Question

Because of oxygen and nutrient requirements, cells in a tissue must reside with 100 µm of a blood vessel. Based on this information, explain why many malignant tumors often possess gain-of-function mutations in one of the following genes: bFGF, TGFa and VEGF.

Answer 1

TUMOR ANGIOGENESIS

In Cancer, formation of new vascular network is important as the proliferation and metastatic spread of Cancer cells depend on the availability of of oxygen, nutrients and removal of waste products.

This is accomplished by processes- lymphangiogenesis and angiogenesis. These processes are mediated by activators and inhibitors.

The level of expression of angiogenic factors by the tumor cells indicate the aggressiveness of the tumor cells. Therefore, anti-angiogenic treatments can be used in treating tumors that have high levels of expression of angiogenic factors, though practical efficiency has not been proven.

In the absence of vascular support, like any other cell, the tumor cells also become necrotic or even apoptotic.

The diagram represents tumor angiogenesis.

The tumor cells(shown green) secrete angiogenic factors like VEGF(Vascular endothelial growth factor), bFGF(Basic fibroblastic growth factor) and other angiopoetins(substances that induce angiogenesis).

These stimulate the endothelial cells to proliferate and migrate. Stroma is also an additional source of angiogenic factors.

Tumor associated fibroblasts also secrete chemokines such as Stromal cell derived fibroblasts, SDF-1,that cause recruitment of Bone Marrow derived angiogenic cells(BMCs).

BMCs may also be recruited by VEGF.

Tumor cells also secrete PDGF A and C(Platelet derived growth factor), Transforming Growth Factor b(TGFb), which are stromal recruitment factors.

Endothelial cells produce PDGF B, that promote pericytes recruitment to the microvasculature.

All these increase the concentration of angiogenic factors that finally result in increased vascularization or angiogenesis.

Thus, tumor cells possessing gain of function mutation and expressing high levels of VEGF, TGFb and bFGF have the ability to induce angiogenesis near them by the above mechanism and therefore they ensure continuous supply of adequate amounts of nutrients and oxygen.