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

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.

Keywords: angiogenesis; combinational therapy; immunotherapy; non-small cell lung cancer; tumor endothelial cells; tumor microenvironment; vascular endothelial growth factor.

FIGURE 1

Mechanisms of tumor vascularization in NSCLC. Tumor vascularization in lung cancer can be promoted by various processes which overlap during cancer progression. In general tumor vascularization/angiogenesis can be stimulated on the cellular level (TEC properties), the environmental level (TME stimuli) or facilitated in absence of angiogenic signaling (non-angiogenic processes). TECs exhibit upregulated metabolism to enable high angiogenic activity which includes processes involved in proliferation (cholesterol synthesis and glycolysis) and processes that enable migration via ECM remodeling (collagen synthesis). Potential targets involved in these pathways (SQLE, PFKFB3, and ALDH18A1, respectively) are considered to increase the angiogenic potential of TECs in NSCLC. Hypoxia and acidosis induced by high levels of lactate due to upregulated glycolysis constitute to a highly pro-angiogenic tumor environment. Angiogenesis stimulating factors (VEGF, bFGF, PDGF, HIF-1α, tryptase, and MMPs) are released by both, cancer cells and stromal cells, including fibroblasts, pericytes, tumor associated macrophages and ECs. Non-angiogenic processes constitute to tumor vascularization and are inaccessible for anti-angiogenic agents, thus contributing to therapy resistance. VM comprises the formation of tubular structures arising from cancer cells that gain endothelial like properties to maintain vascular supply during cancer progression. Another mechanism of cancer cells to persist in circulation is to grow along existing vasculature, which is referred to as vessel co-option. In this figure we summarized the various mechanism of tumor vascularization that should be considered when targeting the inhibition of tumor vessels in NSCLC.

FIGURE 2

The multifaced picture of TECs in NSCLC. TECs possess features that enable continuous angiogenic activity for progressing vascularization of the tumor. These features are ensured by genetical changes in the tumor endothelium that are triggered by diverse stimuli of the TME e.g., hypoxia and growth factor release. The stroma, consisting of various cells, promote angiogenesis by directly releasing signaling molecules into the adjacent tissue, thereby stimulating TECs. Fibroblasts and myeloid derived suppressor cells (MDSCs) activate angiogenesis by releasing VEGF and bFGF into the TME. Additionally, CSF-1 molecules, expressed by cancer cells, further recruit MDSCs into the tumor niche. Tumor associated macrophages (TAMs) can directly induce angiogenesis by releasing VEGF, bFGF, and PlGF, or indirectly by releasing matrix metalloproteinases (MMPs) which promote endothelial migration. Mast cells secrete tryptase (TRYPT) into the TME which stimulates EC proliferation and enables ECM remodeling. Furthermore, to facilitate enhanced angiogenesis, TECs upregulate the surface expression of angiogenic receptors as well as increase metabolic activity including energy and amino acid metabolism and the biosynthesis of nucleotides. In addition to the high angiogenic activity, TECs can directly suppress inflammatory responses by downregulation of inflammatory cytokines for immune cell recruitment (CCL2, CCL8, and IL-6), receptors required for immune cell homing (ICAM) or lymphocyte activation (MHC I and MHC II) which results in impaired immune cell trafficking and migration into the TME. In summary the complex interaction of tumor-protecting environmental conditions and the pathological features of TECs lead to a pro-angiogenic and immune suppressive TME in NSCLC.