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Vascular normalisation as the stepping stone into tumour microenvironment transformation

Magnussen, Anette L., Mills, Ian G.·2021·British Journal of Cancer
DOI 10.1038/s41416-021-01330-zPMC PMC8329166
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Abstract

A functional vascular system is indispensable for drug delivery and fundamental for responsiveness of the tumour microenvironment to such medication. At the same time, the progression of a tumour is defined by the interactions of the cancer cells with their surrounding environment, including neovessels, and the vascular network continues to be the major route for the dissemination of tumour cells in cancer, facilitating metastasis. So how can this apparent conflict be reconciled? Vessel normalisation—in which redundant structures are pruned and the abnormal vasculature is stabilised and remodelled—is generally considered to be beneficial in the course of anti-cancer treatments. A causality between normalised vasculature and improved response to medication and treatment is observed. For this reason, it is important to discern the consequence of vessel normalisation on the tumour microenvironment and to modulate the vasculature advantageously. This article will highlight the challenges of controlled neovascular remodelling and outline how vascular normalisation can shape disease management.

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Fig. 1 Schematic illustration of the vascular network undergoing sprouting or intussusceptive angiogenesis. The two mechanism of angiogenesis are not always exclusive, and a tumour can present characteristics of both, especially after anti-angiogenic therapy. On the left the cartoon illustrates how endothelial filaments called sprouts extending into the extravascular space. The accompanying confocal microscope image shows a filamentous bridge between two capillaries across the extracellular space. The endothelial cells and filaments are positive for PECAM-1 (green) and α5β1 integrin (red) in the Rip-Tag2 mouse model of pancreatic cancer. The cartoon on the right magnifies the cylindrical microstructures spanning the lumen of a capillary that are the distinctive feature of intussusception. For reasons not well understood endothelial cells on opposite sides on the lumen start to bulge until they meet to create the intussusceptive pillar. In the scanning electron micrograph on the right, those pillars appear as tiny holes on the outer surface on the vessel. The vascular casts of a colon tumour xenograft model reveal those very characteristic tiny holes of intussusceptive angiogenesis in the larger capillaries. The small diameter of ≈3–5 µm exclude them as mesh-structure in the vasculature. At this point, intussusceptive angiogenesis seems favoured over endothelial cell sprouting in those capillaries.
Fig. 1 Schematic illustration of the vascular network undergoing sprouting or intussusceptive angiogenesis. The two mechanism of angiogenesis are not always exclusive, and a tumour can present characteristics of both, especially after anti-angiogenic therapy. On the left the cartoon illustrates how endothelial filaments called sprouts extending into the extravascular space. The accompanying confocal microscope image shows a filamentous bridge between two capillaries across the extracellular space. The endothelial cells and filaments are positive for PECAM-1 (green) and α5β1 integrin (red) in the Rip-Tag2 mouse model of pancreatic cancer. The cartoon on the right magnifies the cylindrical microstructures spanning the lumen of a capillary that are the distinctive feature of intussusception. For reasons not well understood endothelial cells on opposite sides on the lumen start to bulge until they meet to create the intussusceptive pillar. In the scanning electron micrograph on the right, those pillars appear as tiny holes on the outer surface on the vessel. The vascular casts of a colon tumour xenograft model reveal those very characteristic tiny holes of intussusceptive angiogenesis in the larger capillaries. The small diameter of ≈3–5 µm exclude them as mesh-structure in the vasculature. At this point, intussusceptive angiogenesis seems favoured over endothelial cell sprouting in those capillaries.CC BY · PubMed Central
Fig. 2 Schematic illustration of the vascular network in its normal, abnormal and normalised state. Angiogenic and anti-angiogenic factors are finely tuned in healthy tissues to create an organised vessel structure and to maintain vascular function. In tumours, the angiogenic switch has taken place and the balance has tipped in favour of angiogenic factors. As a result, the structure of neovessels is abnormal on all levels, with highly impaired vascular function. In the normalised state, angiogenic and anti-angiogenic factors are nearly balanced and vascular function is transiently re-established.
Fig. 2 Schematic illustration of the vascular network in its normal, abnormal and normalised state. Angiogenic and anti-angiogenic factors are finely tuned in healthy tissues to create an organised vessel structure and to maintain vascular function. In tumours, the angiogenic switch has taken place and the balance has tipped in favour of angiogenic factors. As a result, the structure of neovessels is abnormal on all levels, with highly impaired vascular function. In the normalised state, angiogenic and anti-angiogenic factors are nearly balanced and vascular function is transiently re-established.CC BY · PubMed Central
Fig. 3 Illustration of the major signalling pathways that either control angiogenesis and therefore represent potential targets for anti-angiogenic intervention. In normal tissues, prolyl hydroxylases (PHDs) hydroxylate hypoxia-inducible factor (HIF)-1α; the level of HIF-1α is low or it gets degraded. Hypoxia, however, prevents the hydroxylation and HIF-1α levels rise. The HIF-1α/β complex binds to the hypoxia-response element (HRE) of the gene promoter for transactivation and expression of angiogenic factors, prominent among which are VEGF/VEGFR-2 and other activated tyrosine kinase receptors that determine cell survival, proliferation and cell motility. Tie2 and Ang-1 are vital for maturation and maintenance of the neovessels. Ang-2 in combination with VEGF promotes neovascularisation, but in the absence of VEGF triggers vessel regression. Neuropilin-1 is the specific receptor for class 3 Semaphorin (Sema) proteins. The anti-angiogenic Sema3/neuropilin complex controls endothelial cell motility by negatively regulating cytoskeletal events via small GTPase signalling. VEGF-dependent Notch-1/DLL4 receptor activation specifies endothelial cell fate. In cells with high Notch-1 activation the angiogenic potential is lowered, those cells remain quiescent, in cells with low Notch-1 activation the angiogenic potential is raised and they become sprouting cells. The pathways that regulate angiogenesis are interlinked.
Fig. 3 Illustration of the major signalling pathways that either control angiogenesis and therefore represent potential targets for anti-angiogenic intervention. In normal tissues, prolyl hydroxylases (PHDs) hydroxylate hypoxia-inducible factor (HIF)-1α; the level of HIF-1α is low or it gets degraded. Hypoxia, however, prevents the hydroxylation and HIF-1α levels rise. The HIF-1α/β complex binds to the hypoxia-response element (HRE) of the gene promoter for transactivation and expression of angiogenic factors, prominent among which are VEGF/VEGFR-2 and other activated tyrosine kinase receptors that determine cell survival, proliferation and cell motility. Tie2 and Ang-1 are vital for maturation and maintenance of the neovessels. Ang-2 in combination with VEGF promotes neovascularisation, but in the absence of VEGF triggers vessel regression. Neuropilin-1 is the specific receptor for class 3 Semaphorin (Sema) proteins. The anti-angiogenic Sema3/neuropilin complex controls endothelial cell motility by negatively regulating cytoskeletal events via small GTPase signalling. VEGF-dependent Notch-1/DLL4 receptor activation specifies endothelial cell fate. In cells with high Notch-1 activation the angiogenic potential is lowered, those cells remain quiescent, in cells with low Notch-1 activation the angiogenic potential is raised and they become sprouting cells. The pathways that regulate angiogenesis are interlinked.CC BY · PubMed Central
Fig. 4 Anti-angiogenic treatment is approved by the FDA for the treatment of advanced cancers after conventional chemotherapy has failed or if cancer has metastasised (last reviewed 2019 source NIH, cancer.gov). Only three anti-angiogenic dugs are applied in combination with traditional chemotherapy (bevacizumab, lenvatinib mesylate, ramucirumab). Thalimodide and lenvatinib mesylate are the only two treatments that are used in the early stages following diagnosis or as a first-line treatment and if surgery is not an option. The vast majority of anti-angiogenic drugs are tyrosine kinase inhibitors with some of them acting specifically on the VEGFR-2 receptor.
Fig. 4 Anti-angiogenic treatment is approved by the FDA for the treatment of advanced cancers after conventional chemotherapy has failed or if cancer has metastasised (last reviewed 2019 source NIH, cancer.gov). Only three anti-angiogenic dugs are applied in combination with traditional chemotherapy (bevacizumab, lenvatinib mesylate, ramucirumab). Thalimodide and lenvatinib mesylate are the only two treatments that are used in the early stages following diagnosis or as a first-line treatment and if surgery is not an option. The vast majority of anti-angiogenic drugs are tyrosine kinase inhibitors with some of them acting specifically on the VEGFR-2 receptor.CC BY · PubMed Central

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Metadata

Authors
Magnussen, A. L., & Mills, I. G.
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2021-04-07
Volume
125
Issue
3
Pages
324-336
ISSN
  • 0007-0920
  • 1532-1827
DOI
10.1038/s41416-021-01330-z
PMC
PMC8329166
Cited by
146
References
12
Language
en
Licence

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