O2 sensing and angiogenesis Flashcards
Oxygen essential component for life on earth
Proving fundamantal element in the survival of aerobic organisms
The circulatory system provides an important mechanism for the transport of oxygen to the cells of the body
with blood vessels acting as the transport routes for delivery of oxygen to the tissues
Angiogenesis describes the formation of new blood vessels from pre-existing vessels
Following discovery in 1971 by Folkov, the phenomenon was initially thought to be a non-specific by-product of inflammation
However the research community has since recongised the importance of angiogenesis in health and disease
In healthy individuals, angiogenesis is involved in processes such as wound healing response, embyrogenesis and ovarian follicle development
In disease states
Angiogenesis can play a role in disease progression with cancer the primary candidate
Cancer is the second leading cause of death worldwide
1 in 2 will get it
1 in 4 will die from it
Emphasising need to understand mechanism
To make new therapies
The early work of Gimbrone (1972)
Demonstrated the ability of cancer cells to hijack angiogenesis in the absence of inflammation
Implanting cancer cells in an avascular site was shown to trigger vessel sprouting, essential for tumour growth
Angiogenesis in cancer leads to
development of immature, structurally unsound blood vessels
Impaired nutrient and oxygen delivery
Oncogenes
Mutated genes in cancer
Normal function in cell growth
Mutated leads to uncontrolled proliferation
KRAS and EGFR
Pro-angiogenic
Upregulate VEGF
VEGF
Potent angiogenic factor
HIF pathway target gene
HIF
Oxygen sensing
Cancer development
HIF stabilised in hypoxia
Hypoxia - VEGF transcription
Promotes angiogenesis
Tumour progression
Most tumours arise as avascular masses
Oxygen by diffusion
Become hypoxic - HIF - VEGF
Angiogenesis activated
Pathological angiogenesis
Intensifies hypoxia
Therapy resistance
Excessive angiogenesis promotes hypoxia
Metastasis
Angiogenesis provides an exit mechanism for cancer cells to invade other tissues and distant organs
Angiogenic switch activated by hypoxia
Dormant cancer cells regain tumourgenic potential
Oxygen sensing pathways
mTOR
AMP/ADP
AMPK - mTOR
upstream reg of HIF-VEGF
Unfolded protein response - severe hypoxia
Blocking HIF and angiogenesis
Simultaneous blockade of HIF and angiogenesis
Improve patient outcome
Disrupt feed forward loop of HIF hypoxia and metastasis
HIF1 - digoxin
HIF2 - belzutifam
VEGF - bevacizuma
