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Lipid rafts: integrated platforms for vascular organization offering therapeutic opportunities

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Abstract

Research on the nanoscale membrane structures known as lipid rafts is relevant to the fields of cancer biology, inflammation and ischaemia. Lipid rafts recruit molecules critical to signalling and regulation of the invasion process in malignant cells, the leukocytes that provide immunity in inflammation and the endothelial cells that build blood and lymphatic vessels, as well as the patterning of neural networks. As angiogenesis is a common denominator, regulation of receptors and signalling molecules critical to angiogenesis is central to the design of new approaches aimed at reducing, promoting or normalizing the angiogenic process. The goal of this review is to highlight some of the key issues that indicate the involvement of endothelial cell lipid rafts at each step of so-called ‘sprouting angiogenesis’, from stimulation of the vascular endothelial growth factor to the choice of tip cells, activation of migratory and invasion pathways, recruitment of molecules that guide axons in vascular patterning and maturation of blood vessels. Finally, the review addresses opportunities for future studies to define how these lipid domains (and their constituents) may be manipulated to stimulate the so-called ‘normalization’ of vascular networks within tumors, and be identified as the main target, enabling the development of more efficient chemotherapeutics and cancer immunotherapies.

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Abbreviations

ECs:

Endothelial cells

EPCs:

Endothelial progenitor cells

ECM:

Extracellular matrix

VEGF:

Vascular endothelial growth factor

LRs:

Lipid rafts

GPI:

Glycosylphosphatidylinositol

ssBLMs:

Solid-supported bilayer lipid membranes

Cav-1:

Caveolin-1

Cav:

Caveolin

PTRF:

Polymerase I and transcript release factor

VEGFR2:

Vascular endothelial growth factor receptor 2

KDR:

Kinase insert domain receptor

FLK1:

Fetal liver kinase 1

VEGFR1/Flt1:

Vascular endothelial growth factor receptor 1/fms-related tyrosine kinase 1

Prxs:

Peroxirederoxins

ROS:

Reactive oxygen species

MMP:

Metalloprotease

TACE:

Tumor necrosis alpha converting enzyme

MMPs:

Matrix metalloproteinases

uPAR:

Urokinase-type-plasminogen activator receptor

MT1-MMP:

Membrane-type-1-MMP

DEP1:

Density-enhanced tyrosine phosphatase

ERK1/2:

Extracellular signal-regulated kinase 1/2

Robos:

Roundabouts

UNC5B:

Unc-5 homolog B

Nrps:

Neuropilins

Slit1-3:

Slit homolog 1-3

RGMa:

Repulsive guidance molecule a

FLRT3:

Fibronectin and leucine rich transmembrane protein 3

Semas:

Semaphorins

vSMC:

Vascular smooth muscle cell

PDGFRβ:

Platelet-derived growth factor receptor β

S1P:

Sphingosine-1-phosphate

TGF β1:

Transforming growth factor-β1 (TGFβ1)

ALK1:

Activin receptor-like kinase 1

ALK5:

Activin receptor-like kinase 5

TIE2:

TEK tyrosine kinase

Ang:

Angiopoietin

n-3 PUFA:

n-3 polyunsaturated fatty acids

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Acknowledgments

This work was supported by grants of the Ente Cassa di Risparmio di Firenze to MDR, GF and GM; Istituto Toscano Tumori to MDR; Associazione Italiana Ricerca sul Cancro to MDR (AIRC Grant No. IG 2013 N. 14266); Brazilian FAPERJ to TDR. FM was supported by a post-doctoral joint fellowship of the European Union and Regione Toscana within the project UNIFI-4 MELOTAC.

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    1. Section of Experimental Pathology and Oncology, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy

      Anna Laurenzana, Gabriella Fibbi, Anastasia Chillà, Elisabetta Rovida, Mario Del Rosso & Francesca Margheri

    2. Institute of Complex Systems (ISC), Consiglio Nazionale delle Ricerche (CNR), Florence, Italy

      Giancarlo Margheri

    3. Department of Physics, Pontificia Universidade Catolica do Rio de Janeiro, Rio de Janeiro, Brazil

      Tommaso Del Rosso

    4. Istituto Toscano Tumori, Florence, Italy

      Mario Del Rosso

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    A. Laurenzana and G. Fibbi contributed equally to this work.

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    Laurenzana, A., Fibbi, G., Chillà, A. et al. Lipid rafts: integrated platforms for vascular organization offering therapeutic opportunities. Cell. Mol. Life Sci. 72, 1537–1557 (2015). https://doi.org/10.1007/s00018-014-1814-x

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