Cancerous cells are unable to generate their ATP through the aerobic glycolytic pathway, therefore they try to compensate for that through anaerobic facet. The product is lactic acid and the accumulation of this lactic acid leads to a low pH. What gives the microenvironment of cancerous cells their acidity is Lactic acid.
I am sorry to disagree with Dr Temitope Adelusi. Cancer cells retain the possibility of OX-PHOS. As a matter of fact Warburg found that almost 50% of energy in cancer cells came from oxydative phosphorylation. The other 50% came from aerobic glycolysis.
Aerobic glycolysis is not the consequence of COMPENSATION DUE TO ENERGY SHORTAGE, but it is the direct result of oncogenic mutations and oncogenic pathways that enhance the expression of glycolyic enzymes. Increased expression of HIF 1 is an important responsible of the whole process of aerobic glycolisis and represents a consequence of oncogenic mutations.
Increased extracellular acidity with normal or slightly alkaline intracellular pH is a consequence of increased intracellular acid production (through hydrolisis of ATP) that is quickly exported to the extracelluar media thanks to incresed expression and increased activity of ion transporters like NHE-1 and VGSCs and proton pumps. All these transporters are highly expressed on the invadopodia complex.
The 'why/how' conundrum to cancer's pH hallmark starts making a lot more sense when we look at acid base from the perspective of the Stewart Kellum model. You should be able to source the 2nd edition of the Stewart Kellum book in your medical school/university library. There are a number of Stewart papers too on CO2/SIG/TotWeak Acid ...and here is a website http://www.acidbase.org
Peritumoral acidity is immunosuppressive and helps tumors to evade immune responses.
To serve tumor fitness.
Tumor acidity blunts immune system, mediates cancer chemotherapy resistance and develops metastasis.
So mutations are responsible of the activation of pathways able to enhance glycolytic enzymes leading to the glycolitic phenotype (metabolic reprogramming) of cancer cells. Cancer cells will produce energy mainly by glycolysis and lactate production rather than glycolysis followed by oxidation of piruvate in mitochondria (Warburg Effect), even if oxygen levels are normal. Lactate and protons begin to accumulate leading to acidosis.
It is known that hypoxia is able to induce the expression of HIF (Hipoxia Inducible Factor) that controls the expression of certain genes including several glycolytic enzymes and glucose transporters that will contribute to the Warburg Effect
But is hypoxia a consequence of the insufficient supply of oxygen due to rapidly proliferating tumor cells or are there other reasons?
Lactate exportation from cancer cells is the responsible for the acidic microenvironment of cancer cells. Lactate is the obligatory by-product of glycolysis and the Warburg effect increases glycolysis and therefore lactate production. Lactate is further exported from cancer cells by MCT-1 and MCT-4 transporters. This acidic environment inhibits immune response and also regulates exosomes production, therefore highly involved in the regulation of metastasis.
My understanding is that the acidic microenvironment of cancer cells is a consequence of their metabolic state. Cancer cells are predominantly glycolytic, leading to the production of lactic acid. Although glycolysis is less efficient at generating ATP when compared to mitochondrial OXPHOS, proliferative cells prefer glycolysis because in addition to ATP it also provides most of the building blocks required for cell proliferation.
Here is a paper showing that when glucose is no longer available cells switch from glycolysis to OXPHOS, resulting in the cessation of cell proliferation.
Alexandra I Mot : I think you're talking about the oxidative phenotype. I'd suggest :
In actively proliferating tumors, cells distant from blood vessels become hypoxic because of insufficient oxygen supply. As anaerobic glycolysis is the major source of energy in these hypoxic cells, the accumulation of lactate, a final metabolite of glycolysis, makes these cells acidic. These hypoxic and acidic cells are resistant to radiotherapy, and these tumors can recur when the tumor cells become reoxygenated after the tumor volume is reduced.
If such hypoxic and acidic cells could be radiosensitized, recurrence might be reduced and the effects of radiotherapy be improved. We previously showed that a low pH culture condition enhances the radiosensitizing effect of wortmannin (PI-3K inhibitor).
Central University of Punjab
Isabelle - Müller
Fresenius Medical Care Deutschland GmbH, St. Wendel
Goodwin G. Jinesh
University of Texas MD Anderson Cancer Center
Laco Science Institute
Balraj Singh Gill
Arash Davari Serej
The Institute of Molecular Genetics, CNR, Pavia, Italy
Xuzhou Medical University （徐州医科大学）
Abant İzzet Baysal Üniversitesi
Ain Zubaidah Ayob
University of Malaya
An error occurred while rendering template.