Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis

Nissen, L. Johan; Cao, Renhai; Hedlund, Eva–Maria; Wang, Zongwei; Zhao, X; Wetterskog, Daniel; Funa, Keiko; Bråkenhielm, Ebba; Cao, Yihai

doi:10.1172/jci32479

Cited by 253 publications

(212 citation statements)

References 48 publications

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“…The first type of new blood vessel to form in response to Ad-VEGF-A 164 has a characteristic morphology and has been given the name 'mother vessel' (MV) (Pettersson et al, 2000). However, similar MV-like blood vessels are also induced by polymers containing VEGF-A 164 or basic fibroblast growth factor (Cao et al, 1998) and by tumours expressing VEGF-A or basic fibroblast growth factor and plateletderived growth factor-BB (Paku and Paweletz, 1991;Bjorndahl et al, 2005;Nagy et al, 2007;Nissen et al, 2007). The other types of angiogenic vessels evolve from MVs and thus may be properly regarded as 'daughter' vessels ( Figure 1) (Pettersson et al, 2000;Dvorak, 2003;Nagy et al, 2007).…”

Section: How Do Tumour Blood Vessels Form?mentioning

confidence: 99%

Why are tumour blood vessels abnormal and why is it important to know?

et al. 2009

Br J Cancer

482

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Tumour blood vessels differ from their normal counterparts for reasons that have received little attention. We report here that they are of at least six distinct types, we describe how each forms, and, looking forward, encourage the targeting of tumour vessel subsets that have lost their vascular endothelial growth factor-A (VEGF-A) dependency and so are likely unresponsive to anti-VEGF-A therapies.

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Section: How Do Tumour Blood Vessels Form?mentioning

confidence: 99%

Why are tumour blood vessels abnormal and why is it important to know?

et al. 2009

Br J Cancer

482

425

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“…These ligands bind with high specificity to two cell membrane tyrosine kinases, PDGF receptor (PDGFR)-a and -b, that interact to form three dimeric receptor isoforms, PDGFR-aa, -bb, and -ab. PDGF-BB is a pluripotent angiogenic ligand; it activates all three receptor isoforms to induce target cell proliferation, migration and survival [3][4][5][6][7][8][9][10][11][12][13][14][15] . In mice, genetic deletion of PDGF-BB or PDGFR-b results in a series of vascular abnormalities in association with pericyte loss including vessel dilation, leakage and rupture, and irregular vascular networks.…”

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confidence: 99%

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

et al. 2013

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Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dosedependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-b signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-b and inactivation of the PDGF-b signalling decreases integrin a1b1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.

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“…This process is tightly controlled by ECM-degrading enzymes, including MMPs (35). MMPs, which are a family of closely-related enzymes that degrade ECM, are involved in tumor invasion and migration, and may be associated with the invasion, lymph node metastasis and survival of gastric carcinoma (36,37). MMP-9 is a zinc-containing enzyme that exhibits potent proteolytic .05 vs. groups C and N. NF-κB, nuclear factor-kappa B; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2 associated X protein; VEGF-A, vascular endothelial growth factor-A; MMP-9, matrix metalloproteinase-9; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

Guan

et al. 2016

Oncology Letters

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Abstract.Fentanyl is widely used to treat acute and chronic pain. Previous in vitro studies by the present authors demonstrated that fentanyl inhibits the progression of the MGC-803 human gastric carcinoma cell line by affecting apoptosis-related genes, including nuclear factor-kappa B (NF-κB) and phosphatase and tensin homolog. In the present study, the effects of fentanyl on NF-κB-dependent gene expression were investigated in vivo. Nude mice were inoculated with an MGC-803 cell suspension, and mice that developed subcutaneous tumors measuring >1.0x1.0 cm were selected for study. Mice were administered intraperitoneal injections of fentanyl (0.05 mg/kg, group F1; 0.1 mg/kg, group F2; 0.2 mg/kg, group F3; and 0.4 mg/kg, group F4) for 14 consecutive days. Non-fentanyl-treated mice (group C) and normal saline-treated mice (group N) served as the control groups. Tumor growth was monitored by calculating the time-shift of the growth curve. Morphological changes were also observed using microscopy. The expression of NF-κB, B-cell lymphoma-2 (Bcl-2), B-cell associated X protein (Bax), vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP-9) in the subcutaneous tumor tissue was also analyzed by reverse transcription-polymerase chain reaction and western blot analysis, and confirmed using immunohistochemistry. The relative tumor volumes of groups F1, F2, F3 and F4 were significantly reduced compared with groups C and N. Furthermore, subcutaneous tumor cells exhibited nuclear swelling, chromatin condensation, reduced chromatin and nuclear fragmentation in the F1, F2, F3 and F4 groups. The number of NF-κB + , Bcl-2 + , VEGF-A + and MMP-9 + subcutaneous tumor cells was reduced, whereas the number of Bax + cells was increased in the F1, F2, F3 and F4 groups. Additionally, in these groups, tumor expression of NF-κB, Bcl-2, VEGF-A and MMP-9 transcripts and proteins was downregulated, while Bax messenger RNA and protein expression levels were upregulated. The results revealed that fentanyl inhibits the growth of subcutaneous human gastric carcinoma tumors in mice. Therefore, it could be hypothesized that this antineoplastic activity may result from the inhibition of NF-κB activation, suppression of downstream VEGF-A and MMP-9 expression, and normalization of the pro-apoptotic Bax/Bcl-2 ratio. IntroductionAt present, gastric carcinoma is the fourth most common human neoplasm and the second most common cause of carcinoma-associated mortality worldwide, accounting for 986,600 novel cases and 738,000 mortalities annually (1). The incidence and mortality rates of this disease are higher in China than in other Asian countries (1). The molecular pathogenesis of gastric carcinoma has been investigated extensively with the aim of developing more effective therapeutic strategies for this type of tumor (2). Thus, there is an urgent requirement for the development of strategies to prevent and treat this disease.Fentanyl, which is the most frequently used analgesic, exhibits minimal cardiovascular effects and d...

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Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis

Cited by 253 publications

References 48 publications

Why are tumour blood vessels abnormal and why is it important to know?

Why are tumour blood vessels abnormal and why is it important to know?

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

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