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 offtarget 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.

The Chemokine CXCL7 Is Related to Angiogenesis and Associated With Poor Prognosis in Colorectal Cancer Patients

“…Meanwhile, VEGF can increase capillary permeability, which allows fibrinogen and other proteins to diffuse into the extracellular matrix where they crosslink into a fibrous gel, thus effectively promoting formation of a capillary network (15,16). VEGF is highly expressed in many tumors where it is the strongest driver of angiogenesis, thus contributing to tumor growth and metastasis (17,18).…”

The Role of Anti-angiogenesis in the Treatment Landscape of Non-small Cell Lung Cancer – New Combinational Approaches and Strategies of Neovessel Inhibition

“…In a recent study, Hosaka et al could show that dual angiogenesis inhibition could sensitize resistant off-target tumors to therapy. Therefore they created mouse models of breast cancer or fibrosarcoma, both resistant to anti-VEGF and anti-PDGF treatment due to increased tumor associated expression of bFGF, a molecule which modulates the vasculature via pericyte recruitment in a PDGF-dependent process (Hosaka et al, 2020). Neither anti-VEGF nor anti-PDGF monotherapy had a significant antitumor effect on bFGF-positive tumors, but the combination of both agents produced a superior benefit, inhibiting cancer growth by suppressing proliferation and triggering apoptosis of tumor cells.…”

“…The inhibition of VEGF/VEGFR, for example, was shown to prompt tumors to sustain angiogenesis via the secretion of substitute factors such as PDGF (Crawford et al, 2009), bFGF (Babina and Turner, 2017) and angiopoietin-2 (Rigamonti et al, 2014), or by the recruitment of pro-angiogenic cells such as tryptase secreting mast cells (Wroblewski et al, 2017) thus, resisting single-target therapies. Previous studies using dual or multi-target antibodies which simultaneously inhibit several angiogenic signals exhibited an incremental anti-angiogenic efficacy in different tumor types (Li et al, 2016;Peterson et al, 2016;Liu et al, 2018;Hosaka et al, 2020). However, many processes and factors contributing to inefficacy and resistance to angiogenesis inhibitors, in particular those involving the tumor endothelium, remain ambiguous.…”

Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications

“…Besides its role in physiological angiogenesis, FGF2 is implied in tumor-induced angiogenesis and metastatic process and appears to direct tumor-associated macrophages toward a protumorigenic state (23)(24)(25). FGF4 promotes cancer cell proliferation, invasion and migration by causing a switch of the receptor FGFR2-IIIb, a splice variant expressed in epithelial cells, into FGFR2-IIIc, expressed in mesenchymal cells and able to induce epithelial-mesenchymal transition (26).…”