Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD-1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.
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PMID:Current Insights into the role of HIF-1 in cutaneous wound healing. 2137 91

Tumor-mobilized bone marrow-derived CD11b(+) myeloid cells promote tumor angiogenesis, but how and when these cells acquire proangiogenic properties is not fully elucidated. Here, we show that CD11b(+) myelomonocytic cells develop proangiogenic properties during their differentiation from CD34(+) hematopoietic progenitors and that placenta growth factor (PlGF) is critical in promoting this education. Cultures of human CD34(+) progenitors supplemented with conditioned medium from breast cancer cell lines or PlGF, but not from nontumorigenic breast epithelial lines, generate CD11b(+) cells capable of inducing endothelial cell sprouting in vitro and angiogenesis in vivo. An anti-Flt-1 mAb or soluble Flt-1 abolished the generation of proangiogenic activity during differentiation from progenitor cells. Moreover, inhibition of metalloproteinase activity, but not VEGF, during the endothelial sprouting assay blocked sprouting induced by these proangiogenic CD11b(+) myelomonocytes. In a mouse model of breast cancer, circulating CD11b(+) cells were proangiogenic in the sprouting assays. Silencing of PlGF in tumor cells prevented the generation of proangiogenic activity in circulating CD11b(+) cells, inhibited tumor blood flow, and slowed tumor growth. Peripheral blood of breast cancer patients at diagnosis, but not of healthy individuals, contained elevated levels of PlGF and circulating proangiogenic CD11b(+) myelomonocytes. Taken together, our results show that cancer cells can program proangiogenic activity in CD11b(+) myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner. These findings impact breast cancer biology, detection, and treatment.
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PMID:Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. 2150 36

PlGF, one of the ligands for VEGFR-1, has been implicated in tumor angiogenesis. However, more recent studies indicate that genetic or pharmacological inhibition of PlGF signaling does not result in reduction of microvascular density in a variety of tumor models. Here we screened 12 human tumor cell lines and identified 3 that are growth inhibited by anti-PlGF antibodies in vivo. We found that efficacy of anti-PlGF treatment strongly correlates with VEGFR-1 expression in tumor cells, but not with antiangiogenesis. In addition, PlGF induced VEGFR-1 signaling and biological responses in tumor cell lines sensitive to anti-PlGF, but not in refractory tumor cell lines or in endothelial cells. Also, genetic ablation of VEGFR-1 signaling in the host did not affect the efficacy of PlGF blockade. Collectively, these findings suggest that the role of PlGF in tumorigenesis largely consists of promoting autocrine/paracrine growth of tumor cells expressing a functional VEGFR-1 rather than stimulation of angiogenesis.
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PMID:Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. 2170 13

Choriocarcinomas are a rare form of cancer that develops in the uterus from tissue which would normally become the placenta. Choriocarcinomas are a trophoblastic gestational disease and have been studied largely to investigate conditions related to pregnancy such as preeclampsia. Choriocarcinomas are highly angiogenic and produce high levels of placental growth factor (PlGF) to promote the development of blood vessels. Upregulation of PlGF expression also occurs during the development of other human malignancies such as breast cancer and melanoma. Both tumor specimens and plasma samples have higher levels of PlGF than normal tissues. Hence, PlGF has emerged as a valid target for anti-angiogenic therapy. The cell lines BeWo, JAR and JEG-3, derived from human choriocarcinomas, were investigated in vitro and in vivo for suitability as PlGF-dependent models. BeWo, JAR and JEG-3 cells were characterized in culture and were implanted into immunodeficient mice to generate subcutaneous tumors. The PlGF and VEGF angiogenic profiles of the choriocarcinoma cells and tumors were investigated by ELISA and by immunohistochemical methods. Double immunofluorescence methods were applied to choriocarcinoma xenograft sections to characterize the cellular components of the blood vessels. sFLT01, a fusion protein that neutralizes PlGF, was assessed in cell culture experiments and xenograft studies. The novel results presented here validate the importance of human choriocarcinoma cell lines and xenografts in further exploring the role of PlGF in tumor angiogenesis, for evaluating PlGF as an anti-angiogenic target, and for developing therapies that may provide clinical benefit.
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PMID:Human choriocarcinomas: placental growth factor-dependent preclinical tumor models. 2207 22

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have crucial roles in both physiological and pathological angiogenesis. The VEGF family consists of VEGF-A (generally called VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). These peptides show different affinities for VEGFR subtypes. VEGFR exists as three subtypes, VEGFR-1, VEGFR-2, and VEGFR-3, and is structurally related to platelet-derived growth factor receptors. All subtypes possess seven immunoglobulin-like domains in the extracellular region and a tyrosine kinase domain in the intracellular region. VEGF-A activates VEGFR-1 and VEGFR-2, whereas VEGF-B and PlGF bind to only VEFGR-1. VEGF-C and VEGF-D only bind to VEGFR-3. VEGFR-1 (fms-like tyrosine kinase-1, Flt-1) negatively regulates embryonic vasculogenesis and is involved in tumor angiogenesis via activation of monocytes and macrophages. VEGFR-2 (KDR in humans or Flk-1 in mice) is predominantly responsible for both embryonic vasculogenesis and tumor angiogenesis. In contrast, VEGFR-3 (Flt-4) regulates lymphangiogenesis. Consequently, VEGF-A and VEGFR-2 are currently the main targets for antiangiogenic therapy. Bevacizumab is a humanized monoclonal antibody against VEGF-A, and aflibercept (VEGF-Trap) is a soluble fusion protein of the extracelluar domain of VEGFR-1 and VEGFR-2 and the Fc region of immunoglobulin G (IgG). They neutralize VEGF-A, resulting in prevention of tumor angiogenesis. VEGFR tyrosine kinase inhibitors such as sunitinib and sorafenib are also effective in antiangiogenic tumor therapy by inhibiting VEGFR signaling. Anti-VEGF drugs are a promising therapy for cancer patients.
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PMID:Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. 2213 Feb 31

ADAMTS5 is a member of the A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs (ADAMTS) family of secreted metalloproteinases with multiple proteoglycan substrates. Although well characterized for its role in cartilage degradation and arthritis, how it influences cancer remains unclear. We have previously shown that the first thrombospondin type 1 repeat (TSR1, the central TSR) but not TSR2 (the C-terminal TSR) of ADAMTS5 is anti-angiogenic in vitro. Coupled with previous reports that ADAMTS5 expression is altered in several human cancers, we hypothesized that this proteoglycanase may play an important role in cancer and angiogenesis. Here, we demonstrated that overexpression of full-length ADAMTS5 suppressed B16 melanoma growth in mice. The reduced tumor growth is correlated with diminished tumor angiogenesis, together with reduced tumor cell proliferation and increased tumor cell apoptosis. Catalytically active ADAMTS5 proteolytic fragment also suppressed angiogenesis in vitro. The catalytic activity of ADAMTS5 is dispensable for its anti-tumorigenic function, as the full-length active site mutant E411A presented similar tumor suppression activity. Domain mapping and mechanistic studies revealed that ADAMTS5 inhibits B16 tumorigenesis through its TSR1 by suppressing tumor angiogenesis, likely by down-regulating pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and platelet-derived endothelial growth factor (PD-ECGF) in the tumor milieu. This is the first report that ADAMTS5 is an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity.
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PMID:ADAMTS5 functions as an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. 2282 41

The diverse pathways and molecules involved in angiogenesis, the formation of new blood vessels, have been targeted for the treatment of colorectal and other cancers. Vascular endothelial growth factor (VEGF)-A binding to VEGF receptor (VEGFR)-2 is believed to be the key signaling pathway mediating angiogenesis. Other VEGF pathways involved in angiogenesis include VEGF-A, VEGF-B, and placental growth factor binding to VEGFR-1, and VEGF-C and VEGF-D binding to VEGFR-2 and VEGFR-3. VEGF signaling also intersects with other pathways, including angiopoietin/Tie, Notch, hypoxia-inducible factor, and integrin pathways. The roles of these pathways in tumor angiogenesis and in various human cancers will be explored in this article. In addition, preclinical and clinical data on bevacizumab, aflibercept (known as ziv-aflibercept in the US), and investigational antiangiogenic agents in development for the treatment of colorectal and other cancers will be reviewed.
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PMID:Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy. 2305 39

The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.
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PMID:Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs. 2326 58

Angiogenesis is the process of formation of new blood vessels due to over expression of VEGF (vascular endothelial growth factor) which plays a critical role in the growth and development of all solid tumor types. With the advancement in understanding of tumor angiogenesis and VEGF, there have been a number of agents developed to target VEGF for the treatment of cancer. These targeted agents can affect downstream VEGF signal transduction by unique mechanisms at different cellular and extracellular levels. FDA has recently approved Aflibercept or VEGF-Trap in August 2012 for the treatment of colorectal cancer. It is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting VEGF-A, VEGF-B and placental growth factor. VEGF-Trap exerts its antiangiogenic effects through regression of tumor vasculature, remodelling or normalization of surviving vasculature and inhibition of new tumor vessel growth. In this review, pre-clinical and clinical data have been summarized for aflibercept alone and in combination with chemotherapy to explore its efficacy and benefits in ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, glioblastoma, adenocarcinoma and renal cell cancer xenograft models.
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PMID:Aflibercept: a novel VEGF targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple tumors. 2331 99

Therapies that target angiogenesis and the VEGF pathway are a component of treatment for patients with metastatic colorectal cancer (mCRC). Bevacizumab is a humanized monoclonal antibody that binds to VEGFA. Chemotherapy plus bevacizumab has led to improved outcomes for mCRC patients. Despite these benefits, progressive disease invariably ensues. Multiple members of the VEGF family can potentially contribute to tumor angiogenesis and/or evasion of antiangiogenic therapy if one pathway should be inhibited. Aflibercept, a new biological agent, is a multiple angiogenic factor trap that prevents not only VEGFA, but also VEGFB and PlGF from activating their native receptors. Key clinical data for bevacizumab and aflibercept for treatment of mCRC, clinical evidence for use of these agents beyond progression, and the search for angiogenic biomarkers to better define patients most likely to benefit from these interventions will be reviewed.
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PMID:The evolving role of VEGF-targeted therapies in the treatment of metastatic colorectal cancer. 2343 98


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