At this time of writing, such reliable biomarkers are not clinically available. The other key unsettled issue is to identify reliable biomarkers to predict therapeutic efficacy in cancer patients 5.
Both intrinsic and evasive drug resistance counteract therapeutic benefits and compensatory production of factors that are not within the targets of AADs are recognized as a common mechanism 29, 30. One of the key unsolved obstacles for antiangiogenic cancer therapy is the development of drug resistance 5. Inhibition of the PDGF-B-PDGF receptor β (PDGFRβ) signaling ablates pericyte coverage of blood vessels in healthy and pathological tissues 28. Angiogenic endothelial cells produce PDGF-B to recruit PVCs onto the newly formed nascent vasculature 27. PDGF-B is a main vascular remodeling factor acting on perivascular cells (PVCs), including pericytes and vascular smooth muscle cells 26. While FGF-2 stimulates endothelial proliferation, VEGF mainly induces endothelial migration and tip formation 25. It appears that FGF-2 and VEGF have distinguished biological activities on endothelial cells. FGF-2 directly acts on endothelial cells through FGF receptors (FGFRs) to stimulate proliferation and to display a potent angiogenic effect 22, 23, 24. In addition to VEGF, fibroblast growth factor 2 (FGF-2) and platelet-derived growth factors (PDGFs) significantly contribute to tumor neovascularization and vascular remodeling 17, 18, 19, 20, 21. The VEGF-VEGFR2 signaling is crucial for vascular patterning by the formation of endothelial cell tips at the leading edge of the growth cone 16. Currently, most clinically available AADs contain inhibitory components that target VEGF, VEGFR, and their downstream signaling 15. Treatment of tumors with VEGF blockades including neutralizing antibodies and its soluble receptors could restore a healthy vascular phenotype 10, 13, 14. VEGF is one of the key angiogenic factors that largely contribute to development of disorganized and highly leaky tumor vessels 11, 12. These unique features represent imbalanced production of angiogenic factors, accumulation of metabolites, hypoxia, and alteration of the TME. Tumor microvessels distinguish from the healthy ones by possessing several unique features, including disorganization, tortuosity, leakiness, low perfusion, instability, lacking sufficient perivascular cell coverage, and lacking completeness of the basement membrane 9, 10. As the growth of all solid tumors depends on angiogenesis, targeting the tumor vasculature provides a generic approach for treating different types of cancers 8. For examples, anti-vascular endothelial growth factor (VEGF) and anti-VEGF receptor (VEGFR) agents are commonly used drugs in the clinic for treating various cancers 6, 7. Indeed, antiangiogenic drugs (AADs) by blocking tumor-derived factors demonstrate clinical benefits in human cancer patients 3, 5. Targeting these factors and their signaling pathways provides attractive approaches for treating various cancers 1, 2, 3, 4. In the tumor microenvironment (TME), malignant cells and stromal cells produce various angiogenic factors to induce neovascularization, vascular remodeling, tumor growth, and metastasis 1. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. 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. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2 + breast cancer and fibrosarcoma models. FGF-2 + tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Here we show that FGF-2 modulates tumor vessels by recruiting NG2 + pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. However, effective drugs for treating FGF-2 + tumors are unavailable. FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling.
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