Targeting Angiogenesis in the TME

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Tumor angiogenesis is a hallmark of solid tumors. As a fundamental process, angiogenesis help to supply tumors with oxygen and nutrition required for their growth and survival. As malignancy develops, cells progress from a prevascular stage (normal to early hyperplasia) to a vascular stage (late hyperplasia to dysplasia to invasive carcinoma). Unlike normal vessels in healthy tissues, the tumor vasculature possesses abnormal morphology, high permeability and compressive force. The hypoxic and acidic tumor microenvironment (TME) contributes to this pathological angiogenic process. The abnormal vascular structure and function in turn cause a hypoxic and acidic TME.

Fig.1 Tumor vessels are structurally and functionally abnormal. (Carmeliet, 2011)

Angiogenesis and Anti-angiogenesis Therapies

Immature, tortuous, and highly permeable vessels are the most common features of intratumoral vasculature. The regulation of angiogenesis is dependent on pro- and anti-angiogenic regulators. Targeting these regulators can improve TME. The vessel depletion/inhibition, tumor blood vessels regression and vessel normalization represent three attractive approaches to reverse abnormal tumor vessels. Current vascular targeting strategies are based on the inhibition of key angiogenic signaling pathways known to promote tumor angiogenesis. Several strategies have been developed to inhibit angiogenesis that is suitable for clinical trials.

Fig.2 The nature of the TME influences immune cell composition and angiogenesis. (Schaaf, 2018)

Several targets in anti-angiogenesis therapies

Growth factors

Some important growth factors are responsible for tumor-driven angiogenesis such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), etc. The most extensively clinically used direct anti-angiogenic strategy targets VEGF-A or its receptors.

ANG-TIE pathway

Angiopoietins (ANGs) constitute another important class of angiogenic molecules that bind the endothelial-specific receptor tyrosine kinase (TIE) and act as a regulator of ANG-TIE signaling during angiogenesis. ANG1 stabilizes the tumor vasculature While ANG2 strongly promotes excessive angiogenic sprouting. Drugs that target the ANG-TIE pathway are in clinical development for oncological applications.

Cytokines

Several cytokines in the TME play an important role in tumor angiogenesis. Transforming growth factor-β (TGF-β) is a controversial pro-angiogenic cytokine because a few studies have revealed its inhibitory effect. Interferons (IFNs) are multifaceted in the regulation of tumor angiogenesis with enhancing or reducing angiogenesis. Interleukins play an important role in promoting tumor angiogenesis. In contrast, TNF-α is an anti-angiogenic and pro-angiogenic factor.

HIFs

Hypoxia induces angiogenesis, a target of several immunotherapeutics. The key regulator, the transcription factor hypoxia-inducible factor (HIF), can induce the expression of a large number of pro-angiogenic factors thus promoting angiogenesis. The newly formed vasculature is disorganized and leaky, which facilitates tumor cell invasion and metastasis, impairs drug delivery and further aggravates hypoxia in the tumor and the TME.

Endothelial progenitor cells (EPCs)

EPCs contribute to many processes, such as wound healing, myocardial ischemia, neovascularization, and tumor growth. Blocking EPC mobilization would inhibit the formation of new blood vessels and the metastatic niche.

Fig.3 Strategies of angiogenesis inhibition. (Pons-Cursach, 2019)

Multifactorality and the complexity of interactions in TME might limit the success of therapeutic approaches targeting only single angiogenesis molecules. Combination therapies or agents with a multimodal mode of action could be more effective. Moreover, nanotechnologies approaches could improve the efficiency of drugs delivery and favor their selective accumulation in tumors.

Creative Biolabs is dedicated to assisting our clients to develop reshaping TME strategies. We provide you with various angiogenesis models and many assays such as tube formation assay that help assess the anti-angiogenic potential of new tumor therapeutic strategies.

References

Carmeliet, P.; Jain, R.K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nature reviews Drug discovery. 2011, 10(6): 417-427.
Schaaf, M.B.; et al. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell death & disease. 2018, 9(2): 1-14.
Pons-Cursach, R.; Casanovas, O. Mechanisms of anti-angiogenic therapy. Tumor Angiogenesis, 2019: 183-208.