic and non-metastatic lymph node tissues. The relationship of CXCL12/CXCR4 with clinical and microscopic parameters was also evaluated. The analysis of mRNA expression revealed a higher expression of CXCR4 in oral SCC compared with healthy oral mucosa (p = 0.006). The density of CXCR4+ cells was higher in parenchyma of OCSCC with lymph node metastases than in LSCC. With regard to the stroma, OCSCC showed a greater CXCR4+ and CXCL12+ cell percentage in relation to LSCC. Furthermore, the density of CXCL12+ and CXCR4+ nodal cells was higher in metastatic than non-metastatic lymph nodes in the same patients. Considering clinical and microscopic parameters, we found a positive association between the percentages of CXCL12+ and CXCR4+ stromal cells and the tumor proliferation index. Our findings suggest that the CXCL12/CXCR4 system may play a role in tumor cell spread to lymph nodes and also in neoplastic development.
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PMID:Involvement of CXCL12 and CXCR4 in lymph node metastases and development of oral squamous cell carcinomas. 1878 Oct 98

The abilities of chemokines in orchestrating cellular migration are utilised by different (patho-)biological networks including malignancies. However, except for CXCR4/CXCL12, little is known about the relation between tumour-related chemokine expression and the development and progression of solid tumours like breast cancer. In this study, microarray analyses revealed the overexpression of chemokine CXCL13 in breast cancer specimens. This finding was confirmed by real-time polymerase chain reaction in a larger set of samples (n = 34) and cell lines, and was validated on the protein level performing Western blot, ELISA, and immunohistochemistry. Levels of CXCR5, the receptor for CXCL13, were low in malignant and healthy breast tissues, and surface expression was not detected in vitro. However, we observed a strong (P = 0.0004) correlation between the expressions of CXCL13 and CXCR5 in breast cancer tissues, indicating a biologically relevant role of CXCR5 in vivo. Finally, we detected significantly elevated serum concentrations of CXCL13 in patients with metastatic disease (n = 54) as compared with controls (n = 44) and disease-free patients (n = 48). In conclusion, CXCL13 is overexpressed within breast cancer tissues, and increased serum levels of this cytokine can be found in breast cancer patients with metastatic disease pointing to a role of CXCL13 in the progression of breast cancer, suggesting that CXCL13 might serve as a useful therapeutic target and/or diagnostic marker in this malignancy.
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PMID:Chemokine CXCL13 is overexpressed in the tumour tissue and in the peripheral blood of breast cancer patients. 1878 Nov 50

Breast cancer is the most common malignancy and second leading cause of cancer death in women. Ninety percent of mortality in breast cancer is often associated with metastatic progression or relapse in patients. Critical stages in the development of aggressive breast cancer include the growth of primary tumors and their ability to spread to foreign organs and form metastases, as well as the establishment of an independent blood supply within the new tumors. Hence, it is imperative to characterize the key molecules that regulate the metastasis of human breast cancer cells. The expression of CXCR4/CXCL12 in breast tumors has been correlated with a poor prognosis, increased metastasis, resistance to conventional therapeutic agents and a poor outcome in the pathogenesis of breast cancer. However, effective anti-CXCR4 therapy remains a challenge. Here, we will review the putative involvement of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Characterization of signaling events important for breast cancer cell growth and their metastasis to the brain should provide insights into breast cancer therapies and improved, successful treatments for breast cancer.
Clin Exp Metastasis 2010 Feb
PMID:Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. 1881 42

Interaction between the chemokine CXCL12 (SDF1) and the G-protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ-specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4-dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non-seminomas is significantly associated with organ-confined disease post-orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility.
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PMID:Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents. 1883 94

Although chemokines and their receptors were initially identified as regulators of cell trafficking during inflammation and immune response, they have emerged as crucial players in all stages of tumor development, primary growth, migration, angiogenesis, and establishment as metastases in distant target organs. Neuroectodermal tumors regroup neoplasms originating from the embryonic neural crest cells, which display clinical and biological similarities. These tumors are highly malignant and rapidly progressing diseases that disseminate to similar target organs such as bone marrow, bone, liver and lungs. There is increasing evidence that interaction of several chemokine receptors with corresponding chemokine ligands are implicated in the growth and invasive characteristics of these tumors. In this review we summarize the current knowledge on the role of CXCL12 chemokine and its CXCR4 and CXCR7 receptors in the progression and survival of neuroectodermal tumors, with particular emphasis on neuroblastoma, the most typical and enigmatic neuroectodermal childhood tumor.
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PMID:Chemokines in neuroectodermal cancers: the crucial growth signal from the soil. 1901 30


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