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Angiogenesis

Basement membranes: structure, assembly and role in tumour angiogenesis

Key Points

  • Vascular basement membranes (BMs) are important structural and functional components of all blood vessels/capillaries and have a crucial role in determining the progression of cancer.

  • Constituents of vascular BMs, such as type IV collagen, laminin, SPARC and perlecan, have emerged as key regulators of angiogenesis.

  • Type IV collagen and laminin can exert both positive and negative regulation of angiogenesis, depending on their structural integrity and assembly.

  • Cryptic domains of type IV collagen can be liberated by proteolytic enzymes, such as matrix metalloproteinases, to expose novel integrin binding sites and angiogenesis inhibitory sequences.

  • Arrestin, canstatin, tumstatin and endostatin are novel BM-derived endogenous inhibitors of angiogenesis.

  • Not all vascular BMs are the same, providing a novel tissue-specific regulation of endothelial-cell behaviour and possibly the rate of cancer progression in a given organ.

Abstract

In recent years, the basement membrane (BM) — a specialized form of extracellular matrix (ECM) — has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.

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Figure 1: Basic structure of BM and its major constituents.
Figure 2: Schematic illustration of a BM scaffold formation outside the cell.
Figure 3: Matrix transitions during angiogenesis.
Figure 4: Integrin binding sites on various BM molecules.
Figure 5: Endogenous angiogenesis inhibitors derived from type IV collagen and type XVIII collagens.

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Acknowledgements

I wish to thank L. Siniski and M.A. Soubasakas for their assistance with the figures and preparation of this manuscript. The schematics (modified) in figures 2 and 4 were kindly provided by P. Yurchenco. This work is supported by National Institutes of Health grants to R.K., research funds of the Center for Matrix Biology and the Espinosa Liver Fibrosis Fund, and generous financial gifts from the Ann L. and Herbert J. Siegel Philanthropic Support of the Jewish Communal Fund and the Joseph Lubrano Memorial Goldfield Family Charitable Trust Donation.

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DATABASES

LocusLink

α1β1 integrin

α2β1 integrin

α5β1 integrin

αvβ3 integrin

β1 integrin

agrin

arrestin

canstatin

dystroglycan

endostatin

entactin

FGF

fibulins

laminin

MMP2

MMP9

mTOR

PDGF

perlecan

SPARC

thrombin

tumstatin

VEGF

OMIM

Alport syndrome

Goodpasture syndrome

FURTHER INFORMATION

BD Biosciences

National Institutes of Health

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Glossary

BASEMENT MEMBRANE

A term first used by ultrastructural histologists when they observed an amorphous, dense and proteinaceous structure that is present basolateral to various cells in many tissues. It is also known as the basal lamina.

EXTRACELLULAR MATRIX

(ECM). Fibres of proteins that are present between clusters of cells in all tissues. These proteins are long and filamentous, and provide tensile strength and channels for communication and movement of cells in a given tissue.

INTERSTITIUM

The space between epithelial monolayers in a given organ, usually separated by a basement membrane.

CRYPTIC

These domains are hidden within a folded or assembled protein structure.

PROTOMER

The basic building unit of collagens, including type IV collagen. A protomer consists of three α-chains, which wind around each other to form a triple-helical structure. They interact with each other to form networks.

LAMININ TRIMERS

The building unit of a laminin network is a trimeric cruciform-like structure that is composed of three polypeptides termed α, β and γ chains.

CAP-DEPENDENT TRANSLATION

Protein synthesis in eukaryotes is predominantly driven by cap-dependent translation of mRNA. More than 95% of protein synthesis in eukaryotes is accomplished by cap-dependent translation.

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Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3, 422–433 (2003). https://doi.org/10.1038/nrc1094

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