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Integrins in angiogenesis and lymphangiogenesis

Key Points

  • Angiogenesis and lymphangiogenesis have important roles in cancer progression: angiogenesis, the growth of new blood vessels, promotes tumour growth and tumour metastasis, and lymphangiogenesis, the growth of new lymphatic vessels, promotes tumour metastasis. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface adhesion receptors.

  • The integrin family is an extensive group of structurally related receptors for extracellular matrix proteins and immunoglobulin superfamily molecules. Integrin ligation promotes intracellular signal transduction, cell migration and survival in angiogenesis and lymphangiogenesis.

  • A number of endothelial cell integrins regulate angiogenesis in diverse manners, including integrins α1β1, α2β1, α4β1, α5β1, α9β1 and α6β4. αv integrins are also important in angiogenesis, although the exact nature of these roles is hotly disputed. Expression and function analysis of αv integrins in wild-type animals using integrin antagonists as well as analysis of knock-in mutant mice indicate that αv integrins promote angiogenesis, whereas genetic deletion studies suggest that αv integrins are not required for angiogenesis.

  • Although less is known about the integrins that regulate lymphangiogenesis, integrin α9 is required for normal developmental lymphangiogenesis. Integrins α4β1, α2β1 and α1β1 have also been implicated in the regulation of tumour lymphangiogenesis.

  • Integrins on bone marrow-derived myeloid cells can also promote angiogenesis. Circulating bone marrow-derived cells migrate into tumours in response to tumour-secreted chemokines and cytokines and integrins α4β1 and αMβ2 (CD11b) have key roles in this process, indirectly influencing tumour angiogenesis.

  • Antagonists of several integrins, including αvβ3, αvβ5 and α5β1, are currently under investigation as clinical agents to suppress tumour angiogenesis and growth either alone or in combination with current cancer therapeutics.

Abstract

Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.

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Figure 1: Mechanisms regulating angiogenesis and lymphangiogenesis.
Figure 2: Myeloid cells promote angiogenesis.

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Acknowledgements

This work was supported by NIH grants R01CA83133 and R01CA126820 to J.V. and a postdoctoral research fellowship from the California Breast Cancer Research Program to B.G.-S.

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Correspondence to Judith A. Varner.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

glioblastoma

melanoma

multiple myeloma

non-small cell lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

renal cell carcinoma

National Cancer Institute Drug Dictionary

Abegrin

ATN-161

Avastin

cilengitide

CNTO 95

dacarbazine

volociximab

FURTHER INFORMATION

CNTO 95 clinical trial

Integrin inhibitors: rationale for development and clinical results in patients with solid tumors (Ronald M. Bukowski)

Cilengitide clinical trial

Glossary

Peyer's Patches

Secondary lymphoid organs, named after the 17th century Swiss anatomist Joseph Conrad Peyer, that are comprised of round lymphoid follicles in the mucosa of the small intestine.

Angiogenic switch

The induction of new blood vessel sprouting at an early time point in tumour development that leads to rapid, exponential tumour growth.

Chick chorioallantoic membrane

A thin, highly vascularized fetal membrane formed by fusion of the chorion and allantois in fertilized chicken eggs that is often used to evaluate pro- and anti-angiogenic agents.

Choroidal angiogenesis

The development of new blood vessels in the highly vascular area of the eye that lies between the retina and the sclera.

Teratoma

A germ cell tumour composed of undifferentiated and differentiated cells derived from the three germ layers: mesoderm, ectoderm and endoderm. Teratomas may include hair, teeth and other complex structures.

Forskolin

A diterpene derived from the Indian coleus plant that raises cAMP levels in cells by activating adenyl cyclase.

Posterior somites

Cuboidal, segmented masses of mesoderm organized in pairs and distributed along the developing neural tube. Posterior somites give rise to the thoracic, lumbar and sacral vertebrae.

Pericyte

A mesenchymal cell precursor to vascular smooth muscle that associates with endothelial cells during angiogenesis and provides support to small capillaries.

Hemidesmosome

An organized adhesive structure on the surface of epithelial cells comprising integrin α6β4 attached on the exterior of the cell to laminin and on the interior of the cells to plectin and cytosolic keratins.

Alpha granules

Endosomes or granules in platelets that contain growth factors such as VEGF, TGFβ and PDGF.

Humanized antibody

A humanized antibody is a synthetic monoclonal antibody comprised of a human antibody backbone fused with the antigen recognition regions of a mouse monoclonal antibody through recombinant DNA techniques, which is developed to eliminate immunogenic sequences.

Leiomyosarcoma

A neoplasm comprising tumour cells arising from smooth muscle (sarcoma) and frequently found in the stomach and small intestines.

Dacarbazine

A chemotherapeutic, DNA-alkylating agent used in the treatment of malignant melanoma and Hodgkin disease.

PEGylated

Covalently modified with poly(ethylene glycol) to make a hydrophobic drug more soluble and to mask a drug from the host immune system.

Microbubbles

Small (≥3 μm) gas-filled bubbles that serve as contrast-enhancing agents in diagnostic medical ultrasound imaging.

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Avraamides, C., Garmy-Susini, B. & Varner, J. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8, 604–617 (2008). https://doi.org/10.1038/nrc2353

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