Angiogenesis

mTOR Activation Promotes Angiogenesis

mTOR plays a key role in angiogenesis—the formation of new blood vessels to provide oxygen and nutrients to growing and dividing cells.^1-3

Specifically, mTOR controls the production of the HIF1-α and HIF1-β proteins, which are subunits of hypoxia-inducible factor (HIF), a master transcription factor that mediates the expression of a wide variety of genes whose products play a role in angiogenesis as well as cell metabolism, proliferation, motility, adhesion, and survival.^1-3

Two of the key gene products induced by HIF are vascular endothelial growth factors (VEGFs) and angiopoietin-2. VEGFs attract vascular endothelial cells to hypoxic areas where new blood vessels are needed, and orchestrate the formation of these blood vessels. Angiopoietin-2 destabilizes existing blood vessels so that they can "sprout" new extensions, which are created from the endothelial cells attracted and guided by VEGFs.¹

In normal cells, the process of angiogenesis is tightly controlled. In the presence of adequate oxygen—when additional blood vessel formation is not needed—HIF is rapidly inactivated and degraded; this process is primarily mediated by the von Hippel-Lindau (VHL) protein. In normal cells, excessive levels of HIF also lead to apoptosis.¹

The role of mTOR in angiogenesis.

In many cancers, angiogenesis is deregulated. This may occur because:

• mTOR is inappropriately "switched on" due to the abnormal activation of one or more of the upstream signaling pathways that regulate mTOR activity, resulting in overproduction of HIF^1,3
• The VHL protein is missing or defective, so HIF is not inactivated and degraded^{1, 3}

Increased levels of HIF1-α and HIF1-β have been shown to correlate with increased mortality in a number of tumor types, including cervical cancer, breast cancer, nonsmall cell lung cancer, ovarian cancer, head and neck cancer, and gastrointestinal stromal tumors.³ In addition, loss of the VHL protein, which also results in increased levels of HIF1-α, is a primary cause of many cases of renal cell carcinoma, and has been implicated in pancreatic cancer and neuroendocrine tumors (NET) as well.^4,5

Recently, activated mTOR was also shown in vitro and in animal models to upregulate production of VEGF-C, a key inducer of lymphangiogenesis.⁶ In cancer, lymphangiogenesis has been shown to play a causal role in lymph node metastasis. Inhibition of mTOR has been shown to significantly suppress lymph node metastasis in animal models.⁶