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

Sophia Daum,Hannes Hagen,Dominik Wolf,Andreas Pircher,Erin Naismith

doi:10.3389/fcell.2020.610903

Abstract

Tumor progression depends primarily on vascular supply, which is facilitated by angiogenic activity within the malignant tissue. Non-small cell lung cancer (NSCLC) is a highly vascularized tumor, and inhibition of angiogenesis was projected to be a promising therapeutic approach. Over a decade ago, the first anti-angiogenic agents were approved for advanced stage NSCLC patients, however, they only produced a marginal clinical benefit. Explanations why anti-angiogenic therapies only show modest effects include the highly adaptive tumor microenvironment (TME) as well as the less understood characteristics of the tumor vasculature. Today, advanced methods of in-depth characterization of the NSCLC TME by single cell RNA sequencing (scRNA-Seq) and preclinical observations enable a detailed characterization of individual cancer landscapes, allowing new aspects for a more individualized inhibition of angiogenesis to be identified. Furthermore, the tumor vasculature itself is composed of several cellular subtypes, which closely interact with other cellular components of the TME, and show distinct biological functions such as immune regulation, proliferation, and organization of the extracellular matrix. With these new insights, combinational approaches including chemotherapy, anti- angiogenic and immunotherapy can be developed to yield a more target-oriented anti-tumor treatment in NSCLC. Recently, anti-angiogenic agents were also shown to induce the formation of high endothelial venules (HEVs), which are essential for the formation of tertiary lymphoid structures, and key components in triggering anti-tumor immunity. In this review, we will summarize the current knowledge of tumor-angiogenesis and corresponding anti-angiogenic therapies, as well as new aspects concerning characterization of tumor-associated vessels and the resulting new strategies for anti-angiogenic therapies and vessel inhibition in NSCLC. We will further discuss why anti-angiogenic therapies form an interesting backbone strategy for combinational therapies and how anti-angiogenic approaches could be further developed in a more personalized tumor-oriented fashion with focus on NSCLC.

Highlights

Angiogenesis is regulated by the balance of pro-angiogenic and anti-angiogenic factors present in a tissue, if vascular remodeling is required this balance shifts to an activating state, called the “angiogenic switch” (Bergers and Benjamin, 2003)
In the following part we summarize currently available methods for investigating tumor angiogenesis as well as anti-angiogenic agents that have already been accepted for treating Non-small cell lung cancer (NSCLC)
Angiogenesis is a main therapeutic concept in oncology, especially in NSCLC, where three approved agents are available in combination with chemotherapy or immunotherapy

Summary

INTRODUCTION

Angiogenesis is regulated by the balance of pro-angiogenic and anti-angiogenic factors present in a tissue, if vascular remodeling is required this balance shifts to an activating state, called the “angiogenic switch” (Bergers and Benjamin, 2003). A similar activated angiogenic phenotype occurs which promotes endothelial cell (EC) proliferation, migration, elongation and dissemination of metastases to distant organs (Teleanu et al, 2019) These findings proposed inhibiting angiogenesis as a highly potent anti-cancer therapeutical approach and have intensified the research for agents to hamper vessel formation in diverse tumors over the past decades (Augustine et al, 2019). CDC42, a protein involved in actin-dependent formation of cytoplasmatic extensions, together with CD44, a protein crucial for establishing cell-cell contact, enable the connection between tumor cells and vessel covering pericytes for vessel co-option (Caspani et al, 2014) Another non-angiogenic mechanism termed “VM” describes the process where cancer cells gain endothelial abilities to form their own circulatory network consisting of microvascular tubes to preserve blood supply (Pinto et al, 2016). To better understand the biological mechanisms behind drug resistance or lack of clinical benefit, further investigation into the detailed characterization of the endothelial compartment in the TME are essential

TRADITIONAL METHODS FOR VESSEL INHIBITION IN NSCLC

DISCUSSION