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)

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.
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PMID:Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. 1633 1

Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P < 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.
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PMID:Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. 1648 19

The level of expression of the chemokine receptor CXCR4 has been shown to play a crucial role in determining the ability of cancer cells to metastasize from the primary tumor and become established in tissue sites that are rich in the CXCR4 ligand CXCL12/SDF-1alpha. High CXCR4 expression on cancer cells is associated with an increased risk of recurrence and poorer overall survival. We propose that local tissue mediators within the primary tumor or at secondary sites may modulate the level of CXCR4 expression and, therefore, potentially affect the ability of the cancer cells to metastasize. The purine nucleoside adenine-9-beta-D-ribofuranoside (adenosine) is generated at high concentrations within the extracellular fluid of solid tumors because of their hypoxia. We show here that adenosine acts through A(2A) and A(2B) adenosine receptors on human colorectal carcinoma cells to upregulate CXCR4 mRNA expression up to 10-fold and selectively increases cell-surface CXCR4 protein up to 3-fold. This increase in cell-surface CXCR4 enables the carcinoma cells to migrate toward CXCL12, and enhances their proliferation in response to CXCL12. Adenosine may therefore be one of the factors within the tumor microenvironment that facilitates tumor dissemination, by upregulating CXCR4 on certain cancer cells and enhancing cellular responses to CXCL12.
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PMID:Adenosine upregulates CXCR4 and enhances the proliferative and migratory responses of human carcinoma cells to CXCL12/SDF-1alpha. 1682 36

The propensity of uveal melanoma cells for invasion and metastasis is critical factor for the clinical outcome of this form of cancer, and the essential biology of its aggressiveness is not completely understood. In the present study we investigated the involvement of hypoxia-inducible factor 1 (HIF-1) in uveal melanoma migration, invasion and adhesion, the hallmarks of aggressive behavior of cancer cells. We demonstrate that exposure to hypoxia increased migration, invasion and adhesion of uveal melanoma cells in in vitro assays. The "silencing" of HIF-1alpha, the oxygen-regulated subunit of HIF-1, using RNA interference technology resulted in a marked decrease of the uveal melanoma cell migration, invasion and adhesion. GeneChip microarray analysis revealed that a number of genes which regulate cancer invasion and metabolism such as CXCR4, angiopoietin-related protein, pyruvate dehydrogenase kinase 1 (PDK1) are also activated by hypoxia in a HIF-1-dependent manner in Mum2B uveal melanoma cells. We further demonstrate that serum deprivation resulted in HIF-1 and CXCR4 activation, suggesting specific metabolic regulation of HIF-1 in these cells. Microarray analysis of serum-deprived cells identified among the upregulated genes a number of cancer invasion-related genes, some of them being known HIF-1-regulated targets. Taken together, these results suggest that the involvement of HIF-1 in uveal melanoma tumorigenesis is significant and complex, and that metabolic regulation of HIF-1 activation in Mum2B uveal melanoma cells has its specificities.
Clin Exp Metastasis 2006
PMID:Involvement of HIF-1 in invasion of Mum2B uveal melanoma cells. 1682 25

Nasopharyngeal carcinoma (NPC) is an epithelial cancer that metastasizes predictably to cervical lymph nodes or distant organs. To assess whether the chemokine receptors of NPC cells play important roles in metastasis and are associated with radiotherapy history, the significance of various chemokine receptors (CCR1-10, CXCR1-6, XCR1, and CX3CR1) in NPC cell lines (TW01, TW04, HONE1, BM1, and AS1) and 52 NPC tumour biopsies from 48 patients with NPC was evaluated by mRNA and cytometric analyses, chemotaxis and actin polymerization assays, and immunohistochemical staining. Quantitative real-time reverse transcription-polymerase chain reaction revealed substantial expression of CCR7, CCR9, CXCR4, and CXCR6 mRNA in all the NPC cell lines. Of these, however, only CCR7, CXCR4, and CXCR6 were functional in NPC cells. Negative immunoreactivity for CCR7, CXCR4, and CXCR6 was demonstrated in almost all nasopharyngeal (NP) specimens from patients with primary NPC (n = 12) and in those with regional metastatic NPC (n = 15). However, expression of two or three of these chemokine receptors was demonstrated in NP specimens from patients with liver metastasis. Strong positivity was demonstrated for all three of these chemokine receptors in almost all of the regional and distant metastasis specimens. Significant differences in the expression of CCR7, CXCR4, and CXCR6 were found between primary tumours and metastases (p < 0.001, p < 0.001, and p < 0.002, respectively). This observation was further confirmed by laser capture microdissection of freshly frozen tumours from primary (n = 5) and metastatic (n = 8) NPC sites (p = 0.04, 0.03, and 0.03 for CCR7, CXCR4, and CXCR6, respectively). Finally, significant differences in CXCR4 expression were demonstrated between de novo and post-radiotherapy groups (1/22 vs. 5/8; p < 0.003). It appears reasonable to conclude, therefore, that CCR7, CXCR4, and CXCR6 are expressed and active in human NPC metastases, while CXCR4 expression is associated with radiotherapy history.
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PMID:Chemokine receptor expression profiles in nasopharyngeal carcinoma and their association with metastasis and radiotherapy. 1695 98

Tumor development and progression are multifactorial processes, regulated by a large variety of intrinsic and microenvironmental factors. A key role in cancer is played by members of the chemokine superfamily. Chemokines and their receptors are expressed by tumor cells and by host cells, in primary tumors and in specific metastatic loci. The effects of chemokines on tumorigenesis are diverse: While some members of the superfamily significantly support this process, others inhibit fundamental events required for tumor establishment and metastasis. The current review describes the multifaceted roles of chemokines in malignancy, addressing four major aspects of their activities: (1) inducing leukocyte infiltration to tumors and regulating immune functions, with emphasis on tumor-associated macrophages (and the chemokines CCL2, CCL5), T cells (and the chemokines CXCL9, CXCL10) and dendritic cells (and the chemokines CCL19, CCL20, CCL21); (2) directing the homing of tumor cells to specific metastatic sites (the CXCL12-CXCR4 axis); (3) regulating angiogenic processes (mainly the ELR(+)-CXC and non-ELR-CXC chemokines); (4) acting directly on the tumor cells to control their malignancy-related functions. Together, these different chemokine functions establish a net of interactions between the tumor cells and their microenvironment, and partly dictate the fate of the malignancy cascade.
Cancer Metastasis Rev 2006 Sep
PMID:The multifaceted roles of chemokines in malignancy. 1701 63

Expression of the chemokine receptor CXCR4 by tumor cells promotes metastasis, possibly by activating prosurvival signals that render cancer cells resistant to immune attack. Inhibition of CXCR4 with a peptide antagonist, T22, blocks metastatic implantation of CXCR4-transduced B16 (CXCR4-luc-B16) melanoma cells in lung, but not the outgrowth of established metastases, raising the question of how T22 can best be used in a clinical setting. Herein, whereas the treatment of CXCR4-luc-B16 cells in vitro with the CXCR4 ligand CXCL12 did not reduce killing induced by cisplatin or cyclophosphamide, CXCL12 markedly reduced Fas-dependent killing by gp100-specific (pmel-1) CD8(+) T cells. T22 pretreatment restored sensitivity of CXCR4-luc-B16 cells to pmel-1 killing, even in the presence of CXCL12. Two immune-augmenting regimens were used in combination with T22 to treat experimental lung metastases. First, low-dose cyclophosphamide treatment (100 mg/kg) on day 5 in combination with T22 (days 4-7) yielded a approximately 70% reduction of B16 metastatic tumor burden in the lungs compared with cyclophosphamide treatment alone (P < 0.001). Furthermore, whereas anti-CTL antigen 4 (CTLA4) monoclonal antibody (mAb; or T22 treatment) alone had little effect on established B16 metastases, pretreatment with T22 (in combination with anti-CTLA4 mAb) resulted in a 50% reduction in lung tumor burden (P = 0.02). Thus, in vitro, CXCR4 antagonism with T22 renders B16 cells susceptible to killing by antigen-specific T cells. In vivo, T22 synergizes with cyclophosphamide or anti-CTLA4 mAb in the treatment of established lung metastases, suggesting a novel strategy for augmenting the efficacy of immunotherapy.
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PMID:Sensitization of B16 tumor cells with a CXCR4 antagonist increases the efficacy of immunotherapy for established lung metastases. 1704 Nov 4

Renal cell carcinoma (RCC) is characterized by organ-specific metastases. The chemokine stromal derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 have been suggested to regulate organ-specific metastasis in various other cancers. On this basis, we hypothesized that the biological axis of CXCL12 via interaction with its receptor, CXCR4, is a major mechanism for RCC metastasis. We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC. We detected up-regulation of CXCR4 mRNA and protein levels on a human RCC cell line by either knockdown of the von Hippel-Lindau (VHL) tumor suppressor protein, or incubating the cells under hypoxic conditions. The enhanced CXCR4 expression was mediated through the interaction of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) with the promoter region of the CXCR4 gene. Furthermore, the expression of CXCR4 on human RCC directly correlated with their metastatic ability in vivo in both heterotopic and orthotopic SCID mouse models of human RCC. Neutralization of CXCL12 in SCID mice abrogated metastasis of RCC to target organs expressing high levels of CXCL12; without altering tumor cell proliferation, apoptosis, or tumor-associated angiogenesis. Therefore, our data suggest that the CXCL12/CXCR4 biological axis plays an important role in regulating the organ-specific metastasis of RCC.
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PMID:Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. 1708 23

Basal cell carcinoma (BCC) is one of the most common skin neoplasms in humans and is usually characterized by local aggressiveness with little metastatic potential, although deep invasion, recurrence, and regional and distant metastases may occur. Here, we studied the mechanism of BCC invasion. We found that human BCC tissues and a BCC cell line had significant expression of CXCR4, which was higher in invasive than non-invasive BCC types. Further, of 19 recurrent tumors among 390 BCCs diagnosed during the past 12 years, 17/19 (89.5%) had high CXCR4 expression. We found that the CXCR4 ligand, stromal-cell-derived factor 1alpha (SDF-1alpha), directed BCC invasion and that this was mediated by time-dependent upregulation of mRNA expression and gelatinase activity of matrix metalloproteinase-13 (MMP-13). The transcriptional regulation of MMP-13 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the AP-1 component c-Jun. Finally, CXCR4-transfected BCC cells injected into nude mice induced aggressive BCCs that co-expressed CXCR4 and MMP-13. The identification of SDF-1alpha/CXCR4 as an important factor in BCC invasiveness may contribute insight into mechanisms involved in the aggressive potential of human BCC and may improve therapy for invasive BCCs.
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PMID:Involvement of matrix metalloproteinase-13 in stromal-cell-derived factor 1 alpha-directed invasion of human basal cell carcinoma cells. 1709 30

Tumor cells are known to adapt to and utilize existing physiological mechanisms to promote survival and metastasis. The role of the microenvironment in the establishment of a metastatic lesion has become increasingly important as several factors secreted by stromal cells regulate metastatic pattern in a variety of tumor types. Tumor cells interact with osteoblasts, osteoclasts and bone matrix to form a vicious cycle that is essential for successful metastases. Here we review the current concepts regarding the role of an important chemokine/chemokine receptor (SDF-1 or CXCL12/CXCR4) pathway in tumor development and metastasis. CXCL12 secretion by stromal cells is known to attract cancer cells via stimulation of the CXCR4 receptor that is up regulated by tumor cells. CXCL12/CXCR4 activation regulates the pattern of metastatic spread with organs expressing high levels of CXCL12 developing secondary tumors (i.e., the bone marrow compartment). CXCL12 has a wide range of effects in regards to tumor development but the primary role of CXCL12 appears to be the mobilization of hematopoietic stem cells and the establishment of the cancer stem-like cell niche where high levels of CXCL12 recruit a highly tumorigenic population of tumor cells and promotes cell survival, proliferation, angiogenesis, and metastasis.
Cancer Metastasis Rev 2006 Dec
PMID:The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. 1716 32


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