Normally, tissues demonstrate a slightly acidic intracellular pH (pHi) and slightly alkaline extracellular pH (pHe). However, proliferating tissues demonstrate transient pH Gradient Reversal i.e. alkalinization of pHi and acidification of pHe. Persistent and magnified pH Gradient Reversal is a hallmark of cancer. High acidic pHe is toxic to normal cells and beneficial to tumor cells giving them a proliferative advantage. It further augments tumorigenesis by upregulating proteolysis, genomic instability, immunosuppression, thereupeutic resistance and angiogenesis. A more basic pHi on the other hand protects tumors from acidic pHe induced apoptosis and enhances their proliferation. This event occurs quite early and is essential for tumorigenesis. It increases the activity of glycolytic enzymes, resulting in the augmented production of cancerous building blocks. It inhibits the cell cycle arrest mediated by DNA damage and promotes G2-M transition. This, allows for unrestricted proliferation and accumulation of genetic instability in tumor cells.
The pH Gradient Reversal can possibly be considered as the most distinct cancer specific abnormality and a mandatory event universally present in all kinds of cancerous cells and tissues. Furthermore, it is manifest even during the commencement of tumorigenesis and is essential for the survival and proliferation of tumors, irrespective of their pathology, genetics and origins. Based on these facts, we propose a novel hallmark of cancer – “pH gradient reversal”. A low salt diet enriched with fruits and vegetables due to its alkaline nature can minimize pH Gradient Reversal by the tumors, therby reducing their aggressive nature and therapeutic resistance. Moreover, therapies specifically targeting this tumor hallmark are likely to offer a valuable adjunct to the conventional ones focused exclusively on killing tumor cells, and even replace the older, more toxic and non-selective therapeutic strategies. We firlmy believe that this hallmark should be added to the list of already existing ones.