Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs

Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Tianjin Natural Science Foundation (CMM-Tianjin)|09ZCZDSF04400|Karolinska Institute||Torsten Soderbergs Foundation||Soderbergs Stiftelse||ImClone Systems/Eli Lilly||European Union|222741|European Research Council|250021|
The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.

Yang, XiaojuanKarolinska Institute, Sweden (författare)
Zhang, YinKarolinska Institutet (författare)
Yang, YunlongKarolinska Institutet (författare)
Shibuya, MasabumiTokyo Medical and Dent University, Japan (författare)
Zhong, WeideGuangzhou Medical University, Peoples R China (författare)
Sun, BaocunTianjin Medical University, Peoples R China (författare)
Liu, YizhiSun Yat Sen University, Peoples R China (författare)
Hosaka, KayokoKarolinska Institutet (författare)
Cao, YihaiLinköpings universitet,Avdelningen för kardiovaskulär medicin,Hälsouniversitetet,Karolinska Institute, Sweden(Swepub:liu)yihca64 (författare)
Karolinska InstitutetKarolinska Institute, Sweden (creator_code:org_t)

Ingår i:Proceedings of the National Academy of Sciences of the United States of America: National Academy of Sciences110:2, s. 654-6590027-84241091-6490

Av författaren/redakt...: Eleonora Hedlund ...; Yang, Xiaojuan; Zhang, Yin; Yang, Yunlong; Shibuya, Masabum ...; Zhong, Weide; visa fler...; Sun, Baocun; Liu, Yizhi; Hosaka, Kayoko; Cao, Yihai; visa färre...

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