Decoding Tumor Angiogenesis for Therapeutic Advancements: Mechanistic Insights

Abstract

Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target for therapeutic intervention. The tumor microenvironment is characterized by a complex interplay between proangiogenic and antiangiogenic factors, regulating the vascularization necessary for tumor growth and metastasis. The study of angiogenesis involves a spectrum of techniques, spanning from biomarker assessment to advanced imaging modalities. This comprehensive review aims to provide insights into the molecular intricacies, regulatory dynamics, and clinical implications of tumor angiogenesis. By delving into these aspects, we gain a deeper understanding of the processes driving vascularization in tumors, paving the way for the development of novel and effective antiangiogenic therapies in the fight against cancer.

Keywords: angiopoietin; antiangiogenic factors; endostatin; fibroblast growth factor; interleukins; matrix metalloproteases; platelet-derived growth factor; proangiogenic factors; tumor angiogenesis; vascular endothelial growth factor.

Figure 1

Stages of Angiogenesis in tumor growth. (A) Association of blood vessel formation in different stages of tumor growth. (B) Formation of new blood vessels from pre-existing blood vessels. (C) Different stages of angiogenesis. Broken red arrows denote the direction of blood flow in the lumen, and thick arrows indicate the next steps.

Figure 2

Proangiogenic signaling pathways in endothelial cells associated with tumor microenvironment. Activation of growth factor receptors with specific ligands (e.g., VEGF, PDGF, FGF, HGF, IGF, EGF, TGF-β and KITLG) triggers the activation of different downstream signaling pathways, including the PLCγ/PKC/eNOS, JAK/STAT, P³⁸/MAPK, Src/PI3K/Akt, and Grb2/Sos/Ras/Raf/MEK/ERK signaling pathways. The activation of Tie receptors upon angiopoietin binding leads to the activation of intracellular signaling pathways, including the Src/PI3K/Akt, Grb2/Sos/Ras/Raf/MEK/ERK, and DOKR/NCK/DAK signaling pathways. The activation of integrins with specific ligands (e.g., ECM, collagen, laminin, fibronectin, fibrinogen, cytokines, and growth factors) leads to the activation of the downstream effector, Src, which in turn activates several signaling pathways, including the Ras/Raf/MEK/ERK/MLCK, CRK/DOCK/Rac/RhoA/ROCK, FAK/SH2/PLCγ/NFκB, or FAK/SH2/PI3K/Akt signaling pathways. All of these signaling pathways result in tumor angiogenesis by increasing cellular permeability, focal adhesion, survival, growth, proliferation, and migration. Abbreviations: VEGF, vascular endothelial growth factor, PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; EGF, epidermal growth factor; TGF-β, transforming growth factor beta; KITLG, KIT ligand; ECM, extracellular matrix; PLCγ, phospholipase C gamma; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase; JAK, janus kinase; STAT, transducer and activator of transcription; MAPK, mitogen-activated protein kinases; Src, PI3K, phosphoinositide 3-kinases; PKB, protein kinase B; Grb2, growth factor receptor bound protein 2; Sos, son of sevenless; Ras, rat sarcoma virus; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; DOKR, downstream of kinase-related protein; NCK, noncatalytic region of tyrosine kinase; DAK, dihydroxyacetone kinase; MLCK, myosin light-chain kinase; CRK, CT10-regulated kinase; DOCK, dedicator of cytokinesis; Rac, ras-related C3 botulinum toxin substrate; RhoA, ras homolog family member A; ROCK, rho-associated protein kinase; NFκB, nuclear factor kappa B; FAK, focal adhesion kinase; SH2, src homology 2.

Figure 3

Antiangiogenic signaling pathways in endothelial cells associated with tumor microenvironment. The activation of growth factor receptors with specific ligands (e.g., VEGF) triggers the activation of different downstream signaling pathways, including the PLCγ/PKC/eNOS, JAK/STAT, P³⁸/MAPK, Src/PI3K/Akt, and Grb2/Sos/Ras/Raf/MEK/ERK signaling pathways. The activation of Tie receptors upon angiopoietin binding leads to the activation of intracellular signaling pathways, including the Src/PI3K/Akt, Grb2/Sos/Ras/Raf/MEK/ERK, and DOKR/NCK/DAK signaling pathways. The activation of integrins with specific ligands leads to the activation of the downstream effector, Src, which in turn activates several signaling pathways, including the Ras/Raf/MEK/ERK/MLCK, CRK/DOCK/Rac/RhoA/ROCK, FAK/SH2/PLCγ/NFκB, or FAK/SH2/PI3K/Akt signaling pathways. All of these signaling pathways result in tumor angiogenesis by increasing cellular permeability, focal adhesion, survival, growth, proliferation, and migration. The endogenous antiangiogenic factor, endostatin, prevents the binding of VEGF with KDR/Flk-1 by directly occupying the binding site of VEGF on KDR/Flk-1. Other endogenous antiangiogenic factors, including angiostatin and TIMPs, also inhibit KDR/Flk-1 activation by downregulating the generation of VEGF. Endostatin inhibits integrin signaling by sequestering the binding of specific ligands with integrin. It also inhibits P38/MAPK and ERK signaling, as well as the activation of eNOS. Angiostatin also inhibits Akt and ERK activation. Abbreviations: VEGF, vascular endothelial growth factor; TIMPs, tissue inhibitors of metalloproteinases; KDR, kinase insert domain receptor; Flk-1, fetal liver kinase 1; PLCγ, phospholipase C gamma; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase; JAK, Janus kinase; STAT, transducer and activator of transcription; MAPK, mitogen-activated protein kinases; Src, PI3K, phosphoinositide 3-kinases; PKB, protein kinase B; Grb2, growth factor receptor bound protein 2; Sos, son of sevenless; Ras, rat sarcoma virus; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; DOKR, downstream of kinase-related protein; NCK, noncatalytic region of tyrosine kinase; DAK, dihydroxyacetone kinase; MLCK, myosin light-chain kinase; CRK, CT10-regulated kinase; DOCK, dedicator of cytokinesis; Rac, ras-related C3 botulinum toxin substrate; RhoA, ras homolog family member A; ROCK, rho-associated protein kinase; NFκB, nuclear factor kappa B; FAK, focal adhesion kinase; SH2, src homology 2.

Figure 4

Different strategies to detect tumor angiogenesis. Abbreviations: SPECT, single photon emission computed tomography (SPECT); PET, positron emission tomography; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; IHC, immunohistochemistry.