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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.
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PMID:Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention? 1733 54

Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients.
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PMID:Chemokines: novel targets for breast cancer metastasis. 1771 37

Lung caner cells have a striking tendency to metastasize to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and bone marrow stromal cells and plays a key role for homing of hematopoietic cells to the bone marrow. Reverse transcriptase-polymerase chain reaction and flow cytometry studies demonstrated SDF-1 receptor (CXCR4) messenger RNA (mRNA) and surface expression of CXCR4 in lung cancer cell lines, especially higher in those with high invasiveness (A549) as compared with lower level in H928 cells and H1299 cells. SDF-1, osteoblast-conditioned medium (OBCM) and stromal cell-conditioned medium all induced the invasiveness of lung cancer cells. Matrix metalloproteinase (MMP)-9 small interfering RNA inhibited the SDF-1alpha- or OBCM-induced MMP-9 expression and thereby significantly inhibited the SDF-1alpha- or OBCM-induced cell invasion. Furthermore, mitogen-activated protein kinase kinase inhibitor PD98059 suppressed SDF-1alpha-induced MMP-9 mRNA expression. Transient transfection with dominant-negative extracellular signal-regulated kinase (ERK) mutant also showed that the ERK-signaling pathway was involved in SDF-1alpha-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed the MMP-9 promoter activity enhanced by SDF-1alpha. Both mitogen-activated protein kinase kinase inhibitor and ERK mutant also antagonized SDF-1alpha-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that bone marrow-derived-SDF-1alpha enhances the invasiveness of lung cancer cells by increasing MMP-9 expression through the CXCR4/ERK/NF-kappaB signal transduction pathway.
Carcinogenesis 2008 Jan
PMID:Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. 1791 7

Angiogenesis and inflammation are two processes regulated by numerous common molecular mechanisms. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation; both mechanisms have been shown to be involved in carcinogenesis. With this study we sought to gain an understanding of the molecular mechanisms involved in tumor angiogenesis and inflammation in urinary bladder tumors. Tumor specimens were collected at slaughter from Friesian cows chronically exposed to bracken fern. Bracken chronic toxicity is characterized by the presence of multiple mixed tumors in the bladder, being reported throughout the world under the designation of bovine enzootic hematuria. We conducted molecular analyses of angiogenic factors and chemokine production by real-time RT-PCR, and also assessed microvessel density (MVD), microvessel pericyte coverage index (MPI) to reveal mature vessels, the extent of tumor-infiltrating leukocytes (TILk) and tumor cell apoptosis and proliferation in both epithelial and endothelial-derived bovine urinary bladder tumors. We defined a profile of chemokines/chemokine receptors (Mip1beta, CCR1) and angiogenesis-related factors (VEGF, VEGFR2) that allow distinguishing between urothelial carcinomas (epithelial origin) and hemangiosarcomas (endothelial origin). Taken together, our data reveals previously unrecognized paracrine and autocrine chemo-angiogenic loops in the context of bovine urinary bladder tumorigenesis.
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PMID:Chemo-angiogenic profile of bovine urinary bladder tumors distinguishes urothelial carcinomas from hemangiosarcomas. 1802 98

Oral squamous cell carcinoma (SCC) has a striking tendency to invade to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and plays a key role in homing of hematopoietic cells to the bone marrow. Interleukin (IL)-6 plays an important role in osteoclastogenesis. Herein, we found that SDF-1 alpha increased the secretion of IL-6 in cultured human SCC cells, as shown by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. SDF-1 alpha also increased the surface expression of chemokine receptor 4 (CXCR4) in SCC cells. CXCR4-neutralizing antibody, CXCR4-specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited SDF-1 alpha-induced increase IL-6 production. The transcriptional regulation of IL-6 by SDF-1 alpha was mediated by phosphorylation of extracellular signal-regulated kinases (ERKs) and activation of the nuclear factor-kappa B (NF-kappaB) components p65 and p50. The binding of p65 and p50 to the NF-kappaB element on the IL-6 promoter was enhanced by SDF-1 alpha. In addition, IL-6 antibody antagonized the SCC-conditioned medium-increased osteoclastogenesis. These results suggested that SDF-1 alpha from osteoblasts could induce release of IL-6 in human SCC cells via activation of CXCR4, ERK and NF-kappaB pathway and thereby promote osteoclastogenesis.
Carcinogenesis 2008 Aug
PMID:Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells. 1831 89

Potassium channels, the most diverse superfamily of ion channels, have recently emerged as regulators of carcinogenesis, thus introducing possible new therapeutic strategies in the fight against cancer. In particular, the large conductance Ca(2+)-activated K(+) channels, often referred to as BK channels, are at the crossroads of several tumor-associated processes such as cell proliferation, survival, secretion and migration. Despite the high BK channel expression in osteosarcoma (OS), their function has not yet been investigated in this malignant bone pathology. Here, using stable RNA interference to reduce the expression of hSlo, the human pore-forming alpha-subunit of the BK channel, in human Cal72 OS cells, we show that BK channels play a functional role in carcinogenesis. Our results reveal for the first time that BK channels exhibit antitumoral properties in OS in vivo and affect the tumor microenvironment through the modulation of both chemokine expression and leukocyte infiltration.
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PMID:Silencing of hSlo potassium channels in human osteosarcoma cells promotes tumorigenesis. 1840 72

Fumonisin B1 and ochratoxin A are mycotoxins of importance to public health and agro-economics. Although much is known about their cellular toxicity and carcinogenesis in animals, there are no reports of adverse effects on immune cells (leukocytes) or on the immune modulation of the molecular messengers (cytokines) in humans. This study was designed, therefore, to determine and compare the morphological effects of fumonisin B1 and ochratoxin A on lymphocytes and neutrophils harvested from the circulation of healthy volunteer subjects and patients with oesophageal and breast carcinomas. Both fumonisin B1 and ochratoxin A reduced the number of viable lymphocytes and neutrophils harvested from the circulation of volunteer subjects carcinoma patients in a dose-dependent manner. Leukocyte secretion of cytokines on exposure to the mycotoxins was evaluated by immunocytochemical methods. Expression of granulocyte-colony stimulating factor (G-CSF), tumour necrosis factor (TNF-alpha) and chemokine (CX3CR1) receptors were determined on the circulating leukocytes and the immunolabelling visualized by brightfield-and electron-microscopy. Cytokine levels were determined in the circulation of healthy volunteer subjects and in patients with oesophageal and breast carcinomas since they reflect the status of the immune system in humans. The findings of this study on immunocytes (leukocytes) and the immune molecular messengers (cytokines) suggest that fumonisin B1 and ochratoxin A have an immuno-suppressive effect in humans, in particular patients with cancer by impairing immune surveillance.
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PMID:Modulating effects of fumonisin B1 and ochratoxin A on leukocytes and messenger cytokines of the human immune system. 1844 83

The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.
Carcinogenesis 2008 Jun
PMID:Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. 1848 23

Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.
Carcinogenesis 2008 Aug
PMID:CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. 1848 24

Chemokines are involved in human hepatocellular carcinoma (HCC) carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 +/- 1.13, 2.34 +/- 1.16 and 1.63 +/- 1.26, respectively and that the CXCR4 protein levels were 1.38 +/- 0.13, 1.96 +/- 0.32 and 1.86 +/- 0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 +/- 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes (CI) of 3.9 +/- 1.1 and 4.1 +/- 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 +/- 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.
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PMID:Roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells. 1895 61


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