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

Ehnman, Monika; Li, H; Fredriksson, Linda; Pietras, Kristian; Eriksson, Ulf

doi:10.1038/onc.2008.410

Cited by 19 publications

(17 citation statements)

References 27 publications

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“…In contrast, the latent full-length form of PDGF-DD has been suggested to be freely diffusible (43). It is thus reasonable to assume that PDGF-DD has a distinct distribution in the tumor stroma, being able to reach non-vessel-associated PDGFRβ-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, plateletderived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development.However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

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Section: Discussionmentioning

confidence: 99%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Matrix retention has previously been shown for activated (core) PDGF-D, while unprocessed FL-PDGF-D remains freely diffusible (Ehnman et al, 2009;Huang and Kim, 2015). Accordingly, we show that heparin only promotes the binding of active, core PDGF-D to NRP1, but not that of FL-PDGF-D. Likely, the heparin-binding domain is covered by the CUB domain and thus inaccessible in FL-PDGF-D. We suggest that the heparin-binding domain in PDGF-D is located between the CUB domain and the growth factor domain.…”

Section: Pdgf-d Induces the Interaction Of Pdgfrβ And Nrp1 In Trans Bmentioning

confidence: 99%

“…PDGF-A and PDGF-B are secreted in their active form, while secreted PDGF-C and -D polypeptide chains contain a N-terminal CUB (homology to complement components C1r/C1 s, Uegf, Bmp1) domain that needs to be proteolytically removed to enable receptor binding, and are thus produced and released as latent, inactive growth factors (Bergsten et al, 2001;Li et al, 2000;Ustach and Kim, 2005). The activation of PDGF-D is executed by serine proteases, such as urokinase-type plasminogen activator (uPA, also known as PLAU) or matriptase (Ehnman et al, 2009;Ustach et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling

Muhl

Folestad

Gladh

et al. 2017

Journal of Cell Science

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Platelet-derived growth factor (PDGF)-D is a PDGF receptor β (PDGFRβ)-specific ligand implicated in a number of pathological conditions, such as cardiovascular disease and cancer, but its biological function remains incompletely understood. In this study, we demonstrate that PDGF-D binds directly to neuropilin 1 (NRP1), in a manner that requires the PDGF-D C-terminal Arg residue. Stimulation with PDGF-D, but not PDGF-B, induced PDGFRβ-NRP1 complex formation in fibroblasts. Additionally, PDGF-D induced translocation of NRP1 to cell-cell junctions in endothelial cells, independently of PDGFRβ, altering the availability of NRP1 for VEGF-A-VEGFR2 signaling. PDGF-D showed differential effects on pericyte behavior in ex vivo sprouting assays compared to PDGF-B. Furthermore, PDGF-D-induced PDGFRβ-NRP1 interaction can occur in trans between molecules located in different cells (endothelial cells and pericytes). In summary, we show that NRP1 can act as a co-receptor for PDGF-D-PDGFRβ signaling and is possibly implicated in intercellular communication in the vascular wall.

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“…A few uPA substrates other than plasminogen have been identified. Under physiologically relevant conditions, uPA can directly cleave uPAR [59], PDGF-DD [60], the epithelial Na ? channel ENaC [61], and the a6 integrin of the laminin receptor [62].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Almholt

Lærum

Nielsen

et al. 2015

Clin Exp Metastasis

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Urokinase-type plasminogen activator (uPA) is an extracellular protease that plays a pivotal role in tumor progression. uPA activity is spatially restricted by its anchorage to high-affinity uPA receptors (uPAR) at the cell surface. High tumor tissue expression of uPA and uPAR is associated with poor prognosis in lung, breast, and colon cancer patients in clinical studies. Genetic deficiency of uPA leads to a significant reduction in metastases in the murine transgenic MMTV-PyMT breast cancer model, demonstrating a causal role for uPA in cancer dissemination. To investigate the role of uPAR in cancer progression, we analyze the effect of uPAR deficiency in the same cancer model. uPAR is predominantly expressed in stromal cells in the mouse primary tumors, similar to human breast cancer. In a cohort of MMTV-PyMT mice [uPAR-deficient (n = 31) or wild type controls (n = 33)], tumorigenesis, tumor growth, and tumor histopathology were not significantly affected by uPAR deficiency. Lung and lymph node metastases were also not significantly affected by uPAR deficiency, in contrast to the significant reduction seen in uPA-deficient mice. Taken together, our data show that the genetic absence of uPAR does not influence the outcome of the MMTV-PyMT cancer model.

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

Cited by 19 publications

References 27 publications

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

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