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)

Biophytum sensitivum is a traditional oriental herbal medicine that is known for its immunostimulatory and antitumor effects. Tumor metastasis is the most important cause of cancer death. Although B sensitivum was shown to inhibit metastasis, the mechanism underlying this action is not well understood. In the present report, the authors had studied the effect of B sensitivum on the invasion and motility of B16F-10 melanoma cells and investigate the regulatory effect on the expression of matrix metalloproteases (MMPs), prolyl hydoxylase, lysyl oxidase, nm23, extracellular signal-regulated kinase (ERK)-1, ERK-2, signal transducer and activator of transcription (STAT)-1, and proinflammatory cytokines in metastatic tumor-bearing lungs. B sensitivum inhibited the invasion and motility of B16F-10 cells in a dose-dependent manner. B sensitivum inhibited the expression of MMP-2 and MMP-9, whereas it activated STAT-1 expression in metastatic tumor-bearing lungs. Similarly, inhibition of prolyl hydroxylase, lysyl oxidase, ERK-1, ERK-2, and vascular endothelial growth factor (VEGF) expression but activation of nm23 by B sensitivum was observed in metastatic tumor-bearing lungs. B sensitivum treatment also downregulated the expression of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and granulocyte monocyte-colony stimulating factor in metastatic tumor-bearing lungs. In B16F-10 cells, B sensitivum also inhibited the production of proinflammatory cytokines. Overall, the results indicate that B sensitivum exhibits antimetastatic effects through the inhibition of invasion and motility. The results also suggest that MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERKs, VEGF, STAT, and proinflammatory cytokines are critical regulators of the B sensitivum-mediated antimetastatic effect.
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PMID:Biophytum sensitivum (L.) DC inhibits tumor cell invasion and metastasis through a mechanism involving regulation of MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERK-1, ERK-2, STAT-1, and proinflammatory cytokine gene expression in metastatic lung tissue. 1829 94

IL-6 cytokine family is composed by several members. IL-6, LIF, and gp130 have been associated with cancer progression. Cytokines play an important role in tumoral growth, invasion of the vessels and development of metastases. Immunoexpressions of LIF, OSM, LIFRbeta and OSMRbeta were studied in benign breast lesion, in situ and infiltrating tumors by Western blot and immunohistochemistry. Percentages of positive samples to OSM, LIF and OSMRbeta were higher in in situ carcinoma than in benign diseases and even higher in infiltrating tumors. gp130-positive samples was higher in infiltrating tumor than in benign diseases. All samples studied were LIFRbeta-positive. Infiltrating tumors showed the most intense immunostaining to LIFRbeta, OSM and OSMRbeta; comparing present results revealed an association between the expression of these proteins and increasing malignancy. In conclusions, development of breast tumor increases the expression of OSM, LIF, OSMRbeta, LIFRbeta and gp130, and this expression may be associated with the malignancy. IL-6 family exert their action through transducer receptor gp130, and gp130 expression increase with malignance, it might be a crucial point in the development of infiltrative adenocarcinoma. The secretion of OSM and LIF by both epithelial and stromal (paracrine manner) cells seems to promote tumor growth.
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PMID:OSM, LIF, its receptors, and its relationship with the malignance in human breast carcinoma (in situ and in infiltrative). 1831 62

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

Cancer cells often acquire a constitutively active nuclear factor-kappaB (NF-kappaB) program to promote survival, proliferation and metastatic potential by mechanisms that remain largely unknown. Extending observations from an immunologic setting, we demonstrate that microRNA-146a and microRNA-146b (miR-146a/b) when expressed in the highly metastatic human breast cancer cell line MDA-MB-231 function to negatively regulate NF-kappaB activity. Lentiviral-mediated expression of miR-146a/b significantly downregulated interleukin (IL)-1 receptor-associated kinase and TNF receptor-associated factor 6, two key adaptor/scaffold proteins in the IL-1 and Toll-like receptor signaling pathway, known to positively regulate NF-kappaB activity. Impaired NF-kappaB activity was evident from reduced phosphorylation of the NF-kappaB inhibitor IkappaBalpha, reduced NF-kappaB DNA-binding activity and suppressed expression of the NF-kappaB target genes IL-8, IL-6 and matrix metalloproteinase-9. Functionally, miR-146a/b-expressing MDA-MB-231 cells showed markedly impaired invasion and migration capacity relative to control cells. These findings implicate miR-146a/b as a negative regulator of constitutive NF-kappaB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.
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PMID:Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. 1850 31

Over the past five decades, those interested in markers of radiation effect have focused primarily on tumor response. More recently, however, the view has broadened to include irradiated normal tissues-markers that predict unusual risk of side-effects, prognosticate during the prodromal and therapeutic phases, diagnose a particular toxicity as radiation-related, and, in the case of bioterror, allow for tissue-specific biodosimetry. Currently, there are few clinically useful radiation-related biomarkers. Notably, levels of some hormones such as thyroid-stimulating hormone (TSH) have been used successfully as markers of dysfunction, indicative of the need for replacement therapy, and for prevention of cancers. The most promising macromolecular markers are cytokines: TGFbeta, IL-1, IL-6, and TNFalpha being lead molecules in this class as both markers and targets for therapy. Genomics and proteomics are still in nascent stages and are actively being studied and developed.
Cancer Metastasis Rev 2008 Sep
PMID:Molecular markers of radiation-related normal tissue toxicity. 1850 99

Metastatic breast cancer cells (BCs) colonize a mineralized three-dimensional (3D) osteoblastic tissue (OT) grown from isolated pre-osteoblasts for up to 5 months in a specialized bioreactor. Sequential stages of BC interaction with OT include BC adhesion, penetration, colony formation, and OT reorganization into "Indian files" paralleling BC colonies, heretofore observed only in authentic pathological cancer tissue. BCs permeabilize OT by degrading the extra-cellular collagenous matrix (ECM) in which the osteoblasts are embedded. OT maturity (characterized by culture age and cell phenotype) profoundly affects the patterns of BC colonization. BCs rapidly form colonies on immature OT (higher cell/ECM ratio, osteoblastic phenotype) but fail to completely penetrate OT. By contrast, BCs efficiently penetrate mature OT (lower cell/ECM ratio, osteocytic phenotype) and reorganize OT. BC colonization provokes a strong osteoblast inflammatory response marked by increased expression of the pro-inflammatory cytokine IL-6. Furthermore, BCs inhibit osteoblastic bone formation by down-regulating synthesis of collagen and osteocalcin. Results strongly suggest that breast cancer disrupts the process of osteoblastic bone formation, in addition to upregulating osteoclastic bone resorption as widely reported. These observations may help explain why administration of bisphosphonates to humans with osteolytic metastases slows lesion progression by inhibiting osteoclasts but does not bring about osteoblast-mediated healing.
Clin Exp Metastasis 2008
PMID:Metastatic breast cancer cells colonize and degrade three-dimensional osteoblastic tissue in vitro. 1854 66

Chronic inflammation is a complex process that promotes carcinogenesis and tumor progression; however, the mechanisms by which specific inflammatory mediators contribute to tumor growth remain unclear. We and others recently demonstrated that the inflammatory mediators IL-1beta, IL-6, and PGE(2) induce accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing individuals. MDSC impair tumor immunity and thereby facilitate carcinogenesis and tumor progression by inhibiting T and NK cell activation, and by polarizing immunity toward a tumor-promoting type 2 phenotype. We now show that this population of immature myeloid cells induced by a given tumor share a common phenotype regardless of their in vivo location (bone marrow, spleen, blood, or tumor site), and that Gr1(high)CD11b(high)F4/80(-)CD80(+)IL4Ralpha(+/-)Arginase(+) MDSC are induced by the proinflammatory proteins S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration. MDSC also synthesize and secrete S100A8/A9 proteins that accumulate in the serum of tumor-bearing mice, and in vivo blocking of S100A8/A9 binding to MDSC using an anti-carboxylated glycan Ab reduces MDSC levels in blood and secondary lymphoid organs in mice with metastatic disease. Therefore, the S100 family of inflammatory mediators serves as an autocrine feedback loop that sustains accumulation of MDSC. Since S100A8/A9 activation of MDSC is through the NF-kappaB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients.
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PMID:Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. 1880 69

This study evaluates the effects of gingival fibroblasts, type I collagen and autocrine/paracrine elements on cytokine expression in paired primary and metastatic human squamous cell carcinoma (HNSCC) cell lines. Additionally, the effects of IL-1alpha, IL-1beta, IL-6, TNF-alpha, TGF-beta and HGF on MMPs and cell invasion were investigated. RT-PCR results indicated the presence of mRNAs for IL-1alpha, IL-1beta, IL-6, TNF-alpha, and TGF-beta in primary and metastatic HNSCC cell lines but high expression of cytokines was not a prerequisite for metastatic cancer cells. HGF mRNA was not detected in the cancer cell lines. Co-culturing of HNSCC cells with fibroblasts caused increases in cytokine expression. Type I collagen and conditioned media derived from HNSCC cells or fibroblasts enhanced cytokine expression in the cancer cells. Cytokines also enhanced MMP-2 and MMP-9 enzymatic activities as well as HNSCC cell invasion. Our findings suggest that the interactions between cancer cells, the extracellular matrix and fibroblasts, as mediated by cytokines, play important roles in the progression of HNSCC.
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PMID:Tumor-stroma interactions influence cytokine expression and matrix metalloproteinase activities in paired primary and metastatic head and neck cancer cells. 1899 11

Over 70% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Mesenchymal Stem Cells (MSCs) and their derivative osteoblasts are subpopulations of cells within the bone marrow environment, postulated as potential interacting targets for disseminating cancer cells because of their ability to secrete a range of chemokines. This study aimed to investigate chemokine secretion throughout MSC differentiation into osteoblasts and their effect on the breast cancer cells. Primary MSCs and osteoblast progenitors were cultured in appropriate conditions to induce differentiation into mature osteoblasts. Chemokines secreted throughout differentiation were detected using ChemiArray and ELISA. Migration of breast cancer cells in response to the bone-derived cells was quantified using Transwell inserts. Breast cancer cells were cocultured with MSCs, retrieved using magnetic beads, and changes in CCL2 expression were analyzed. MSCs secreted a range of factors including IL-6, TIMP-1 and CCL2, the range and level of which changed throughout differentiation. CCL2 secretion by MSCs increased significantly above control cells as they differentiated into mature osteoblasts (p<0.05). The bone-derived cells stimulated migration of breast cancer cells, and this was inhibited (21-50%) in the presence of a CCL2 antibody. CCL2 gene expression in breast cancer cells was upregulated following direct coculture with MSCs. The varying levels of chemokines secreted throughout MSC differentiation may play an important role in supporting tumor cell homing and progression. These results further highlight the distinct effect MSCs have on breast cancer cells and their potential importance in supporting development of metastases.
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PMID:Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells. 1900 62

Cachexia is a devastating process especially in pancreatic cancer patients and contributes to their poor survival. We attempted to clarify the pathological and molecular changes that occur in the liver during the development of cachexia. Using immunohistochemistry we investigated the infiltration of inflammatory mononuclear cells in liver biopsies of pancreatic cancer patients with or without cachexia, and the potential relevance of the cells for the nutritional and inflammatory status. Additionally, these findings were compared with the patients' clinical parameters. We found a significantly higher amount of CD68 immunoreactive macrophages in liver cross sections of patients with pancreatic cancer and cachexia. The number of CD68-positive macrophages was significantly inversely correlated with the nutritional status. Additionally, in these CD68-positive areas a significant increase in IL-6 and IL-1 immunoreactive cells was localized. Moreover, we found significantly increased areas of CD68-positive macrophages in liver biopsies of patients with a more dedifferentiated (aggressive) grading of the tumor. In conclusion, these results suggest that a crucial interaction between the tumor, PBMCs, and the liver may play a central role in the development and regulation of cachexia. Furthermore, pancreatic cancer may be able to alter systemic organ function even without obvious metastatic disease.
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PMID:Liver macrophages contribute to pancreatic cancer-related cachexia. 1914 9


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