1.6. Acidosis:
Acidification of the tumor microenvironment is related to metabolic
adaptation and reprogramming [148]. Moreover, tumor acidosis affects
metastasis, invasion, and therapeutic response and can act as a
regulator of tumor progression [148]. Tumor cells have high
metabolic demands that lead to the accumulation of a high amount of\(\ \)n the TME, and due to the disordered nature of tumor vasculature,
effective removal of \(H^{+}\)from the extracellular environment is prevented, accordingly, the
accumulation of \(H^{+}\) ions in the TME is intensified [148, 149].
Consequently, it causes hypoxic conditions and changes in glycolytic
metabolism. In addition, in areas where oxidative conditions prevail,
the accumulation of \(H^{+}\) causes the hydration of carbon dioxide,
which meets the bioenergetic and biosynthetic needs of cancer cells,
these processes happen at a high speed [148]. Low pH in TME can
promote the motility of cancer cells and subsequently, influence
fibroblasts and activity and polarization of macrophages by bringing
about alterations in cytoskeletal dynamics [150]. In tumor regions
where the lowest pH conditions prevail, the highest rate of invasion can
occur and vice versa [148]. To adapt to the acidic environment,
tumor cells employ all enzyme systems [106]. In general, the
establishment of acidic conditions in the TME involves two events: CO2
by respiration and lactic acid formed by glycolytic metabolism
[106]. Evidence shows that acidic conditions overlap both in hypoxic
areas and at the tumor-stroma interface, which strongly influences tumor
invasion and proliferation [151]. Moreover, according to multiple
evidence, the conditions of extracellular acidosis create a suitable and
beneficial environment for dormant tumor cells to support the survival
of disseminated tumor cells and the formation of metastasis, and
subsequently, the chemotherapy-resistant phenotype is maintained [106,
152].