Tumor vessel co-option: The past & the future

Abstract

Tumor vessel co-option (VCO) is a non-angiogenic vascularization mechanism that is a possible cause of resistance to anti-angiogenic therapy (AAT). Multiple tumors are hypothesized to primarily rely on growth factor signaling-induced sprouting angiogenesis, which is often inhibited during AAT. During VCO however, tumors invade healthy tissues by hijacking pre-existing blood vessels of the host organ to secure their blood and nutrient supply. Although VCO has been described in the context of AAT resistance, the molecular mechanisms underlying this process and the profile and characteristics of co-opted vascular cell types (endothelial cells (ECs) and pericytes) remain poorly understood, resulting in the lack of therapeutic strategies to inhibit VCO (and to overcome AAT resistance). In the past few years, novel next-generation technologies (such as single-cell RNA sequencing) have emerged and revolutionized the way of analyzing and understanding cancer biology. While most studies utilizing single-cell RNA sequencing with focus on cancer vascularization have centered around ECs during sprouting angiogenesis, we propose that this and other novel technologies can be used in future investigations to shed light on tumor EC biology during VCO. In this review, we summarize the molecular mechanisms driving VCO known to date and introduce the models used to study this phenomenon to date. We highlight VCO studies that recently emerged using sequencing approaches and propose how these and other novel state-of-the-art methods can be used in the future to further explore ECs and other cell types in the VCO process and to identify potential vulnerabilities in tumors relying on VCO. A better understanding of VCO by using novel approaches could provide new answers to the many open questions, and thus pave the way to develop new strategies to control and target tumor vascularization.

Keywords: anti-angiogenic therapy resistance; molecular mechanisms; mouse models; state-of-the-art analysis; tumor vascularization; vessel co-option.

Figure 1

Metastatic tumor growth via vessel co-option versus sprouting angiogenesis. Schematic overview of metastatic tumor growth by vessel co-option versus sprouting angiogenesis. Growth via vessel co-option (left panel): During vessel co-option, cancer cells co-opt the healthy lung structures in an irregular and infiltrative manner, resulting in a tumor with a necrotic core. Cell types thus far associated with vessel co-option are indicated (neutrophils, M1-like macrophages, matrix-remodeling macrophages). Growth via sprouting angiogenesis (right panel): Metastases growing mainly via sprouting angiogenesis are characterized by a globular shape, excluding healthy alveolar cells. New blood vessel formation is achieved by proliferation and migration of ECs out of pre-existing blood vessels. M2-like macrophages are enriched in metastases growing via sprouting angiogenesis. This figure is adapted from (10).

Figure 2

Vessel co-option in human tumors. Schematic overview of human tumors (per organ) with evidence for vessel co-option.

Figure 3

Cell-cell interactions during vessel co-option. Schematic graph showing key regulators (L1CAM, CDC42, CD44, integrins, serpins) of non-angiogenic, co-opted cancer cells, which cause cancer cells’ adhesion to vessels – a hallmark of vessel co-option. Cancer cells’ attachment to the pre-existing vessels leads to vessel compression, which in turn results in hypoxia. All abbreviations can be found in the list of abbreviations.

Figure 4

Molecular pathways in cancer cells and vascular cells driving angiogenesis. Schematic graph showing the known pathways associated with angiogenesis, the inhibition of which has been associated with vessel co-option. Ang2-Tie signaling: Signaling of Ang-2 through its receptor Tie-2 can cause sprouting angiogenesis if VEGF levels in the tumor microenvironment are high. If VEGF levels are low, Ang-2- Tie-2 signaling leads to regression of co-opted vessels. IRE1 signaling: IRE1 in cancer cells promote VEGF production, which can induce sprouting angiogenesis. On the other hand, it is indicated, that IRE1 impedes cancer cell invasion via inhibition of anti-angiogenic factors, such as SPARC and Decorin. All abbreviations can be found in the list of abbreviations.

Figure 5

Molecular pathways in cancer cells and vascular cells driving vessel co-option. Schematic graph showing the known pathways associated with vessel co-option (VCO) and how they relate to each other creating a complex network. Top: Cancer cells: The pathways involved in VCO in cancer cells and their roles are shown: metastasis (YAP/TAZ), invasion (HIF1α, FAK-ERK1/2, Wnt, CXCR4), motility (FAK-ERK1/2, ARP2/3) and EMT (GSK3β, MET, YAP/TAZ). Bottom: Tumor vessels: Binding of cancer cells to tumor vessels via integrins and L1CAM can result in motile and invasive cancer cell phenotypes. All abbreviations can be found in the list of abbreviations.

Figure 6

Molecular and cellular targeting to inhibit vessel co-option. Schematic graph showing the cellular components of a typical VCO-related tumor microenvironment and their potential as targets to inhibit VCO, either by inhibiting (A–C) or promoting the presence and/or signaling of these cells. Targets for inhibition: (A) Tumor cells with signaling pathways and molecules for potential targeting highlighted (TGF-β1, ARP2/3, EGFR, L1CAM, Serpins, CD44, CDC42, CXCR4, β1-integrin, FAK, ERK1/2, Wnt7), (C) Hypoxia-related macrophages (PD-L1 as potential target) and (E) Neutrophils (LOXL-4 presenting a potential target) Targets for dual inhibition and stimulation: (B) ECs could potentially dually targeted: VEGF signaling could be inhibited, while simultaneously promoting Ang-2 signaling. = Targets for stimulation: (D) M1-like macrophages should be promoted. All abbreviations can be found in the list of abbreviations. All figures were generated with Biorender.com.