Involvement of platelet‐derived growth factor ligands and receptors in tumorigenesis

Heldin, Carl‐Henrik; Lennartsson, Johan; Westermark, Bengt

doi:10.1111/joim.12690

Cited by 146 publications

(129 citation statements)

References 366 publications

(374 reference statements)

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“…PDGF-AB, AZA and serum are indispensable ingredients in reprograming media but how they cooperate to induce cell conversion is speculative. PDGF-AB is reported to bind and signal via PDGFR-αα and -αβ but not -ββ subunits (21). Mouse osteocytes and human adipocytes lack PDGFRα, although surface expression was detectable as cells transition during reprogramming (mouse; day 2/8 (14) and human day 21/25).…”

Section: Discussionmentioning

confidence: 99%

“…Although the relationship between DNA hypomethylation and therapeutic efficacy in MDS/AML is unclear, AZA is known to induce an interferon response and apoptosis in proliferating cells (18)(19)(20). PDGF-AB, the other critical reprogramming agent is one of five PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD), which bind to one of two PDGF receptors (PDGFRα and PDGFRβ) (21). PDGF isoforms are potent mitogens for mesenchymal cells and recombinant human PDGF-BB is used as an osteoinductive agent in the clinic (22).…”

Section: Introductionmentioning

confidence: 99%

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Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine

Yeola

Subramanian

Oliver

et al. 2020

Preprint

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Terminally differentiated murine osteocytes and adipocytes can be reprogrammed using platelet-derived growth factor-AB and 5-Azacytidine into multipotent stem cells with stromal cell characteristics. To generate a product that is amenable for therapeutic application, we have modified and optimised culture conditions to reprogram human adipocytes into induced multipotent stem cells (iMS) and expand them in vitro. The basal transcriptomes of adipocytederived iMS cells and matched adipose-tissue-derived mesenchymal stem cells were remarkably similar. However, there were distinct changes in histone modifications and CpG methylation at cis-regulatory regions consistent with an epigenetic landscape that was primed for tissue development and differentiation. In a non-specific tissue injury xenograft model, iMS cells contributed directly to new muscle, bone, cartilage and blood vessels with no evidence of teratogenic potential. In a cardiotoxin muscle injury model, iMS cells contributed specifically to satellite cells and myofibres without ectopic tissue formation. Taken together, human adipocyte derived iMS cells regenerate tissues in a context dependent manner without ectopic or neoplastic growth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine

Yeola

Subramanian

Oliver

et al. 2020

Preprint

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“…Targeting the PDGF‐induced signaling pathways is considered to be an attractive approach for cancer treatment, because the hyperactivation of the PDGF‐induced signaling is involved not only in growth stimulation of tumor cells, but also in functional regulations of tumor stroma fibroblasts and tumor angiogenesis (Heldin, Lennartsson, & Westermark, ; Pietras, Sjöblom, Rubin, Heldin, & Östman, ). Indeed, several inhibitors for the PDGF‐induced signaling pathways, including low molecular weight inhibitors, humanized mAbs or DNA aptamers, are being developed or in clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several inhibitors for the PDGF‐induced signaling pathways, including low molecular weight inhibitors, humanized mAbs or DNA aptamers, are being developed or in clinical use. The hyperactivation of the PDGF‐induced signaling pathways is mainly due to an over‐expression of PDGF or the PDGF receptor, although there are a few tumor types in which mutations in the genes for PDGF isoforms or receptors drive tumor development (Heldin et al., ). It is possible that the over‐expressed PDGF receptor β increases an opportunity to form a complex with endogenous Necl‐5, thereby enhancing the Necl‐5–PDGF receptor β‐induced signaling.…”

Section: Discussionmentioning

confidence: 99%

Roles of the third Ig‐like domain of Necl‐5/PVR and the fifth Ig‐like domain of the PDGF receptor in its signaling

et al. 2018

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The immunoglobulin (Ig)-like cell adhesion molecule nectin-like molecule (Necl)-5/poliovirus receptor is up-regulated in many types of cancer cells and implicated in their abnormally enhanced cell proliferation and movement. We previously showed that Necl-5 cis-interacts with the platelet-derived growth factor (PDGF) receptor β through the extracellular region and enhances its signaling. Although this cis-interaction does not affect the PDGF-induced tyrosine phosphorylation of the receptor, the interaction of the cytoplasmic region of Necl-5 with sprouty2 and the regulation of its activity are required for the enhancement of the PDGF receptor β signaling by Necl-5. We investigated here the more detailed mechanism for this cis-interaction of Necl-5 with the PDGF receptor β. Necl-5 contains three Ig-like domains and the PDGF receptor β contains five Ig-like domains at their extracellular regions. We showed here that the third Ig-like domain of Necl-5 cis-interacted with the fifth Ig-like domain of the PDGF receptor β. The recombinant protein of the third Ig-like domain of Necl-5 inhibited the cis-interaction of full-length Necl-5 with the PDGF receptor β and the PDGF-induced activation of the ERK signaling pathway that was enhanced by Necl-5. These results revealed the novel roles of the third Ig-like domain of Necl-5 and the fifth Ig-like domain of the PDGF receptor β in its signaling.

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“…One possible explanation for this ineffectiveness is the redundancy of the angiogenesis pathway, which can bypass VEGF inhibition. Tumor angiogenesis can be stimulated by various other pathways, including fibroblast growth factor, PDGF, and hepatocyte growth factor pathways. However, use of these pathways involves the problem of acquired resistance to inhibitors .…”

Section: Introductionmentioning

confidence: 99%

Curcumin analog, GO‐Y078, overcomes resistance to tumor angiogenesis inhibitors

Shimazu

Inoue

Sugiyama³

et al. 2018

Cancer Science

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Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO‐Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO‐Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC‐R). GO‐Y078 inhibited the growth and mobility of HUVEC‐R at 0.75 μmol/L concentration. Expression analyses by microarray and RT‐PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO‐Y078. In a knockdown experiment using Si‐oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO‐Y078. Knockdown of FN1 resulted in the suppression of HUVEC‐R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO‐Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO‐Y078.

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Involvement of platelet‐derived growth factor ligands and receptors in tumorigenesis

Cited by 146 publications

References 366 publications

Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine

Induction of Muscle Regenerative Multipotent Stem Cells from Human Adipocytes by PDGF-AB and 5-Azacytidine

Roles of the third Ig‐like domain of Necl‐5/PVR and the fifth Ig‐like domain of the PDGF receptor in its signaling

Curcumin analog, GO‐Y078, overcomes resistance to tumor angiogenesis inhibitors

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