Plasmalemmal vacuolar H+-ATPases in angiogenesis, diabetes and cancer.

Angiogenesis, i.e., new blood vessel formation, is required in normal and pathological states. A dysfunction in the microvascular endothelium occurs in diabetes, leading to decreased blood flow and limb amputation. In cancer, angiogenesis is increased to allow for growth, invasion, and metastasis of tumor cells. Better understanding of the molecular events that cause or are associated with either of these diseases is needed to develop therapies. The tumor and angiogenic cells micro-environment is acidic and not permissive for growth. We have shown that to survive this environment, highly metastatic and angiogenic cells employ vacuolar H+-ATPase at their plasma membranes (pmV-ATPases) to maintain an alkaline pHcyt. However, in lowly metastatic and in microvascular endothelial cells from diabetic model, the density of pmV-ATPase and the cell invasiveness are decreased. Therefore, the overexpression of the pmV-ATPase is important for cell invasion, and essential for tumor progression, angiogenesis and metastasis. Both, cancer and diabetes are heterogenous diseases that involve many different proteins and signaling pathways. Changes in pHcyt have been associated with the regulation of a myriad of proteins, signaling molecules and pathways affecting many if not all cellular functions. Since changes in pHcyt are pleiotropic, we hypothesize that alteration in a single protein, pmV-ATPase, that can regulate pHcyt may explain the dysfunction of many proteins and cellular pathways in diabetes and cancer. Our long term goal is to determine the molecular mechanisms by which pmV-ATPase expression regulates tumor angiogenesis and metastasis. Such knowledge would be useful to identify targets for cancer therapy.