Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas

Fjällskog, Marie-Louise; Hessman, Ola; Eriksson, Barbro; Janson, Eva Tiensuu

doi:10.1080/02841860601048388

Cited by 61 publications

(36 citation statements)

References 15 publications

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“…Our findings are supported by previous studies showing that besides stromal cells, human primary PanNET and metastatic cells express high levels of PDGFRβ compared with normal tissue (51,52). Moreover, clinical reports show evidence of PDGFR activation and copy number alteration in small intestine, gastroenteropancreatic, and pancreatic NET, although the use of whole tumor cell lysates precludes identification of the cell type expressing PDGFRβ (21,53).…”

Section: Discussionsupporting

confidence: 78%

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: Discussionsupporting

confidence: 78%

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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“…PDGFR-β expression was upregulated in primary pancreatic NET and metastases compared with normal endocrine pancreatic tissue, and in tumor stroma compared with normal pancreatic stroma [39]. In a gene profiling study, PDGFR-β was upregulated in pancreatic neuroendocrine carcinomas with metastases compared with benign pancreatic NET [40].…”

Section: Molecular Targets In Pancreatic Netmentioning

confidence: 99%

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

2011

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Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.

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“…As panNETs are highly vascularized tumours, dysregulation of vascular endothelial growth factor (VEGF), platelet-derived growth factor, and their receptors are reported to play vital roles in tumour growth and angiogenesis [2,3]. Inhibition of angiogenesis would therefore be expected to result in growth inhibition and regression of these tumours.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours

et al. 2018

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Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

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Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas

Cited by 61 publications

References 15 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

From Targets to Treatments: A Review of Molecular Targets in Pancreatic Neuroendocrine Tumors

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours

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