Autocrine PDGF stimulation in malignancies

Heldin, Carl‐Henrik

doi:10.3109/03009734.2012.658119

Cited by 69 publications

(61 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, a remarkable dose-dependent inhibition on PDGF-induced Matrigel invasion was observed in roneparstat-treated cells. The phospho-RTK array confirmed a constitutive activation of PDGFRα in U2OS cells (Supplementary Figure S1) accordingly to the described PDGF-mediated autocrine loop [31]. The reduced receptor phosphorylation observed following roneparstat-treatment (Figure 1) was further validated by immunoprecipitation (Figure 4B).…”

Section: Resultssupporting

confidence: 67%

“…Differently from TC71 cells, displaying a barely detectable phosphorylation of PDGFRβ in the phospho-RTK array, SK-N-MC cells showed a marked activation of PDGFRα in the presence of serum which was completely inhibited in drug-treated cells (Figure 1). Western blotting of SK-N-MC cell lysates confirmed the abrogation of phosphorylation at tyrosine residue 849, the major autophosphorylation site in the receptor activation loop, which was evident in both the precursor and the mature forms [31] (Figure 4A). Moreover, a remarkable dose-dependent inhibition on PDGF-induced Matrigel invasion was observed in roneparstat-treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…The striking effects of roneparstat in sarcoma cells endowed with PDGFR activating autocrine loops [31 and our data not shown] prompted us to investigate the ability of the HS mimic to inhibit the transforming potential of the COL1A1/PDGFB chimeric protein generated by the chromosomal translocation t(17;22) in DFSP [4, 5]. In this tumor, the fusion protein is processed into a functional PDGFBB leading to an autocrine activation of PDGFRβ which is recognized as driver of the oncogenic transformation.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

Cassinelli

Favini

et al. 2016

Oncotarget

View full text Add to dashboard Cite

The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.

show abstract

Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

Cassinelli

Favini

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…PDGF is a key player in the persistence of chronic fibrosis, exerting a strong mitogenic signal upon fibroblasts and myofibroblasts (32). Also, PDGF can stimulate the proliferation of epithelial cancer cells in different types of tumors, exerting its influence through both paracrine and autocrine mechanisms (133,287). Hence, PDGF-induced cell proliferation could very well sustain a desmoplastic reaction while supporting tumor progression, thus fueling a protumorigenic vicious cycle (20).…”

Section: Platelet-derived Growth Factormentioning

confidence: 99%

The wound healing, chronic fibrosis, and cancer progression triad

Rybinski

Franco‐Barraza

Cukierman

2014

Physiological Genomics

215

175

View full text Add to dashboard Cite

For decades tumors have been recognized as “wounds that do not heal.” Besides the commonalities that tumors and wounded tissues share, the process of wound healing also portrays similar characteristics with chronic fibrosis. In this review, we suggest a tight interrelationship, which is governed as a concurrence of cellular and microenvironmental reactivity among wound healing, chronic fibrosis, and cancer development/progression (i.e., the WHFC triad). It is clear that the same cell types, as well as soluble and matrix elements that drive wound healing (including regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor progression. Hence, here we review the relationship between fibrosis and cancer through the lens of wound healing.

show abstract

“…PDGF is one of the numerous growth factors that stimulate multiple cellular processes, including cell proliferation, chemotaxis, survival, and differentiation (Heldin, 2012). Various cell types, including platelets, fibroblasts, and macrophages, release PDGF (Barrientos et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effect of dual growth factor administration on oxidative markers during acute stage wound healing in rats

Dindar¹,

Kaltalıoğlu²,

Cevher³

2017

Turk J Zool

View full text Add to dashboard Cite

Wound healing is a complex process affected by various conditions, including oxidative stress. The present study explored the time-dependent effects of platelet-derived growth factor (PGDF) and vascular endothelial growth factor (VEGF) administration on oxidative markers during acute stage wound healing. Thirty-six Wistar rats were distributed into three major groups; skin wounds were inflicted in all groups. The wounds were either left untreated (control group), treated topically with blank chitosan gel (blank chitosan gel group), or treated topically with a combination of PDGF and VEGF in chitosan gel (PDGF + VEGF chitosan gel group). Wounds were sampled on postsurgery days 3 and 7; samples were assayed for the oxidant markers nitric oxide (NOx) and thiobarbituric acidreactive substances (TBARs) and the antioxidant markers glutathione (GSH), ascorbic acid (AA), and superoxide dismutase (SOD) activity. PDGF + VEGF administration increased and decreased NOx levels on days 3 and 7, respectively. PDGF + VEGF administration lowered TBARs levels, compared with blank chitosan gel administration, on day 7. PDGF + VEGF administration increased GSH levels. These results demonstrate that PDGF + VEGF administration changes oxidative status of wound tissue. This study provides valuable insights for the development of therapeutic targets that promote wound healing.

show abstract

Autocrine PDGF stimulation in malignancies

Cited by 69 publications

References 98 publications

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

The wound healing, chronic fibrosis, and cancer progression triad

Effect of dual growth factor administration on oxidative markers during acute stage wound healing in rats

Contact Info

Product

Resources

About