Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival
Loading...
Date
2023-01
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis,
and the end product of this pathway is fermented into lactate which accumulates
in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells
cannot use lactate; therefore, they dump it into the TME and subsequently
augment the acidity of the tumour milieu. Furthermore, the TME acts as a
lactate sink with stope variable amount of lactate in different pathophysiological
condition. Regardless of the amount of lactate pumped out within TME, it
disappears immediately which still remains an unresolved puzzle. Recent
findings have paved pathway in exploring the main role of lactate acidosis in
TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to
initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the
suppression of immunity. Furthermore, lactate re-programme the lipid
biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately
hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer
cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity
secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic
cancer cells whereas it is converted back to PUFAs after a sequence of reactions
and then liberated in the TME to be utilized in the severely hypoxic cancer cells.
Although much is known about the role of lactate in these biological processes, the
exact molecular pathways that are involved remain unclear. This review attempts
to understand the molecular pathways exploited by lactate to initiate angiogenesis,
invasiveness, suppression of immunity and cause re-programming of lipid
synthesis. This review will help the researchers to develop proper understanding
of lactate associated bimodal regulations of TME.