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

The metastatic spread of tumors is a well-coordinated process in which different types of cancers tend to form metastases in defined organs. The formation of site-specific metastases requires full compatibility between the intrinsic properties of the tumor cells and the tumor microenvironment. It was recently found that chemokines which are expressed in specific loci promote the adhesion, migration and invasion of tumor cells that express the corresponding receptor(s). Of the different members of the family, the CXCL12 chemokine and its cognate CXCR4 receptor are the prototypes of this process, although other members of the family (e.g. CCR7 and CCR10) also play a role in determination of the metastatic spread. This commentary addresses the fundamental roles of chemokines and their receptors in site-specific metastasis, with emphasis on CXCL12-CXCR4. The article also describes some of the efforts that were performed thus far in order to identify the intracellular components involved in this process. The focus is put on the roles played by proteins that regulate adhesion and migration of tumor cells in response to CXCL12, including mainly focal adhesion kinase (FAK), Pyk2/RAFTK and members of the Rho family of GTPases (RhoA, Rac, Cdc42). This is followed by discussion of open questions that need to be addressed in future research, and of the potential therapeutic implications of the findings that are available to date in this field.
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PMID:Site-specific metastasis formation: chemokines as regulators of tumor cell adhesion, motility and invasion. 1955 Jan 36

Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity.
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PMID:Latent bone metastasis in breast cancer tied to Src-dependent survival signals. 1957 4

The cytokine C-X-C motif chemokine 12 (CXCL12) is synthesised by metastasis target tissues and has been shown to attract tumour cells that express the receptor, C-X-C chemokine receptor type 4 (CXCR4). However, epigenetic silencing of CXCL12 has recently been reported to increase the metastatic potential of breast cancer cells and the reintroduction of the cytokine gene into MDA-MB-231 breast carcinoma cells decreases the number of metastases formed in vivo. We therefore wished to know whether CXCL12 expression correlates with relapse-free and overall survival in human breast cancer patients. The expression of C-X-C motif chemokine 12 (CXCL12) and C-X-C chemokine receptor type 4 (CXCR4) was analysed in 100 archival breast cancer samples by immunohistochemistry and in two breast cancer microarray datasets of 408 cases. Data were analysed by univariate and multivariate COX regression analyses. CXCL12 and CXCR4 are expressed by epithelial tumour cells and by stromal and endothelial cells. Microarray gene expression analysis and immunohistochemistry revealed that expression of CXCL12 but not of CXCR4 significantly correlates with disease-free and overall survival in oestrogen receptor-positive and -negative cancers. The expression of the oestrogen receptor alpha and that of CXCL12 do not correlate. CXCL12 is a strong, independent prognostic marker. We propose that saturation of the receptor through autocrine CXCL12 production reduces chemotaxis towards CXCL12-releasing metastasis target tissues.
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PMID:CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. 1964 61

The CXCL12 chemokine binds to the CXCR4 receptor and contributes to survival, proliferation, and migration of malignant cells. Recent reports indicate that breast cancer cells lacking expression of CXCL12 but exhibiting CXCR4 can metastasize to target organs that secrete CXCL12. We observed that Tamoxifen (Tam), similarly to 5-dAzaC, results in significantly increased levels of CXCL12 transcript and protein in MCF-7 breast cancer cells. Bisulfite sequencing suggests that Tam, similarly to 5-dAzaC, may increase CXCL12 expression via reduction in methylation of cytosine in the cytosine-guanosine (CpG) dinucleotide island of the CXCL12 promoter of MCF-7 cells. Our results, together with findings of other researches, may suggest that Tam epigenetically activates CXCL12 expression in breast cancer cells and can make these cells less susceptible to attraction by exogenous CXCL12 to metastasis sites.
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PMID:Tamoxifen epigenetically modulates CXCL12 expression in MCF-7 breast cancer cells. 1974 59

Chemokine CXCL12 is proposed to promote multiple steps in growth of primary tumors and progression to metastatic disease in more than 20 different cancers. Functions of CXCL12 previously were believed to be controlled only by receptor CXCR4, but CXCR7 was recently identified as a second receptor for this chemokine. CXCR7 increases tumor formation and metastasis in mouse models, suggesting that this receptor may also be a key target for blocking effects of CXCL12 in cancer. To image activation of CXCR7 in intact cells and living mice, we tested the hypothesis that binding of chemokine ligands to CXCR7 recruits beta-arrestins, a family of cytosolic adapter proteins that interact with many activated chemokine and related seven-transmembrane receptors. Using firefly luciferase protein fragment complementation, we established that chemokine ligands CXCL12 and CXCL11 significantly increase association of CXCR7 and beta-arrestins with preferential interaction of the receptor with beta-arrestin 2. The magnitude of interactions between CXCR7 and beta-arrestin 2 increased over time after treatment with ligands, contrasting with transient association of beta-arrestin 2 and CXCR4. beta-Arrestin 2 increased uptake of CXCL12 in cells expressing CXCR7, emphasizing the functional relevance of the interaction between CXCR7 and beta-arrestin 2. In an orthotopic xenograft model of human breast cancer, we used bioluminescence imaging to quantify changes in the association of CXCR7 and beta-arrestin 2. These studies demonstrate ligand-dependent interactions of CXCR7 with beta-arrestin 2 that promote accumulation of chemokines and establish an imaging assay for the dynamic regulation of CXCR7 by chemokines and candidate therapeutic agents in cell-based assays and living mice.
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PMID:Imaging ligand-dependent activation of CXCR7. 1979 61

The chemokine receptor, CXCR4, and its specific ligand, CXCL12, have been proven to regulate the directional trafficking and invasion of breast cancer cells to sites of metastases, and similar phenomena have also been identified in many malignant tumors that aberrantly overexpress CXCR4. Therefore, blocking the interaction between CXCR4 and CXCL12 is considered a possible approach to efficiently prevent cancer metastasis. Employing a cellular phenotypic knockout strategy based on intrakines, we developed a novel recombinant chimeric protein, TAT/54R/KDEL, which contains three distinct functional domains: CXCL12/54R, a mutant of CXCL12 with CXCR4 antagonism, as well as HIV-derived TAT (47-57) and an endoplasmic reticulum retention four-peptide sequence KDEL that links at its NH(2) and COOH termini, respectively. Using the MOLT-4 cell line, which expressed CXCR4 highly and stably in vitro, we determined that TAT/54R/KDEL was able to efficiently transfer into the endoplasmic reticulum of tumor cells, where it specifically binds to the newly synthesized CXCR4 and prevents the latter from reaching the surface. Chemotaxis assays showed that the cells treated with TAT/54R/KDEL failed to migrate toward CXCL12. Furthermore, we observed that the systemic treatment of TAT/54R/KDEL could impair lung metastasis in a highly metastatic mammary cancer cell line, 4T1 cells, with the decrease of CXCR4 on their membrane. Our results suggest that the phenotypic knockout strategy of CXCR4 using a novel recombinant protein TAT/54R/KDEL might be a possible approach for inhibiting relative tumor metastasis mediated by CXCR4/CXCL12 interaction.
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PMID:Phenotypic knockout of CXCR4 by a novel recombinant protein TAT/54R/KDEL inhibits tumors metastasis. 1982 96

The chemokine receptor CXCR4 is involved in the metastasis of many cancers. Recent evidence suggests that CXCR4 may be also involved in the metastasis of renal cell carcinoma. We analyzed the expression of CXCR4 in primary carcinomas, metastatic tissues and normal tissues using immunohistochemistry. We further investigated the migration of renal carcinoma cells in response to stimulation by CXCL12 in vitro. We also studied the subcellular localization of CXCR4 in renal cell carcinoma cells in response to CXCL12 by confocal microscopy. We observed the highest percentage of CXCR4 expression in renal cell carcinoma metastases compared with that in renal cell carcinomas and normal renal tissues. We further found that CXCR4 was localized predominantly in the membrane in primary renal cell carcinomas and predominantly in the cytoplasm in renal cell carcinoma metastases. Moreover, we found that CXCR4 was translocated from the cytoplasmic membrane to the cytoplasm upon stimulation by its ligand CXCL12. Renal cell carcinoma metastasis was associated with higher expression of CXCR4 and interaction of CXCR4 and its ligand CXCL12 resulted in the internalization of CXCR4 from the cytoplasmic membrane. These findings implicate the CXCR4-CXCL12 axis in the metastasis of renal cell carcinoma.
Clin Exp Metastasis 2009
PMID:Strong expression of chemokine receptor CXCR4 by renal cell carcinoma cells correlates with metastasis. 1985 17

Despite improvements in early diagnosis of uveal melanoma, prognosis is still poor due to metastases development. Neoangiogenesis and migration are requisites to metastasis promotion. Cross-talking between CXCR4-CXCL12 axis and the VEGF pathway was shown to favours tumour progression. CXCR4-CXCL12-VEGF expression was evaluated by immunohistochemistry in 53 selected cases of primary uveal melanoma and in liver melanoma metastases. CXCR4 protein was detected in 41.4 per cent cases, CXCL12 in 43.4 per cent cases and VEGF expression in 39.6 per cent cases. A significant correlation was found between CXCR4 and VEGF expression (p=0.011), CXCL12 and both tumour dimension and (p=0.006) and epithelioid-mixed cytotype (p=0.012). The two cases of uveal melanoma liver metastases in our series showed CXCR4 expression, weak immunoreactivity for CXCL12 and absent VEGF immunostaining. These data indicate that CXCR4-CXCL12 axis and its cross-talking with VEGF plays a role in uveal melanoma metastases and may be new prognostic markers in UMM. Moreover, these results suggest that targeted inhibition of CXCR4 could be introduced to control metastasis development in UMM.
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PMID:"CXCR4-CXCL12 and VEGF correlate to uveal melanoma progression". 2003 48

Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. Vascular endothelial growth factor (VEGF), carbonic anhydrase (CA-IX), hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2alpha expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition and development was altered including increased expression of the C-X-C chemokine receptor type 4 (CXCR4), an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand, CXCL12 (stromal cell-derived factor 1 (SDF-1)), activated the mitogen-activated protein kinase (MAPK) p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, HIF-2alpha and CXCR4. Signalling through the CXCL12-CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for carcinoid tumour disease.
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PMID:Hypoxia stimulates CXCR4 signalling in ileal carcinoids. 2007 57

Metastasis is considered the obvious mark for most aggressive cancers. However, little is known about the molecular mechanism of the regulation of cancer metastasis. Recent evidence increasingly suggests that the interaction between chemokines and chemokine receptors is pivotal in the process of metastasis. The chemokine receptor CXCR4 and its ligand CXCL12, for example, have been reported to play a vital role in cancer metastasis. Another chemokine and chemokine receptor pair, the CXCL16/CXCR6 axis, has been studied by several independent research groups. Here, we summarize recent advances in our knowledge of the function of CXC chemokine receptor CXCR6 and its ligand CXCL16 in regulating metastasis and invasion of cancer. CXCR6 and CXCL16 are up-regulated in multiple cancer tissue types and cancer cell lines relative to normal tissues and cell lines. In addition, both CXCR6 and CXCL16 levels increase as tumor malignancy increases. Trans-membranous CXCL16 chemokine reduces proliferation while soluble CXCL16 chemokine enhances proliferation and migration. TM-CXCL16 functions as an inducer for lymphocyte build-up around tumor sites. High trans-membranous CXCL16 expression correlates with a good prognosis. Moreover, the Akt/mTOR signal pathway is involved in activating the CXCR6/CXCL16 axis. These findings suggest multiple opportunities for blocking the CXCR6/CXCL16 axis and the Akt/mTOR signal pathway in novel cancer therapies.
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PMID:CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. 2012 97


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