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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A primitive neuroectodermal tumor (PNET) presented as a cerebral hemispheric mass in a 33-year-old man. Bone marrow metastases were discovered 11 months later. A cell line (CHP707m) was derived from these metastases. In culture, the cells showed features of neuronal differentiation, forming short neurites and synthesizing low-molecular-weight neurofilament protein. Northern blotting showed the tumor cells express nerve growth factor (NGF) receptor messenger RNA, and fluorescence-activated cell-sorting demonstrated NGF receptors on the cell surface. Western blotting showed CHP707m NGF receptors are truncated. The receptors are functional; they bind iodine 125-labeled mouse NGF with an affinity of 1.6 x 10(-9) M, and short-term treatment with NGF induces expression by the tumor cells of the proto-oncogene, c-fos. Although CHP707m is the first central nervous system PNET cell line proven to express NGF receptors, immunohistological survey of tissue sections prepared from human central nervous system PNETs showed that 13 of 35 contained NGF receptor-positive tumor cells. Thus, more than one-third of such tumors might be responsive to the effects of NGF.
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PMID:Human central nervous system primitive neuroectodermal tumor expressing nerve growth factor receptors: CHP707m. 217 17

The formation of brain metastases is an important clinical end point in patients with cancer. The brain provides a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. In the brain microcirculation, brain-metastatic tumor cells must attach to endothelial cells, respond to brain-derived invasion factors, and invade the blood-brain barrier. Neurotrophins are important brain invasion-stimulating factors in this process, and in responsive tumor cells neurotrophins can promote invasion by enhancing the production of basement-membrane-degradative enzymes (gelatinase and heparanase) capable of locally destroying the blood-brain barrier. We examined human melanoma variant lines that express low-affinity p75 neurotrophin receptor in relation to their brain-metastatic potentials. Expression of p75 in these variants occurs in the absence of expression of trkA, the gene encoding the high-affinity nerve growth factor (NGF) tyrosine kinase receptor. Brain-metastatic tumor cells can also produce factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for tumor growth factor-beta, basic fibroblast growth factor, tumor growth factor-alpha, and interleukin-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain tissues. In support of this, we found increased amounts of NGF in tumor-adjacent tissues at the invasion front of human melanoma tumors in the brain. These and other factors may determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system.
Invasion Metastasis
PMID:Involvement of neurotrophins and growth factors in brain metastasis formation. 765 30

The brain is a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. To metastasize to the brain malignant tumor cells must attach to microvessel endothelial cells, respond to brain-derived invasion factors, invade the blood-brain barrier and respond to survival and growth factors. Trophic factors are important in brain invasion because they can act to stimulate this process. In responsive malignant cells trophic factors such as neurotrophins can promote invasion by enhancing the production of basement membrane-degradative enzymes (such as type IV collagenase/gelatinase and heparanase) capable of locally destroying the basement membrane and the blood-brain barrier. We examined human melanoma cell lines that exhibit varying abilities to form brain metastases. These melanoma lines express low-affinity neurotrophin receptor p75NTR in relation to their brain-metastatic potentials but the variants do not express trkA, the gene encoding a high affinity nerve growth factor (NGF) tyrosine kinase receptor p140trkA. Melanoma cells metastatic to brain also respond to paracrine factors made by brain cells. We have found that a paracrine form of transferrin is important in brain metastasis, and brain-metastatic cells respond to low levels of transferrin and express high levels of transferrin receptors. Brain-metastatic tumor cells can also produce autocrine factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for the following autocrine growth factors: TGF beta, bFGF, TGF alpha and IL-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain cells, such as oligodendrocytes and astrocytes. Increased amounts of NGF were found in tumor-adjacent tissues at the invasion front of human melanoma tumors in brain biopsies. Trophic factors, autocrine growth factors, paracrine growth factors and other factors may determine whether metastatic cells can successfully invade, colonize and grow in the central nervous system.
Clin Exp Metastasis 1995 Mar
PMID:The role of trophic factors and autocrine/paracrine growth factors in brain metastasis. 788 17

The raf genes encode for a family of cytoplasmic proteins (A-raf, B-raf and c-raf-1) with associated serine/threonine kinase activities. Raf-1 is an important mediator of signals involving cell growth, transformation and differentiation. It is activated in response to a wide variety of extracellular stimuli such as insulin, nerve growth factor (NGF), platelet derived-growth factor (PDGF), and in response to expression of oncogenes, v-src and v-ras, in a cell-specific manner. Recently, the first physiological substrate for Raf-1 protein kinase was identified. Raf-1 was found to phosphorylate and activate Mitogen-Activated Protein Kinase Kinase (MEK), an activator of MAP kinase, thus linking the Raf-1 signaling pathway with that of MAP kinase. Cell specific differences in signalling pathways involving Raf-1 and MAP kinase have also been discovered. Accumulating evidence indicates that membrane tyrosine kinases, ras, Raf-1, MEK and MAP kinase are interconnected via a complex network rather than via a linear pathway involving multiple substrates and feedback loops.
Cancer Metastasis Rev 1994 Mar
PMID:Signal transduction pathways involving the Raf proto-oncogene. 814 42

An important clinical endpoint in patients with cancer is formation of metastases in the brain. Understanding this phenomenon is important in several types of malignancies, including melanoma, lung and breast cancers. Metastatic tumor cells use specific adhesion molecules to home to brain, and there they must attach to microvessel endothelial cells and respond to brain endothelial cell-derived motility factors and brain invasion factors to invade the CNS. Neurotrophins are important invasion factors in this process, and the ability to invade into the brain may well depend on metastatic cell responses to neurotrophins and production of basement membrane-degradative enzymes capable of locally destroying the blood-brain barrier. Brain-metastatic human melanoma cells express low-affinity p75 receptor for neurotrophins such as nerve growth factor, but they do not express the high-affinity-type receptors for nerve growth factor encoded by the protooncogene trkA. Tumor cells can proliferate in the CNS in response to local paracrine growth factors and inhibitors, but their growth also depends on their producing and responding to autocrine growth factors. A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS.
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PMID:Tumor metastasis to brain: role of endothelial cells, neurotrophins, and paracrine growth factors. 851 8

To metastasize to the central nervous system (CNS) malignant cells must attach to brain microvessel endothelial cells, respond to brain endothelial cell-derived motility factors, respond to CNS-derived invasion factors and invade the blood-brain barrier (BBB), and finally, respond to CNS survival and growth factors. Trophic factors such as the neurotrophins play an important role in tumor cell invasion into the CNS and in the survival of small numbers of malignant cells under stress conditions. Trophic factors promote BBB invasion by enhancing the production of basement membrane-degrading enzymes in neurotrophin-responsive cells. The expression of certain neurotrophin receptors on brain-metastasic neuroendocrine cells occurs in relation to their invasive and survival properties. For example, CNS-metastatic melanoma cells respond to particular neurotrophins (nerve growth factor, neurotrophin-2) that can be secreted by normal cells within the CNS. In addition, a paracrine form of transferrin is important in CNS metastasis, and brain-metastatic cells respond to low levels of transferrin and express high levels of transferrin receptors. CNS-metastatic tumor cells can also produce autocrine factors and inhibitors that influence their growth, invasion and survival in the brain. Synthesis of paracrine factors and cytokines may influence the production of trophic factors by normal brain cells adjacent to tumor cells. Moreover, we found increased amounts of neurotrophins in brain tissue at the invasion front of human melanoma tumors in CNS biopsies. Thus the ability to form metastatic colonies in the CNS is dependent on tumor cell responses to trophic factors as well as autocrine and paracrine growth factors and probably other underdescribed factors.
Cancer Metastasis Rev 1995 Dec
PMID:Trophic factors and central nervous system metastasis. 882 Oct 92

The effects of nerve growth factor, a neurotrophin mediating growth and differentiation of neural crest-derived cells, are mediated by the receptor TrkA. TrkA mRNA expression has been associated with a good prognosis in human neuroblastoma (NB). We describe the use of monoclonal antibody 5C3 in detecting TrkA expression by immunohistochemistry in NB and other malignant tumors. A murine anti-TrkA IgG1 monoclonal antibody, 5C3, was generated against the extracellular domain of human p140(TrkA). 5C3 detected a 140-kDa band on Western blots. 5C3 was optimized for immunostaining and used to detect p140(TrkA) on 113 frozen NB samples and 42 samples from nine other malignancies. MOPC21 IgG1 antibody was used as a control. Results by immunohistochemistry were compared to TrkA expression assessed by reverse transcription-PCR and Western analysis. The prognostic value of TrkA expression by these methods was evaluated and compared to other known prognostic variables, including stage, age, and MYCN copy number. TrkA expression was detected by immunohistochemistry in 73 of the 113 NB tumor specimens and strongly correlated with nonmetastatic disease. TrkA expression was specific for NB among small round blue cell tumors. Both TrkA expression by immunohistochemistry and localized/4s disease correlated with survival. Tumors from 55 of 60 patients with localized/4s NB exhibited homogeneous or a mixed pattern of TrkA immunohistochemistry, whereas only 18 of 53 patients with stage 4 NB were immunoreactive. Detection of TrkA by reverse transcription-PCR and Western analysis was much more sensitive and no longer correlated with survival. 5C3 enables rapid detection of p140(TrkA) by immuno-histochemistry and identifies patients more likely to have localized NB with a favorable clinical outcome. Lack of TrkA expression is correlated with metastatic, malignant NB. A subset of patients with NB, however, died of aggressive metastatic disease despite TrkA expression. As a mimic of nerve growth factor, 5C3 may be useful in the study of TrkA-expressing tumors.
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PMID:Prognostic value of TrkA protein detection by monoclonal antibody 5C3 in neuroblastoma. 981 8

Clinical and experimental evidence suggests that tumor cells shed into the circulation from solid cancers are ineffective in forming distant metastasis unless the cells are able to respond to growth conditions offered by the secondary organs. To identify the phenotypic properties that are specific for such growth response, we injected carcinoma cells, which had been recovered from bone marrow micrometastases in a breast cancer patient who was clinically devoid of overt metastatic disease and established in culture, into the systemic circulation of immunodeficient rats. The animals developed metastases in the central nervous system, and metastatic tumor cells were isolated with immunomagnetic beads coated with an antibody that was reactive with human cells. The segregated cell population was compared with the injected cells by means of differential display analysis, and two candidate fragments were identified as up-regulated in the fully metastatic cells. The first was an intracellular effector molecule involved in tyrosine kinase signaling, known to mediate nerve growth factor-dependent promotion of cell survival. The second was a novel gene product (termed candidate of metastasis-1), presumably encoding a DNA-binding protein of helix-turn-helix type. Constitutive expression of candidate of metastasis-1 seemed to distinguish breast cancer cells with metastatic potential from cells without metastatic potential. Hence, our experimental approach identified factors that may mediate the growth response of tumor cells upon establishment in a secondary organ and, thereby, contribute to the metastatic phenotype.
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PMID:Expression of a novel factor in human breast cancer cells with metastatic potential. 1212 56

The role of the neurotrophins (NTs) and their corresponding receptors (NTRs) TrkA, TrkB, TrkC, and p75NTR in neoplasia has received relatively little attention. However, because malignant cell migration within the prostate occurs predominantly by direct extension around prostatic nerves, the presence and possible upregulation of NTs from autocrine/paracrine sources and NTR expression within prostate epithelial tumor cells may be important in metastasis. We have been addressing their expression and interactions in human prostate cancer cell lines (LNCaP, PC-3, and DU145) and their role in prostate cancer invasion. In this study, we demonstrated that nerve growth factor (NGF), the prototypic NT, and NT-4/5 increased in vitro invasion through a reconstituted basement membrane and induced time- and dose-dependent expression of heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase, an important molecular determinant of tumor metastasis. The NT effects were most marked in the DU 145 brain-metastatic cells and were detected at NT concentrations sufficient to fully saturate both low- and high-affinity NTRs. Additionally, we characterized the molecular expression of NT high-affinity (Trk) and low-affinity (p75NTR) receptors in these cell lines by reverse transcription-polymerase chain reaction. These lines had negligible trkA and trkC expression, although trkB was expressed in the three prostatic tumor cell lines examined. The brain-metastatic DU 145 cells were also positive for p75NTR. Our data showed that the NTs and NTRs are important in metastasis and that their expression coincides with transformation to a malignant phenotype capable of invasion along the perineural space and extracapsular metastasis to distant sites. These findings set the stage for more research into this area as related to prostate cancer evolution and may improve therapy for prostate cancer metastasis.
Clin Exp Metastasis 1999 Jun
PMID:Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells. 1054 17

Pancreatic cancer has one of the poorest prognoses of all gastrointestinal malignancies. Today, it is the fourth or fifth leading cause of cancer-related deaths in Western industrialized countries, and the incidence has been increasing throughout the past decades. Insensitivity to growth-inhibitory and apoptotic signals as well as self-sufficiency of growth-promoting factors are hallmarks of the pathogenesis of this malignancy. In pancreatic cancer, a variety of growth factors and their receptors are expressed at increased levels. For example, the concomitant presence of the epidermal growth factor (EGF) receptor and its ligand EGF is associated with enhanced tumor aggressiveness and shorter survival following tumor resection. Furthermore, a number of other growth factors and their receptors, such as nerve growth factor and its receptor, are overexpressed in pancreatic cancer and contribute to its malignant phenotype. Besides factors which directly promote cell proliferation, a variety of other factors such as galectins are upregulated, which influences the tumor environment and the invasiveness of pancreatic cancer cells. In addition, tumor suppressor genes such as KAI1 are expressed at reduced levels, thereby enhancing the ability of pancreatic cells to form metastases. A complex disturbance of factors is present in pancreatic cancer, resulting in a distinct growth advantage which clinically results in rapid tumor progression and poor patient survival.
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PMID:Pancreatic cancer: factors regulating tumor development, maintenance and metastasis. 1212 Feb 31


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