Biological relevance of RGD-integrin subtype-specific ligands in cancer.

Integrins are heterodimeric transmembrane proteins able to connect the cells with the micro-environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg-Gly-Asp (RGD) peptide in their natural extracellular- matrix ligands, have been particularly investigated as tumoral therapeutic targets. In the last 30 years, intense research was dedicated to design specific RGD-like ligands able to discriminate selectively the different RGD-recognizing integrins. Efforts of chemists led to the proposition of modified peptide or peptidomimetic libraries to be used for tumor targeting and/or for tumor imaging.  Here we review, from the biological point of view, the rational underlying the need to clearly delineate each RGD-integrin subtype by selective tools. We describe the complex roles of RGD-integrins (mainly the most studied αvβ3 and α5β1 integrins) in tumors, the steps towards selective ligands and the current usefulness of such ligands. Although the impact of integrins in cancer is well acknowledged, the biological characteristics of each integrin subtype in a specific tumor are far from being completely resolved. Selective ligands may help to reconsider integrins as therapeutic targets in specific clinical settings.