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)

Growth Regulated Oncogene-alpha (GRO-alpha) is an autocrine growth factor in melanoma and is a member of the C-X-C family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC Receptor 2. We found previously that variants of murine squamous cell carcinoma PAM 212 which grow and metastasize more rapidly in vivo constitutively express increased levels of murine GRO-alpha, designated mGRO-alpha, or KC. We have examined the possible role of mGRO-alpha expression in malignant progression of squamous cell carcinoma PAM 212 in homologous BALB/c and BALB CXC Receptor-2 deficient mice. Transfection of the PAM 212 cell line which exhibits low expression of GRO-alpha and malignant potential with a pActin-KC vector encoding mGRO-alpha enabled isolation of PAM-KC expressing cell lines. These PAM-KC transfectants displayed an increased rate of growth and metastasis in BALB/c mice, similar to the highly malignant phenotype observed in spontaneously occurring metastatic variants. Furthermore, the PAM-KC tumors showed an increase in infiltration of host leukocytes and CD31+ blood vessels, consistent with increased CXC chemokine activity. The increased growth of PAM-KC cells was attenuated in CXCR-2 deficient mice, indicating that the increased growth was dependent in part upon host cells responsive to the CXC chemokine. Together, these results show that a CXC chemokine such as GRO-alpha can promote malignant growth of murine squamous cell carcinoma by a host CXCR-2 dependent pathway. Oncogene (2000) 19, 3477 - 3486
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PMID:Growth regulated oncogene-alpha expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. 1091 6

We analyzed the expression of 13 chemokine receptors in mycosis fungoides, in order to assess the contribution of chemotaxis to the pathogenesis of the disease. Material from skin biopsies of six patients with early disease and six patients at the tumor stage of mycosis fungoides was analyzed by immunohistochemistry and partly also by flow cytometry. The receptors CCR1, CCR2, CCR3, CCR5, CCR6, CXCR1, CXCR2, CXCR5, and CX3CR1 were rarely and inconsistently detected in lesional skin and thus their participation in mycosis fungoides could largely be ruled out. In contrast, CCR4, CXCR3, and CXCR4 were substantially expressed on both mycosis fungoides cells and the surrounding reactive T cells in the early patch and plaque stages of the disease, indicating an involvement of these chemokine receptors in the disease process. In the tumor stage of mycosis fungoides, we interestingly observed a loss of a relevant chemokine receptor in four out of six patients. In three patients CXCR3 and in one patient CCR4 was absent on tumor mycosis fungoides cells, whereas the reactive T cells showed normal levels of expression. Within these samples, tumor mycosis fungoides cells exhibited high levels of CCR7, a chemokine receptor central for the entry of T cells to lymphatic tissue. Taken together, our data suggest that the loss of one or more of the chemokine receptors involved in the homing of the mycosis fungoides cells to the skin may trigger the latent potential of these cells to metastasize into regional lymphatic tissue.
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PMID:Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. 1470 5

In the present study, we examined the autocrine/paracrine role of IL-8 in melanoma growth and metastasis by analyzing the expression and functional significance of IL-8 receptors, CXCR1 and CXCR2 in human malignant melanoma cells with different metastatic potential. CXCR1 and CXCR2 mRNA and protein levels were analyzed by reverse trannscriptase-based polymerase chain reaction, immunohistochemistry, immunoprecipitation, flow cytometry and ligand binding assay in melanoma cells in vitro and xenografted in nude mice. Melanoma cells constitutively expressed CXCR1 and CXCR2 mRNA and protein. Highly metastatic A375SM cells expressed higher levels of CXCR1 and CXCR2 mRNA and protein in vitro and in vivo as compared to low metastatic A375P and non-metastatic SBC-2 melanoma cells. Treatment of SBC-2 and A375P cells with exogenously added recombinant IL-8 significantly enhanced their proliferation and invasive potential. Further neutralizing antibodies to CXCR1 and CXCR2 inhibited proliferation and invasive potential of unstimulated and IL-8-stimulated A375P cells. In summary, the data suggest that constitutive expression of CXCR1 and CXCR2 play an important role regulating the IL-8-mediated metastatic phenotype in human malignant melanoma cells.
Clin Exp Metastasis 2003
PMID:Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype. 1471 6

The Glu-Leu-Arg(+) (ELR(+)) CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of nonsmall cell lung cancer-derived angiogenic activity and support tumorigenesis. ELR(+) CXC chemokines share a common chemokine receptor, CXCR2. We hypothesized that CXCR2 mediates the proangiogenic effects of ELR(+) CXC chemokines during tumorigenesis. To test this postulate, we used syngeneic murine Lewis lung cancer (LLC; 3LL, H-2(b)) heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2(+/+)) and deficient in CXCR2 (CXCR2(-/-)). We first demonstrated a correlation of the expression of endogenous ELR(+) CXC chemokines with tumor growth and metastatic potential of LLC tumors. Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2(-/-) mice. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2(-/-) mice. Morphometric analysis of the primary tumors in CXCR2(-/-) mice demonstrated increased necrosis and reduced vascular density. These findings were further confirmed in CXCR2(+/+) mice using specific neutralizing Abs to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer.
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PMID:Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. 1497 86

Solid tumour and leukemic cells expressing chemokine receptors, metastasize to chemokine-secreting organs. Chemokines indirectly affect tumour development by attracting immunocompetent cells with pro- or anti-tumoral activities. Various membrane-associated and soluble proteases selectively cleave specific chemokines. Precursor plasma chemokines (CXCL7, CCL14) need to be proteolytically processed to obtain receptor affinity. Angiogenic CXC chemokines (CXCL1, CXCL8) have increased CXCR1/CXCR2 affinity after limited NH2-terminal processing, whereas truncated angiostatic chemokines (CXCL10) show lower CXCR3 affinity without loss of angiostatic potential. NH2-terminally cleaved monocyte chemotactic proteins (CCL2, CCL7, CCL8) have impaired capacity to attract tumour-associated macrophages and function as receptor antagonists for intact CC chemokines. Migration of Th1/CCR5+ and Th2/CCR4+ effector lymphocytes toward CCR5 (CCL5, CCL3L1) and CCR4 (CCL22) ligands is affected by cleavage. Although proteolytical processing of chemokines is well studied in vitro, the direct or indirect effects on tumour invasion and metastasis are only poorly evaluated.
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PMID:Chemokine-protease interactions in cancer. 1524 56

The purpose of this study was to examine the expression and functional significance of the growth-regulated oncogene (gro) family in human colon carcinoma growth and metastasis. We examined constitutive expression of CXCL1 (gro-alpha), CXCL2 (gro-beta), CXCL3 (gro-gamma) and their receptor, CXCR2 in human colon carcinoma cells with different metastatic potentials. Non-metastatic and low metastatic cells expressed lower levels of CXCL1 and CXCR2 mRNA and protein as compared to high metastatic colon carcinoma cells. No difference in CXCL2 and CXCL3 mRNA expression levels was observed. Colon carcinoma cells expressing higher levels of CXCL1 exhibit increased proliferation and invasive potential. Furthermore, exogenous addition of recombinant human CXCL1 significantly enhanced the proliferation and invasiveness of colon carcinoma cells. Furthermore, treatment of KM12C cells with exogenous CXCL1 enhanced their invasiveness. Neutralizing antibody to CXCL1 in combination with antibody to CXCR2 inhibited highly metastatic KM12L4 (high CXCL1 expressor) cell proliferation. These data demonstrate that the constitutive expression of CXCL1 and its receptor CXCR2 is associated with metastatic potential and modulates colon cancer cell proliferation and an invasive phenotype.
Clin Exp Metastasis 2004
PMID:Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic phenotype. 1578 94

CXC chemokines display pleiotropic effects in immunity, regulating angiogenesis, and mediating organ-specific metastases of cancer. In the context of angiogenesis, CXC chemokines are a unique family of cytokines, known for their ability to behave in a disparate manner in the regulation of angiogenesis. Members that contain the 'ELR' motif are potent promoters of angiogenesis, and mediate their angiogenic activity via binding and activating CXCR2 on endothelium. In contrast, members, in general, those are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis, and bind to CXCR3 on endothelium. This review will discuss the biology of these angiogenic and angiostatic CXC chemokines and discuss their disparate angiogenic activity in the context of a variety of disorders.
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PMID:CXC chemokines in angiogenesis. 1604 80

The pathogenesis of metastasis depends on multiple favorable interactions of tumor cells with host homeostatic mechanisms. Interruption of one or more of these interactions can lead to the inhibition or eradication of cancer metastases. For many years, all efforts to treat cancer concentrated on the inhibition of growth or the destruction of tumor cells. A strategy of both eradication of tumor cells (e.g. by chemotherapy and immunotherapy) and modulation of the host microenvironment (e.g. tumor vasculature and hypoxia) is an additional, relatively novel approach to cancer treatment. Recent advances in our understanding of the biological basis of cancer metastasis open up unprecedented opportunities for translating basic research to clinical treatment of cancer. This research includes the unraveling of the genetic make-up of tumors and genome-wide expression analyses, thereby identifying many potential targets for therapy. Drugs acting on tumor cells which have a metastasis-prone mutational or expression status (by classical or targeted chemotherapy) as well as drugs affecting host-mediated survival pathways must be combined in order to create therapeutic synergy. Therapeutic maneuvers may target receptor tyrosine kinases (EGFR, VEGFR, FGFR), chemokines or G-protein-coupled receptors (CXCR4, CXCR2, EphB2), hypoxia-inducible factor (HIF), and signaling pathways (c-Src, PI3K, Akt, chaperon complexes) in tumor cells. Moreover, stromal and immunological cells and their cytokines coordinate critical pathways that exert important roles in the ability of tumors to invade and metastasize, thus suppressive cytokines (IL-6 and IL-10) and neutralizing specific antibodies might subvert conditions for metastasis.
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PMID:Metastases and their microenvironments: linking pathogenesis and therapy. 1609 51

Previous studies have shown that neutrophils (PMNs) facilitate melanoma cell extravasation [M.J. Slattery, C. Dong, Neutrophils influence melanoma adhesion and migration under flow conditions, Intl. J. Cancer 106 (2003) 713-722] Little is known, however, about the specific interactions between PMNs, melanoma and the endothelium (EC) or the molecular mechanism involved under flow conditions. The aim of this study is to investigate a "two-step adhesion" hypothesis that involves initial PMN tethering on the EC and subsequent melanoma cells being captured by tethered PMNs. Different effects of hydrodynamic shear stress and shear rate were analyzed using a parallel-plate flow chamber. Results indicate a novel finding that PMN-facilitated melanoma cell arrest on the EC is modulated by shear rate, which is inversely-proportional to cell-cell contact time, rather than by the shear stress, which is proportional to the force exerted on formed bonds. Beta2 integrins/ICAM-1 adhesion mechanisms were examined and the results indicate LFA-1 and Mac-1 cooperate to mediate the PMN-EC-melanoma interactions under shear conditions. In addition, endogenously produced IL-8 contributes to PMN-facilitated melanoma arrest on the EC through the CXC chemokine receptors 1 and 2 (CXCR1 and CXCR2) on PMN. These results provide new evidence for the complex role of hemodynamic forces, secreted chemokines and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC.
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PMID:Shear stress and shear rate differentially affect the multi-step process of leukocyte-facilitated melanoma adhesion. 1615 63

Renal cell carcinoma (RCC) accounts for 3% of new cancer incidence and mortality in the United States. Studies in RCC have predominantly focused on VEGF in promoting tumor-associated angiogenesis. However, other angiogenic factors may contribute to the overall angiogenic milieu of RCC. We hypothesized that the CXCR2/CXCR2 ligand biological axis represents a mechanism by which RCC cells promote angiogenesis and facilitate tumor growth and metastasis. Therefore, we first examined tumor biopsies and plasma of patients with metastatic RCC for levels of CXCR2 ligands, and RCC tumor biopsies for the expression of CXCR2. The proangiogenic CXCR2 ligands CXCL1, CXCL3, CXCL5, and CXCL8, as well as VEGF were elevated in the plasma of these patients and found to be expressed within the tumors. CXCR2 was found to be expressed on endothelial cells within the tumors. To assess the role of ELR(+) CXC chemokines in RCC, we next used a model of syngeneic RCC (i.e., RENCA) in BALB/c mice. CXCR2 ligand and VEGF expression temporally increased in direct correlation with RENCA growth in CXCR2(+/+) mice. However, there was a marked reduction of RENCA tumor growth in CXCR2(-/-) mice, which correlated with decreased angiogenesis and increased tumor necrosis. Furthermore, in the absence of CXCR2, orthotopic RENCA tumors demonstrated a reduced potential to metastasize to the lungs of CXCR2(-/-) mice. These data support the notion that CXCR2/CXCR2 ligand biology is an important component of RCC tumor-associated angiogenesis and tumorigenesis.
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PMID:The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. 1621 Jun 41


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