PDGF-D is a potent transforming and angiogenic growth factor

Li, Hong; Fredriksson, Linda; Li, Xuri; Eriksson, Ulf

doi:10.1038/sj.onc.1206223

Cited by 142 publications

(112 citation statements)

References 29 publications

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“…In addition to previous reports demonstrating an oncogenic potential of PDGF-DD (LaRochelle et al, 2002;Li et al, 2003;Xu et al, 2005), the current work shows that a regulated PDGF-DD activation is beneficial for driving tumour growth. This finding was initially unexpected, as the PDGF-DD(GFD) more potently transformed NIH/3T3 cells in vitro.…”

Section: Discussionsupporting

confidence: 78%

“…However, considering that altered pericellular retention and/or matrix interactions are important determinants for the physiological action of many other growth factors (LaRochelle et al, 1991;Ostman et al, 1991;Carmeliet et al, 1999;Grunstein et al, 2000;Lindblom et al, 2003;Lee et al, 2005), this could be a likely mechanism for controlling the function of PDGF-DD as well. In line with this, one could speculate that the observed differences in foci morphology induced by the two PDGF-DD forms are due to different spatial distribution, especially as we have previously shown that smaller and unevenly shaped foci can be formed from NIH/3T3 cells overexpressing matrix-bound PDGF-BB (Li et al, 2003). Indeed, here we show that latent PDGF-DD is diffusible, whereas the activated counterpart is deposited in close association with the producer cell, despite the lack of recognizable C-terminal retention motifs in the primary structure.…”

Section: Discussionsupporting

confidence: 57%

“…High expression levels of uPAR were confirmed by immunoblotting using a goat anti-human uPAR antibody (AF807, RnD Systems, Abingdon, UK). Transfections of other cell lines used were performed as described (Li et al, 2003;Fredriksson et al, 2005). Proteins subjected for immunoblotting were separated by SDS-PAGE under reducing conditions, incubated with specific primary antibodies and visualized by appropriate, HRP-linked, secondary antibodies: donkey anti-goat IgG (sc2020, Santa Cruz Biotechnology, CA, USA), donkey anti-rabbit IgG (NA934V, Amersham Biosciences, Uppsala, Sweden) or sheep anti-mouse IgG (NXA931, Amersham Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…The primers were designed to enable PCR amplification of the entire vector construct. Using mouse PDGF-D(fl) (Li et al, 2003) as template, a processing-resistant mutant was generated by replacing the conserved-R 254 KSK-site with four alanines. The N-and C terminus were separately amplified by PCR using Taq DNA polymerase (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Activated PDGF-DD induces transformation of NIH/3T3 cells more effectively than latent PDGF-DD To investigate how proteolytic removal of the CUB domains from PDGF-DD(fl) affects tumorigenesis, NIH/3T3 cells with stable expression of PDGF-DD(GFD) were generated and compared with cells stably transfected with PDGF-D(fl) (Li et al, 2003). Expression was confirmed by RT-PCR using primers specific for the PDGF-D(GFD) (Figure 5a) and similar PDGF-D transcript levels were ensured by qRT-PCR using the same set of primers (data not shown).…”

Section: Pdgf-dd Interacts Directly With Upamentioning

confidence: 99%

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The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

Ehnman

Fredriksson

et al. 2008

Oncogene

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Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Pdgf-dd Interacts Directly With Upamentioning

confidence: 99%

See 3 more Smart Citations

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

Ehnman

Fredriksson

et al. 2008

Oncogene

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Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

Pohlers

Huber

Ukena

et al. 2006

Arthritis & Rheumatism

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The effects of tumor‐derived platelet‐derived growth factor on vascular morphology and function in vivo revealed by susceptibility MRI

Robinson

Ludwig

Paulsson

et al. 2008

Intl Journal of Cancer

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Platelet-derived growth factors (PDGF) play a major role in pericyte recruitment in tumor capillaries. Pericytes are required for proper vessel development, and contribute to tumor angiogenesis by promoting stabilization and maturation of newly formed vessels. To investigate the effects of pericyte coverage on tumor vessel morphology and function in vivo, tumors derived from B16 melanoma cells transfected with either control plasmid (B16/ctr) or plasmid encoding full-length PDGF-BB (B16/PDGF), the latter previously shown to have enhanced blood vessel pericyte coverage and an increased tumor growth rate, were assessed using histopathological methods, Hoechst 33342-based perfusion analyses, and two noninvasive susceptibility magnetic resonance imaging (MRI) methods. Susceptibility-contrast MRI, incorporating the use of ultrasmall superparamagnetic iron oxide particles, revealed a significant (p < 0.05) reduction in vessel size index (R v ) of B16/ PDGF tumors, and which was validated histologically by the presence of significantly smaller (p < 0.001), more punctate blood vessels identified by fluorescence microscopy of the perfusion marker Hoechst 33342. Intrinsic-susceptibility MRI was used to measure the transverse MRI relaxation rate R 2 *, sensitive to changes in endogenous paramagnetic [deoxyhaemoglobin], and used to probe for vascular maturation and function. Hypercapnia (5% CO 2 / 95% air) induced a negligible DR 2 * response in the B16/ctr and B16/PDGF tumors. In contrast, hyperoxia (5% CO 2 /95% O 2 ) induced a significantly greater R 2 * reduction in the B16/PDGF tumors (p < 0.02). Together the susceptibility MRI-derived biomarkers reveal novel pericyte-dependent changes in the morphology and function of the perfused tumor vasculature in vivo. ' 2007 Wiley-Liss, Inc.Key words: pericyte; PDGF; MRI; biomarker Angiogenesis, the development of new blood vessels to provide a nutritive blood supply, is a prerequisite for tumor growth and survival. [1][2][3] Angiogenesis is stimulated by the release of specific growth factors from tumor cells, endothelial cells or associated macrophages, and production of these factors is upregulated by physiological conditions associated with the classical hallmarks of the tumor microenvironment. 4 Pericytes are vascular mural cells which are embedded in the basement membrane of microvessels. These cells are required for proper vessel development, and contribute to angiogenesis by promoting stabilization and maturation of newly formed vessels. 5,6 Pericytes are also present in tumor capillaries. 7 However, in general, pericyte coverage of tumor capillaries is sparser than in normal vessels, and the extent of pericyte coverage of tumor vessels shows large variability. 8 Also, pericytes of tumor vessels grow in a less organized manner, and are more loosely attached to the vessels. 7,9 The platelet-derived growth factor (PDGF) family of growth factors consists of 4 PDGF polypeptide chains and 5 dimeric isoforms, PDGF-AA, -AB, -BB, -CC and -DD, and play a major role in pericyte r...

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PDGF-D is a potent transforming and angiogenic growth factor

Cited by 142 publications

References 29 publications

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

The effects of tumor‐derived platelet‐derived growth factor on vascular morphology and function in vivo revealed by susceptibility MRI

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