Question

classify some of the inhibitors and activators of angiogenesis [VEGF, FGF, angiostatin, endostatin, thrombospondin] and their mechanism of actions

Answer 1

Angiogenesis is the formation of new blood vessels. It plays a major role in the growth of cancer, because more blood supply is necessery for formation of solid tumors, when they grow beyond a certain size. Tumors activate the blood supply by giving chemical signals which stimulate angiogenesis. Tumors also stimulate the neighbouring normal cells to produce angiogenesis signaling molecules.

The new blood vessels developed, nourish the growing tumor with oxygen and nutrients,by which the tumor enlarges and cancer cells invade the nearby tissues, they move throughout the body, forming new colonies of cancer cells, called metastasis.

To stop the growth of tumor cells scientists developed some drugs called angiogenesis inhibitors, they inhibit the growth of blood vesssels to tumor.

There are also angiogenesis activators , which helps in developing the blood vessels to tumor cells.

Angiogenesis activator examples are:- FGF, VEGF.

Angiogenesis Inhibitors:- Angiostatin, Endostatin, Thrombospondin.

Mechanism of action of FGF and VEGF :-

The fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), stimulates the endothelial cells to secrete many proteases and plasminogen activators, which helps in degrading the vessel basement membrane, allowing the cells to enter the surrounding matrix. The cells migrate, proliferate and gradually differentiate to form a new, lumen having vessel. Finally, the endothelial cells deposit a new basement membrane and secrete the growth factors, like platelet-derived growth factor (PDGF) which attract supporting cells like pericytes.( Pericytes stabilize and monitor the maturation of endothelial cells by direct communication between the cell membrane as well as by paracrine signaling.)

This is a complex process which involves the joint action of several other factors, like angiopoietins and ephrins, acting on specific receptors to regulate vessel stability.

Mechanism of action of Angiogenesis inhibitors:-

Angiogenesis inhibitors are specific, cancer-fighting agents because they block the growth of blood vessels which supports tumor growth instead of blocking the growth of tumor cells.

These inhibitors interfere or block the growth of blood vessels in several ways. In some cases there are monoclonal antibodies which specifically recognize and bind to VEGF. When VEGF gets attached to these drugs, it is unable to activate the VEGF receptor.

Other angiogenesis inhibitors bind to VEGF and/or its receptors and also to other receptors on the surface of endothelial cells or to other proteins in the signaling pathway, blocking their activities.

Some angiogenesis inhibitors are immunomodulatory drugs or agents who stimulate or suppress the immune system which has antiangiogenic properties.

In some cancers, angiogenesis inhibitors are more effective when they were combined with additional therapies.

Angiostatin- It is an endogenous angiogenesis inhibitor.it inhibits the formation of new blood vessels. it directly induces the apoptosis of endothelial cells by disturbing the normal adhesion contacts between the endothelial cells. Angiostatin also acts by inhibiting VEGF and basic fibroblast growth factor (bFGF).

Endostatin:- Endostatin is the carboxy-terminal fragment of collagen XVII. It induces apoptosis in endothelial cells and inhibits their migration to sites where new blood vessels are formed , by interfering the endothelial cell adhesion.

Thrombospondin:- Thrombospondins (TSP) 1and 2 were the first protein inhibitors of angiogenesis which were identified.  A major pathway in which TSP1 or TSP2 inhibits the angiogenesis is their interaction with CD 36 on endothelial cells, which leads to apoptosis of both the liganded ( ligand is a molecule which produces a signal by binding to a site on a target protein. ) and the adjacent cells.  The interaction of TSP1with its receptor, CD47, inhibits angiogenesis by antagonizing nitric oxide signaling in endothelial and vascular smooth muscle cells.The two independent pathways in which TSP-1 can block FGF-2 and VEGF angiogenic signals on endothelial cells.