Review Article | Published:

Microenvironmental regulation of tumour angiogenesis

Nature Reviews Cancer volume 17, pages 457474 (2017) | Download Citation

Abstract

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

Key points

  • Malignant progression of benign tumours is typically associated with an angiogenic switch — the transition from a quiescent to a proliferative vasculature. The de novo recruitment of various innate immune cells was shown to trigger the angiogenic switch in mouse tumour models.

  • Macrophages are important pro-angiogenic cells in the tumour microenvironment. They promote tumour angiogenesis mainly by secreting pro-angiogenic growth factors and facilitating the degradation of the perivascular extracellular matrix.

  • Neutrophils and immature myeloid cells have important roles during the initial angiogenic switch in experimental tumour models. They were also found to sustain tumour revascularization in the context of anti-angiogenic therapy.

  • B cells and T cells may either promote or limit tumour angiogenesis depending on the specific subtype and activation state. In the context of immunotherapy, they may induce the regression of tumour blood vessels.

  • Tumour blood vessels typically display scant pericyte coverage. However, pericytes provide pro-survival cues to angiogenic blood vessels, and their pharmacological targeting improves tumour response to anti-angiogenic therapy.

  • Cancer-associated fibroblasts produce the extracellular matrix and are an important source of pro-angiogenic factors and myeloid cell chemoattractants in the tumour microenvironment.

  • Adipocytes stimulate peri-tumoural angiogenesis by secreting pro-inflammatory and pro-angiogenic cytokines, and by releasing fatty acids that are consumed by angiogenic endothelial cells.

  • The extracellular matrix conveys both pro-angiogenic and angiostatic signals to tumour blood vessels.

  • The metabolic properties of cancer cells and tumour-associated stromal cells influence angiogenesis in many ways (for example, by regulating glucose bioavailability to angiogenic blood vessels).

  • Vascular heterogeneity is a hallmark of cancer and is determined by multiple factors, including the specific organ and tissue in which the tumour arises, the composition of tumour-associated stromal cells, as well as the nature, diversity and relative abundance of pro- and anti-angiogenic mediators.

  • Tumour-associated stromal cells modulate tumour responses to anti-angiogenic therapy.

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Acknowledgements

Work in the authors' laboratories is mainly supported by the European Research Council (to M.D.P.), the Swiss National Science Foundation (grants 31003A-165963 to M.D.P.; 31003A-156266, 31ER30-160674 and 316030-164119 to T.V.P.), the Swiss Cancer League (grants KFS-3759-08-2015 to M.D.P.; KLS-3406-02-2014 to T.V.P.), the Leenaards Foundation, the San Salvatore Foundation, and the Swiss Bridge Foundation (to M.D.P. and T.V.P.).

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Affiliations

  1. The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

    • Michele De Palma
    •  & Daniela Biziato
  2. Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Division of Experimental Pathology, University of Lausanne and University of Lausanne Hospital, 1066 Lausanne, Switzerland.

    • Tatiana V. Petrova

Authors

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  2. Search for Daniela Biziato in:

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Contributions

M.D.P. conceived and wrote the article and display items. T.V.P. contributed to discussions of the content and writing of the article. M.D.P., D.B. and T.V.P. researched the data for the article. M.D.P., D.B. and T.V.P. reviewed and edited the article before submission.

Competing interests

M.D.P. and T.V.P. have received research grants from Hoffmann-La Roche to investigate angiogenesis and macrophage inhibitors.

Corresponding authors

Correspondence to Michele De Palma or Tatiana V. Petrova.

Glossary

Hypoxia

The condition of low oxygen availability. In tumours, hypoxia is observed in cancer cells that reside more than 70–150 μm away from a perfused blood vessel.

Pro-angiogenic factors

Biological molecules that stimulate endothelial cell proliferation and angiogenesis.

Anti-angiogenic factors

Biological molecules that block angiogenesis or promote the regression of angiogenic blood vessels.

Pericyte

Cell that enwraps and promotes the survival of endothelial cells, stabilizing small blood vessels.

Tumour microenvironment

(TME). The complex and dynamic ensemble of cancer cells, tumour-associated stromal cells (TASCs; comprising primarily leukocytes, fibroblasts and vascular cells) and their extracellular products.

Progenitors

Undifferentiated cells capable of producing lineage-committed cellular progeny.

Damage-associated molecular patterns

(DAMPs). Biological molecules that can initiate an inflammatory response independently of infection.

Clodronate liposomes

A formulation of small lipid vesicles containing a bisphosphonate that is capable of inducing macrophage death upon engulfment.

Angiostatic functions

Properties that promote endothelial cell quiescence and limit angiogenesis.

RIP1–Tag2 transgenic mice

Expression of the SV40 large T antigen (Tag) under the control of the rat insulin promoter (RIP) causes β-cell hyperplasia, which progresses through a series of rate-limiting stages to invasive pancreatic neuroendocrine tumour (PNET).

Vascular guidance

The guided, directional growth of blood vessels.

Vascular mimicry

The process whereby vascular-like channels are formed by non-endothelial cells in certain tumours, namely melanomas.

Non-thrombogenic EC-like surfaces

Cellular surfaces capable of preventing the formation of a clot (or thrombus) when in contact with blood.

Type I interferon

A family of secreted proteins with antiviral and immunomodulatory functions, which bind to a common receptor.

Genetically engineered mouse models (GEMMs) of cancer

Transgenic mice in which cancer is initiated and driven by defined genetic alterations, such as the expression of oncogene(s) and/or the inactivation of tumour suppressor gene(s), or both.

Immunocompetent mice

Mice that have an intact immune system. They are permissive to the growth of transplanted tumours with matched genetic background (syngeneic tumours).

T helper 1 (TH1) cells

T cells that can stimulate other immune cells, such as macrophages and cytotoxic T lymphocytes, to kill infected or cancer cells. They do so primarily through the release of the TH1 cytokine interferon-γ.

TH2 cells

T cells that stimulate B cells to produce immunoglobulins. They do so through the release of TH2 cytokines, such as interleukin-4.

Cytotoxic T lymphocytes

(CTLs). T cells capable of killing other cells, including cancer cells, generally through the recognition of specific antigens.

Cancer immunosurveillance

The process whereby immune cells, namely lymphocytes and natural killer cells, recognize initiated cancer cells and eliminate them; it may also lead to the selection of less immunogenic cancer cell clones.

Lipolysis

The process whereby triglycerides are resolved into glycerol and free fatty acids through hydrolysis.

β-Oxidation

The process that occurs in the mitochondrion and that uses fatty acids to generate acetyl-CoA, which is essential for producing ATP through oxidative phosphorylation.

Glycolysis

The metabolic process that occurs in the cell cytoplasm and that uses glucose to generate pyruvate and the high-energy molecules ATP and NADH; in the presence of oxygen, pyruvate may enter the mitochondrion to sustain oxidative metabolism.

Reactive oxygen species

(ROS). Chemically reactive molecular species that contain oxygen; by reacting with biological molecules, ROS can alter their structure and function.

Oxidative metabolism

The metabolic processes that converge on oxidative phosphorylation to produce ATP.

Extracellular vesicles

(EVs). The heterogeneous assortment of secreted vesicles produced by virtually any cell type through diverse biogenesis processes.

Tetraspanins

A family of transmembrane proteins that organize microdomains enriched in membrane-bound signalling proteins.

Orthotopic tumour transplant

An experimental tumour that results from the injection of cancer cells into the tissue or organ from which the cancer cells were originally derived.

Ectopic tumour transplant

An experimental tumour that results from the injection of cancer cells into an anatomical site that is different from the one from which the cancer cells were originally derived. Generally, ectopic tumours are inoculated in the subcutaneous space.

TH17 cells

T cells that have roles in protecting organ surfaces, in particular the gut mucosa, from pathogens. They produce interleukin-17 and stimulate B cell-mediated humoral immunity.

Immune checkpoint

A ligand–receptor pair that either activates or inhibits a stimulatory signal for lymphocytes, resulting in the activation or suppression of an immune response.

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DOI

https://doi.org/10.1038/nrc.2017.51

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