Exploring Tumor Angiogenesis from Intercellular Communications and Intracellular Signaling

The pattern and properties of angiogenic blood vessels in tumor usually vary in their responses to anti-angiogenic therapies because of the complex neoplastic tissue reprogramming processes and the participation of tumor-associated stromal cells and their bioactive products in the tumor microenvironment (TME), such as cytokines and growth factors. By studying the processes and analyzing the related bioactive products in the TME, the potential therapeutic methods might be discovered. In this article, we discuss what are the factors that influence these angiogenic reprogramming processes and go into the details of how they regulate tumor progression and development. Before starting your research, let’s take a look at what’s new in this field.

Angiogenesis is a process that tumors develop new blood vessels from a pre-existing vascular network to satisfy their growth demand or accomplish other metabolic functions, critical for tumor progression especially when they under pre-malignant stage and need to reach out for more oxygen and nutrient to support their growth. However, with the more and more studies about this topic, scientists realized that this seemly straightforward process is not that easy to handle as we thought, since there are so many factors that may play roles in the pattern of tumor vascularization , for instance, the tumor type, grade and stage, the anatomical site, the stromal and immune cell composition, the spatio-temporal expression of pro-angiogenic factors and anti-angiogenic factors. Though the tumor angiogenesis is regulated by both intrinsic and extrinsic factors , this article mainly focus on the extrinsic regulation from the TME, with the premise that harnessing such regulation may help us develop more efficient therapeutic method by targeting the tumor angiogenesis process.

How tumor-associated stromal cells (TASCs) regulate the angiogenesis

Even though the composition and abundance of tumor-associated stromal cells vary a lot between different tumor types and microenvironment, we can roughly divide them into two main categories based on their origin, the haematopoietic origin tumor-infiltrating cells from bone marrow such as monocytes, macrophages, neutrophils, lymphocytes and their immature precursors, and the non-haematopoietic, bone marrow-derived endothelial or mesenchymal progenitors as well as tissue-resident cells. In this chapter, we mainly discuss the cell types that has been widely accepted as the main players in the regulation.

Tumor-associated macrophages (TAMs) are critical players in tumor angiogenesis, which mainly differentiate from circulating monocytes in response to chemokines, damage-associated molecular patterns (DAMPs) and pro-inflammatory signaling molecules. TAMs usually exert pro-angiogenic role in human tumors, as the elimination of TAMs can significantly decrease angiogenesis in various tumor models. But its function highly depends on cytokine milieu and other influencing factors in specific TME. The pro-angiogenic function of TAMs achieves by the secretion of growth factors and inflammatory cytokines which include VEGFA, PIGF, TNF, IL-1β, CXCL8, and FGF2. Some macrophage-derived proteases, such as MMP-2,MMP-9, MMP-12, cathepsin, and plasminogen activator, can also facilitate the growth of tumor blood vessels. Secretion of CXCL12 and ANGPT2 induced by hypoxia can stimulate TAMs accumulation and the expression of CXCR4 and TIE2, which are two critical players in signaling transduction. Neutrophils are stimulated by CSF3, when CSF3R on neutrophil binds with CSF3, it activate Jak and STAT3 pathways to promote proliferation and expansion by upregulating the expression of VEGFA, FGF2, MMP9 and BV8. And CXCL chemokines are responsible for recruiting the neutrophils to tumors through binding with CXCR1 and CXCR2. As for the immature myeloid cells, their pro-angiogenic functions largely overlap with these mature cells which has been mentioned previously, and the tumor-derived factors secreted by other cell types can promote their expansion, inhibit their maturation and activate their pro-agiogenic function. In some cancer types, mast cells also have pro-angiogenic function and secrete tumor-associated factors as well as some proteases such as chymase and tryptase that activate pro-MMPs. Eosinophils can be recruited to hypoxic area in tumor by CCL11 and have similar function as other TASCs. B cells can not only facilitate angiogenesis by releasing various pro-angiogenic mediators, but also stimulate tumor angiogenesis indirectly by polarizing macrophage and through IgG. And there are increasing evidence show that T cells and natural killer cells are also relevant to this process.

Stromal cells like platelets, have complex roles in tumor angiogenesis, tumor can activate platelets by expressing platelet-activating factors such as thrombin, tissue factor(TF), and ADP at sites of vascular hyperpermeability and plasma leakage. Studies also report higher pro-angiogenic factors in platelets of cancer patients which indicates the platelets might have pro-angiogenic function. Moreover, the platelets can also stimulate the mobilization of bone-marrow derived myeloid cells to tumors and help them homing at the sites. Pericytes that responsible for stabilizing the capillaries can stabilize the newly formed vessels in tumors, they express neural cell adhesion molecule 1 (NCAM1) and the NG2 proteoglycan to facilitate vascular maturation by recruiting more pericytes to the sites. Cancer-associated fibroblasts(CAFs) play a key role in providing a reactive stroma that can perpetuate responses of tumor-promoting and tissue repair in tumor development, and usually derived from normal fibroblasts stimulated by transforming growth factor β(TGFβ). CAFs are major source of VEGFA, but they can also facilitate tumor angiogenesis in VEGFA-independent manner by secreting pro-angiogenic factors such as FGF2 and osteopontin. CAFs are indirect regulator of pro-angiogenesis as they secreting lysyl oxidase(LOXs) and hydroxylases, which associated with regulating biomechanical properties of the tumour stroma. Adipocytes have been reported foster the growth of initiated cancer cells through adipokines, and their pro-angiogenic function also exerts by targeting vascular endothelial cells (ECs) and recruiting vascular-modulatory inflammatory cells.

Key signaling pathways involved in the angiogenesis

During the last two decades, a bunch of studies has been done and multiple ligand and receptor complexes have been proved associated with tumor angiogenesis. To date, the most commonly studied ligand-receptor signaling networks would be discussed in the article.

VEGF/Neuropilin Signaling Pathway : VEGF/VEGFR-2 stimulates angiogenesis. Neuropilin-1 and -2 are transmembrane glycoproteins expressed in multiple cell lines and capable of binding at least two

VEGF/Neuropilin Signaling Pathway : VEGF/VEGFR-2 stimulates angiogenesis. Neuropilin-1 and -2 are transmembrane glycoproteins expressed in multiple cell lines and capable of binding at least two different types of ligands, which are growth factors such as VEGF, PDGF, and HGF that promote cell migration and semaphorins that inhibit cell migration. Inhibitors against NRP1 show therapeutic potential in cancer treatment, and molecules that are able to compete for VEGF binding to NRP1 can inhibit VEGF-induced  endothelial cell migration.
Notch Signaling Pathway: The Notch signaling pathway regulates the initial process of cell differentiation in tumor angiogenesis which plays a critical role in sprouting. Notch ligands and receptors are cell-surface transmembrane proteins engaged in juxtacrine and autocrine signaling. Notch signaling pathway is usually activated by DII4 upregulated via PI3K/Akt pathway, and responsible for the formation of angiogenic sprout.
Tie2 Signaling Pathway: The main function of the Tie 2 signaling pathway is to stabilize the newly formed vascular networks and influence the quiescence and homeostasis of the vascular plexus. The cell-matrix Tie 2 signal leads to the activation of Erk/MAPK pathway, while the cell-cell Tie 2 signal stimulate PI3K/Akt signaling which activate the expression of DII4 via β-catenin.
Slit/Robo Signaling Pathway: Mammal cells mainly express 3 Slit ligands ( Slit1, 2 and 3) and 4 Robo receptors ( Robo 1-4). This Slit/Robo signaling pathway play a key role in blood vessel guidance in developmental angiogenesis. Slit 2 is expressed by cancer cells and Robo1 is usually on endothelial cells, the combination of Slit 2 and Robo receptors was shown to induce endothelial cells migration and tube formation via PI3K signaling pathway.

In this blog article, we mainly discussed the roles of different tumor-associated stromal cells during tumor angiogenesis and the signaling pathways that participate in the process. The factors that play vital roles in the process have also been investigated as the potential drug targets for different types of cancers. To date, research studies utilizing anti-angiogenic strategies have got promising outcomes but clinical therapies have not yielded significant results. Further studies still need to be done to identify more therapeutic targets and offer us more treatment options to block this tumor angiogenetic process.

Reference:

Albini, A., et al., Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy. Front Immunol, 2018. 9: p. 527.

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