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)

Rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor of childhood. Nearly 15% of children present with metastatic disease, frequently involving the lungs and bone marrow. The prognosis for patients with metastatic RMS is dismal, with an estimated 3-year overall survival of 30%. Stromal-cell derived factor 1-alpha (SDF1alpha, CXCL12) is a chemokine that plays a crucial role in the metastatic attraction of tumor cells expressing its receptor, CXCR4. We investigated the role of the bone marrow microenvironment on RMS signaling through the CXCR4/SDF1alpha pathway in cell lines and primary tumors. Conditioned media (CM) isolated from cultured patient-derived bone marrow stromal cells (BMS) induced migration and proliferation in multiple RMS cell lines. CXCR4 was expressed in RMS cell lines and primary tumors, with higher expression in alveolar subtype RMS. Further, SDF1alpha was secreted by all BMS cultures and potently induced the migration and proliferation of RMS cells. Small molecule or blocking antibody-mediated inhibition of CXCR4 or SDF1alpha suppressed RMS cell migration towards BMS-CM, confirming the activity of this axis. Our study provides strong evidence for the involvement of the bone marrow microenvironment and CXCR4/SDF1alpha signaling in metastasis of RMS. These results form the basis for future studies to delineate the mechanisms of bone marrow metastasis in RMS.
Clin Exp Metastasis 2008
PMID:The CXCR4-SDF1alpha axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma. 1776 66

Chemokines are a large group of low molecular weight cytokines that are known to selectively attract and activate different cell types. Although the primary function of chemokines is well recognized as leukocyte attractants, recent evidences indicate that they also play a role in number of tumor-related processes, such as growth, angiogenesis and metastasis. Chemokines activate cells through cell surface seven trans-membranes, G-protein-coupled receptors (GPCR). The role played by chemokines and their receptors in tumor pathophysiology is complex as some chemokines favor tumor growth and metastasis, while others may enhance anti-tumor immunity. These diverse functions of chemokines establish them as key mediators between the tumor cells and their microenvironment and play critical role in tumor progression and metastasis. In this review, we present some of the recent advances in chemokine research with special emphasis on its role in tumor angiogenesis and metastasis.
Cancer Metastasis Rev 2007 Dec
PMID:Chemokines in tumor angiogenesis and metastasis. 1782 70

Cancer metastasis results from a non-random process, in which organ selectivity by the tumor cells is largely determined by factors that are expressed at the remote organs that eventually turn into preferred sites of metastasis formation. These factors support the consecutive steps required for metastasis formation, including tumor cell adhesion to microvessel walls, extravasation into target tissue and migration. Of the different components that regulate organ selectivity, instrumental roles were recently attributed to chemokines and their receptors. The present review presents the rationale standing behind the first studies looking at the potential involvement of chemokine-related components in organ selectivity. Based on these studies and many others that followed, the current paradigm is that chemokines that are expressed at specific organs determine to large extent organ specificity by promoting tumor cell adhesion to microvessel walls, by facilitating processes of extravasation into the target tissue and by inducing tumor cell migration. Moreover, chemokines can possibly support additional steps that are required for "successful" establishment of metastases, such as tumor cell proliferation and survival. The review focuses on the CXCL12-CXCR4 pair as the role model in our current understanding of chemokine involvement in organ selectivity. This review also describes the prominent roles played by CCR7 and its corresponding chemokine ligands (CCL21, CCL19) in lymph node metastasis, and of the CCR10-CCL27 axis in melanoma skin survival and metastasis. Overall, the present discussion describes chemokines as important constituents of the tumor microenvironment at metastatic sites, dictating directionality of chemokine receptor-expressing tumor cells, facilitating their adhesion and extravasation, and eventually contributing to organ selectivity.
Clin Exp Metastasis 2008
PMID:Organ selectivity in metastasis: regulation by chemokines and their receptors. 1789 5

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples.
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PMID:Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. 1789 51

Cancer-associated stromal fibroblasts (CAFs) are the main cellular constituents of reactive stroma in primary and metastatic cancer. We analyzed phenotypical characteristics of CAFs from human colorectal liver metastases (CLMs) and their role in inflammation and cancer progression. CAFs displayed a vimentin(+), alpha-smooth-muscle actin(+), and Thy-1(+) phenotype similar to resident portal-located liver fibroblasts (LFs). We demonstrated that CLMs are inflammatory sites showing stromal expression of interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis. In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha). The effect of TNF-alpha on CAFs is inhibited by the nuclear factor-kappaB inhibitor parthenolide. Conditioned medium of CAFs and LFs similarly stimulated the migration of DLD-1, Colo-678, HuH7 carcinoma cells, and human umbilical vein endothelial cells in vitro. Pretreatment of CAFs with TNF-alpha increased the chemotaxis of Colo-678 colon carcinoma cells by conditioned medium of CAFs; however, blockage of IL-8 activity showed no inhibitory effect. In conclusion, these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target.
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PMID:Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. 1791 96

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.
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PMID:Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. 1791 7

Lymph node metastasis is the main prognosis factor in a number of malignancies, including breast carcinomas. The means by which lymph node metastases arise is not fully understood, and many questions remain about their importance in the further spread of breast cancer. Nevertheless, a number of key cellular and molecular mechanisms of lymphatic metastasis have been identified. These include induction of intra- or peri-tumoral lymphangiogenesis or co-option of existing lymphatic vessels to allow tumour cells to enter the lymphatics, although it remains to be established whether this is primarily an active or passive process. Gene expression microarrays and functional studies in vitro and in vivo, together with detailed clinical observations have identified a number of molecules that can play a role in the genesis of lymph node metastases. These include the well-recognised lymphangiogenic cytokines VEGF-C and VEGF-D as well as chemokine-receptor interactions, integrins and downstream signalling pathways. This paper briefly reviews current clinical and experimental evidence for the underlying mechanisms and significance of lymphatic metastasis in breast cancer and highlights questions that still need to be addressed.
Clin Exp Metastasis 2007
PMID:Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. 1798

The chemokine SDF-1 (CXCL12) and its receptor, CXCR4, have been implicated in organ-specific metastases of several malignancies. CXCR4 expression has recently been characterized in many cancer cell types and is thought to play a pivotal role in directing the migration of metastasizing tumor cells to SDF-1-rich tissues. SDF-1, which is highly expressed in the organs where breast cancers preferentially metastasize, has been shown to promote cancer cell migration. The tumor cells use chemotaxis which occurred between CXCR4 and its ligand SDF-1 to direct migration from their primary sites via the circulation to the preferential sites of metastases, and further studies on the mechanism involved in a variety of cellular signaling pathways are beneficial to tumor therapy.
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PMID:[The role of SDF-1 and its receptor CXCR4 in tumor metastasis]. 1802 22

The ability of tumor cells to metastasize is associated with a poor prognosis for cancer. During the process of metastasis, tumor cells circulating in the blood or lymph vessels can adhere to, and potentially transmigrate through, the endothelium and invade the connective tissue. We studied the effectiveness of the endothelium as a barrier against the invasion of 51 tumor cell lines into a three-dimensional collagen matrix. Only nine tumor cell lines showed attenuated invasion in the presence of an endothelial cell monolayer, whereas 17 cell lines became invasive or showed a significantly increased invasion. Endothelial cells cocultured with invasive tumor cells increased chemokine gene expression of IL-8 and Gro-beta. Expression of the IL-8 and Gro-beta receptor, CXCR2, was upregulated in invasive tumor cells. Addition of IL-8 or Gro-beta increased tumor cell invasiveness by more than twofold. Tumor cell variants selected for high CXCR2 expression were fourfold more invasive in the presence of an endothelial cell layer, whereas CXCR2 siRNA knock-down cells were fivefold less invasive. We demonstrate that Gro-beta and IL-8 secreted by endothelial cells, together with CXCR2 receptor expression on invasive tumor cells, contribute to the breakdown of the endothelial barrier by enhancing tumor cell force generation and cytoskeletal remodeling dynamics.
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PMID:Breakdown of the endothelial barrier function in tumor cell transmigration. 1809 34

Metastasis contributes to more than 90% of mortality in breast cancer. Critical stages in the development of aggressive breast cancer include growth of the primary tumours, and their abilities to spread to distant organs, colonize and establish an independent blood supply. The integrin family of cell adhesion receptors is essential to breast cancer progression. Furthermore, integrin-linked kinase can 'convert' localized breast cancer cells into invasive and metastatic cells. Upon stimulation by growth factors and chemokine ligands, integrin-linked kinase mediates the phosphorylation of Akt Ser473, and glycogen synthase kinase-3. The current notion is that overexpression of integrin-linked kinase resulted in an invasive, metastatic phenotype in several cancer model systems in vivo and in vitro, thus, implicating a role for integrin-linked kinase in oncogenic transformation, angiogenesis and metastasis. Here, we will review the role of integrin-linked kinase in breast cancer metastasis. Elucidation of signalling events important for breast tumour metastasis should provide insights into successful breast cancer therapies.
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PMID:Contributions of integrin-linked kinase to breast cancer metastasis and tumourigenesis. 1836 48


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