Understanding metabolic alterations and heterogeneity in cancer progression through validated immunodetection of key molecular components: a case of carbonic anhydrase IX

Abstract

Cancer metabolic heterogeneity develops in response to both intrinsic factors (mutations leading to activation of oncogenic pathways) and extrinsic factors (physiological and molecular signals from the extracellular milieu). Here we review causes and consequences of metabolic alterations in cancer cells with focus on hypoxia and acidosis, and with particular attention to carbonic anhydrase IX (CA IX). CA IX is a cancer-associated enzyme induced and activated by hypoxia in a broad range of tumor types, where it participates in pH regulation as well as in molecular mechanisms supporting cancer cells’ invasion and metastasis. CA IX catalyzes reversible conversion of carbon dioxide to bicarbonate ion plus proton and cooperates with a spectrum of molecules transporting ions or metabolites across the plasma membrane. Thereby CA IX contributes to extracellular acidosis as well as to buffering intracellular pH, which is essential for cell survival, metabolic performance, and proliferation of cancer cells. Since CA IX expression pattern reflects gradients of oxygen, pH, and other intratumoral factors, we use it as a paradigm to discuss an impact of antibody quality and research material on investigating metabolic reprogramming of tumor tissue. Based on the validation, we propose the most reliable CA IX-specific antibodies and suggest conditions for faithful immunohistochemical analysis of molecules contributing to heterogeneity in cancer progression.

SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration

“…Hypoxia triggers metabolic reprogramming in tumor cells, resulting in decreased intracellular pH levels (46). To counter this acidic stress, cancer cells induce the expression of CAIX (11). In various malignancies, CAIX expression associates with advanced disease and treatment failure, underscoring its potential as a biomarker and treatment target (37)(38)(39)(40)(41).…”

“…The hypoxic microenvironment is associated with cancer progression and treatment failure ( 10 ). Cancer cells adapt to low oxygen tension via hypoxia inducible factor 1α (HIF1α) mediated responses including upregulation of carbonic anhydrase (CA) IX ( 11 ). CAs are evolutionary conserved metalloenzymes catalyzing reversible hydration of CO 2 to and H + ( 12 ).…”

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“…There is a particularly important role for dual COX-2/CA inhibitors in the treatment of cancers generally [94,95]. CAIX participates in acidification of the extracellular tumor milieu, with maintenance of an alkaline intracellular milieu with an enhanced growth vigor consequent to this proton efflux across a wide variety of common human cancers [96][97][98][99][100]. Also in OS, CA-mediated cellular proton efflux is an important homeostasis-maintaining accommodation to the malignancy-characteristic aerobic glycolysis that is present in OS [101][102][103][104][105][106].…”

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“…Apart from the cellular involvement in the TME, other altered physical stimuli affect tumor development, as well as the changes that occur in the TME during the cancer progression. In this scenario, the main physical stimuli involved are hypoxia and acidosis [ 42 ]. The rapid growth rate of cancer leads to the formation of hypoxic areas that stimulate a huge release of angiogenic mediators, such as VEGF, thus resulting in the neovascularization of the TME.…”