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Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors.

ABSTRACT: FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2⁺ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2⁺ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2⁺ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2⁺ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.

SUBMITTER: Hosaka K

PROVIDER: S-EPMC7382445 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors.

Hosaka Kayoko K Yang Yunlong Y Seki Takahiro T Du Qiqiao Q Jing Xu X He Xingkang X Wu Jieyu J Zhang Yin Y Morikawa Hiromasa H Nakamura Masaki M Scherzer Martin M Sun Xiaoting X Xu Yuanfu Y Cheng Tao T Li Xuri X Liu Xialin X Li Qi Q Liu Yizhi Y Hong An A Chen Yuguo Y Cao Yihai Y

Nature communications 20200724 1

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a su ...[more]

PMID: 32709869

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Project description:K-ras mutation and p53 loss are the most prevalent genetic alterations in pancreatic cancer. In addition to these two alterations, pancreatic tumors frequently contain a third genetic defect. Mutations in the WNT/ß-catenin signaling molecules occur in 15-20% of pancreatic cancer patients and co-exist with K-ras mutation and p53 loss. However, the contribution of the WNT/ß-catenin pathway in pancreatic tumorigenesis is still unclear. Methods: We generated Pdx1-CreKrasG12Dp53L/+APCL/+ (KPA) mice and compared their phenotypes with Pdx1-CreKrasG12Dp53L/+ (KPC) mice. The signaling pathways specifically activated in the KPA mice were investigated and the therapeutic effect by targeting the activated pathways was evaluated. We finally validated our findings in human blood and tumor samples. Results: Survival of the KPA mice was shorter than that of the KPC mice. The KPA cancer cells are highly invasive and exhibit distorted morphology in organoid culture with extensive invadopodia formation and elevated matrix metalloproteinase (MMP) activity. The platelet-derived growth factor (PDGF) pathway is upregulated in the KPA cancer cells, and PDGF production induced by ß-catenin triggers constitutive activation of the Src kinase via the PDGF receptor in the cells. Serum PDGF concentration of the KPA mice is much higher than that of the normal and KPC mice. The Src inhibitor dasatinib effectively inhibits tumor growth and metastasis of the KPA cancer cells. Patient's serum PDGF level is significantly correlated with the expression of PDGF and phosphor-Src in tumors and elevated PDGF/phosphor-Src level in tumors predicts increased recurrence and poor survival. Moreover, mutations of the WNT/ß-catenin signaling molecules are higher in patients with elevated PDGF/phosphor-Src level. Conclusion: ß-catenin activation, coupled with K-ras mutation and p53 loss, activates an autocrine PDGF/Src signaling in pancreatic cancer and defines a subset of patients who might be sensitive to Src inhibition. In addition, serum PDGF level could be a reliable biomarker for patient selection in clinic.

Dataset Information

Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors.

Publications

Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors.

Similar Datasets

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