Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

Abstract

Angiogenesis is defined as the formation of new blood vessels from pre-existing vessels, and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients, and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time-window. However, anti-angiogenics may excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.

Consensus guidelines for the use and interpretation of angiogenesis assays

“…In order to achieve this, the histopatho-logical evaluations of the tumor vasculature as described here must be supplemented by medical imaging techniques and/or assays, which utilize small biopsies, circulating tumor cells, endothelial cells, or circulating tumor derivatives. Moreover, the importance of an accurate biomarker of ongoing sprouting angiogenesis or non-angiogenic vessel co-option is corroborated by the extensively documented and strong link between angiogenesis and immune suppression [129–131] and the surge of clinical studies that combine anti-VEGF and immunotherapy strategies [132]. In this regard, studies suggested that interactions between endogenous galectins and glycans may link tumor immunosuppression and angiogenesis, conferring resistance to anti-VEGF treatment [133].…”

LncRNA DANCR promotes tumor growth and angiogenesis in ovarian cancer through direct targeting of miR‐145

“…Several cytokines, including VEGF, VEGF‐C, VEGF‐D, bFGF, and HGF, play a crucial role during tumor growth and angiogenesis . Inhibition of VEGF by upstream targets or neutralizing antibodies could efficiently inhibit tumor growth and cancer cell metastasis .…”

“…In the present study, we demonstrated that DANCR was upregulated Several cytokines, including VEGF, VEGF-C, VEGF-D, bFGF, and HGF, play a crucial role during tumor growth and angiogenesis. 22,23 Inhibition of VEGF by upstream targets or neutralizing antibodies F I G U R E 6 miR-145 plays a necessary role during DANCR promoting angiogenesis in ovarian cancer. A, Real-time determination of miR-145 expression in miR-Ctrl and miR-145 transfected A2780 cells (n = 4, **P < .01).…”

Neem Leaf Glycoprotein Restrains VEGF Production by Direct Modulation of HIF1α-Linked Upstream and Downstream Cascades

“…Among various pro-angiogenic factors, vascular endothelial growth factor (VEGF) is the most influential factor responsible for promoting tumor angiogenesis despite the nature and origin of tumor. Thus, VEGF targeting has efficacy in several cancer management (3,4). Rapid tumor cell proliferation creates hypoxia or oxygen deficit (5) and stabilizes HIF1α, the main VEGF regulator along with growth factors and oncogenes (6,7).…”