Glycobiology for cell targeting in hypoxia-dependent pathologic microenvironment
Abstract
Any organ needs oxygen presence and supply to survive and function. The 2019 Nobel Prize awarded to Gregg Semenza, Michael Kaelin and Sir Peter Ratcliffe 1-4 crowns research dedicated to identifying and deciphering the biological mechanisms that are both affected by and regulated by O2 supply, with the biological consequences of this regulation5. Diseases progression is enabled by the establishment of hypoxia in the cell microenvironment. Hypoxia is the partial oxygen pressure below the physiological value i.e. physioxia which depends on the needs to maintain the homeostasis in an organ or tissue.6 This concept is of fundamental importance, as physioxia values range from 11% in the pulmonary alveoli to 1% in the skin. When a mechanical or physiological damage occurs, gas exchange is affected compromising O2 supply, triggering the angiogenic "switch" by endothelial stress responsible for environmental conditioning and reorganization that is permissive for the continuation of the pathology. A great many pathologies depend on proangiogenic signal and endothelial damage to progress. Those include cancer, diabetes, endometriosis, cardiovascular disease, pulmonary insufficiency and nerve degeneration (Alzheimer’s disease, Parkinson’s disease, ALD, etc.). Cancer is the most widely documented pathology that progresses and becomes independent of immune control as soon as hypoxia is established. As O2 diffusion is limited to 100 μm, hypoxic signals appear very early during tumour growth. To compensate oxygen deficit angiogenesis is switched on but exacerbated proangiogenic factors by tumour cells destroy the equilibrium in favour of hyper-formation of vessels by budding, and various other mechanisms, including vascular mimicry by hypoxic tumour cells. New formed vessels in such anarchic angiogenesis are not functional, not allowing any blood flow and maintain the environment hypoxic, thus forcing in situ and/or recruited cells, as immune cells to evolve.
