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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant tumor progression depends on angiogenesis, requiring vascular endothelial cell migration, and proliferation, triggered by tumor-derived vascular endothelial cell growth factor (VEGF). We show that gangliosides, which are actively shed by tumor cells and bind to normal cells in the tumor microenvironment, have the potential to sensitize vascular endothelial cells to respond to subthreshold levels of VEGF: Ganglioside enrichment of human umbilical vein vascular endothelial cells (HUVEC) caused very low, normally barely stimulatory, VEGF concentrations to trigger robust VEGF receptor dimerization and autophosphorylation, as well as activation of downstream signaling pathways, and cell proliferation and migration. Thus, by dramatically lowering the threshold for growth factor activation of contiguous normal stromal cells, shed tumor gangliosides may promote tumor progression by causing these normal cells to become increasingly autonomous from growth factor requirements by a process that we term tumor-induced progression of the microenvironment.
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PMID:Membrane ganglioside enrichment lowers the threshold for vascular endothelial cell angiogenic signaling. 1707 61

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.
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PMID:Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase. 1718 Nov 63

Thymidine phosphorylase (TP) is a key enzyme in the pyrimidine nucleoside salvage pathway, but it also recognizes and inactivates various anti-cancer chemotherapeutic agents. Moreover, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor with anti-apoptotic properties. Increased expression of PD-ECGF/TP is found in many tumor and stromal cells, and elevated TP levels are associated with aggressive disease and/or poor prognosis. Thus, progression and metastasis of TP-expressing tumors might be abrogated by TP inhibitors that are used as single agents or in combination with (TP-sensitive) nucleoside analogues. On the other hand, increased TP activity in tumors may be exploited for the tumor-specific activation of fluoropyrimidine prodrugs, such as capecitabine. This review will focus on the different biological activities of PD-ECGF/TP and their implications for cancer progression and treatment.
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PMID:Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy. 1757 89

Recent studies have revealed that malignant tumors can actively induce the formation of new lymphatic vessels and metastasize through the lymphatic system. Tumor-induced lymphangiogenesis driven by tumors expressed lymphangiogenic growth factors such as VEGF family, fibroblast growth factor 2 (FGF-2), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and platelet-derived growth factors (PDGFs) is correlated with lymph node metastasis in experimental cancer models and in several types of human cancers. Tumor- induced lymphangiogenesis has now been firmly established as a novel mechanism for cancer progression and lymph node metastasis. Recent studies indicate that blockade of the lymphangiogenic growth factors pathway inhibits tumor spread to lymph nodes and likely beyond. The potential effects of most of these newly identified lymphatic growth factors on tumor-induced lymphangiogenesis and lymph node metastasis remain to be further investigated. A number of questions remain to be answered concerning the potential efficacy of targeting at tumor-induced lymphangiogenesis for inhibiting tumor spread to lymph nodes.
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PMID:Tumor lymphangiogenesis and lymphangiogenic growth factors. 1837 46

Platelets are highly reactive components of the circulatory system, which exert not only haemostatic activity but also contribute to the modulation of various pathological conditions including inflammation, atherosclerosis and cancer metastasis through the release of cytokines, chemokines and the presentation of several adhesion molecules. During cancer metastasis, the formation of platelet-tumor cell aggregates in the circulation facilitates immune evasion and the microvascular arrest of tumor cells at distant sites. Several adhesion molecules, such as integrins and glycoproteins, were shown to be involved in this process. Recent findings indicate that P-selectin is another main mediator of platelet-tumor cell interactions. Other effects of activated platelets on cancer progression are associated with a release of platelet-derived factors stimulating tumor growth and angiogenesis. Any interference in platelet-tumor cell interactions resulted in attenuation of cancer metastasis. The well recognized, albeit not fully characterized function of platelets during cancer progression defines platelets as potential targets for cancer therapy. Specifically, the rapid expression of P-selectin on the cell surface of activated platelets and its strong association with metastasis provide a rationale for P-selectin inhibition as an antimetastatic treatment.
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PMID:The role of platelet activation in tumor metastasis. 1869 63

Angiogenesis plays an important role in tumor metastasis and progression, and thus inhibiting angiogenesis is a promising strategy for treatment of cancer. However, tumor-associated angiogenesis is influenced by various angiogenic factors in the tumor microenvironment. Thymidine phosphorylase (TP, EC 2. 4. 2. 4), an enzyme involved in the reversible conversion of thymidine to thymine, is an important mediator of angiogenesis, tumorigenicity, metastasis and invasion. The angiogenic effect of TP requires the enzymatic activity of TP. TP activity is expressed at higher levels in a wide variety of solid tumors than in adjacent non-neoplastic tissue. The tumor microenvironment (hypoxia, acidosis) regulates the expression of TP, and TP expression in tumor tissue shows significant correlation with microvessel density and poor prognosis. 2-Deoxy-D-ribose (D-dRib), one of the degradation products of thymidine generated by TP activity, promotes angiogenesis and the chemotactic activity of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. These findings suggest that D-dRib is a downstream mediator of TP function. 2-Deoxy-L-ribose, a stereoisomer of D-dRib, can inhibit D-dRib's anti-apoptotic effects and suppress metastasis and invasion of TP-expressing tumors in mice. Although the mechanism of action of D-dRib is still unknown, the physiological activities of D-dRib have recently been reported by several groups. We review the role of D-dRib in tumor progression and discuss inhibition of D-dRib as a promising approach for chemotherapy of various tumors.
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PMID:2-Deoxy-D-ribose, a downstream mediator of thymidine phosphorylase, regulates tumor angiogenesis and progression. 1919 68

Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.
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PMID:The dual role of thymidine phosphorylase in cancer development and chemotherapy. 1943 93

Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or platelet-derived growth facter receptor (PDGFRA). Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10-15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is known about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from nine adults and one pediatric case and 21 mutant tumors. Although all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, eight of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome arm 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of approximately 0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.
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PMID:High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors. 1958 85

Natural killer (NK) cells play an important role in cancer immunosurveillance and may prevent tumor progression and metastasis due to their ability to mediate direct cellular cytotoxicity and by releasing immunoregulatory cytokines, which shape adaptive immune responses. Their reactivity is governed by various activating and inhibitory molecules expressed on target cells and reciprocal interactions with other hematopoietic cells such as dendritic cells. In mice, thrombocytopenia inhibits metastasis, and this is reversed by NK cell depletion, suggesting that platelets are an important additional player in NK cell-tumor interaction. Moreover, it has been shown that metastasizing tumor cells do not travel through the blood alone but are rapidly coated by platelets. However, the knowledge about the molecular mechanisms by which platelets influence NK cells is fragmentary at best. Here we show that platelet-derived soluble factors, secreted on coating of tumor cells or after stimulation with classic platelet agonists, impair NK cell antitumor reactivity resulting in diminished granule mobilization, cytotoxicity, and IFN-gamma production. The impaired NK cell reactivity was not due to induction of apoptosis but mediated by down-regulation of the activating immunoreceptor natural killer group 2, member D (NKG2D) on NK cells by platelet-derived transforming growth factor beta (TGF-beta). Neutralization of TGF-beta in platelet releasate not only prevented NKG2D down-regulation but also restored NK cell antitumor reactivity. Thus, our data elucidate the molecular basis of the previously described influence of platelets on NK cell antitumor reactivity and suggest that therapeutic intervention in tumor cell-platelet interaction and the resulting TGF-beta release by platelets may serve to enhance antitumor immunity.
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PMID:Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. 1973 39

Angiogenesis is essential for tumor growth and vascular endothelial cell growth factor (VEGF) plays a key role in this process. Conversely, sphingosine 1-phosphate (S1P) is a biologically active sphingolipid known to play a key role in cancer progression by regulating endothelial cell proliferation and migration. In this study, the authors found that S1P increases the level of VEGF mRNA in human umbilical vein endothelial cells (HUVECs) and immortalized HUVECs (iHUVECs). Additionally, S1P was found to increase VEGF promoter activity in MS-1 mouse pancreatic islet endothelial cells. Furthermore, a pharmacological inhibitory study revealed that G(alpha i/o)-mediated phospholipase C, Akt, Erk, and p38 MAPK signaling are involved in this S1P-induced expression of VEGF. A component of AP1 transcription factor is important for S1P-induced VEGF expression. Taken together, these findings suggest that S1P enhances endothelial cell proliferation and migration by upregulating the expression of VEGF mRNA.
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PMID:Sphingosine 1-phosphate induces vascular endothelial growth factor expression in endothelial cells. 1987 15


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