Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions

Abstract

Hypoxia is a common phenomenon that occurs in most solid tumors. Regardless of tumor origin, the evolution of a hypoxia-adapted phenotype is critical for invasive cancer development. Pancreatic ductal adenocarcinoma is also characterized by hypoxia, desmoplasia, and the presence of necrosis, predicting poor outcome. Carbonic anhydrase IX (CAIX) is one of the most strict hypoxia regulated genes which plays a key role in the adaptation of cancer cells to hypoxia and acidosis. Here, we summarize clinical data showing that CAIX expression is associated with tumor necrosis, vascularization, expression of Frizzled-1, mucins, or proteins involved in glycolysis, and inevitably, poor prognosis of pancreatic cancer patients. We also describe the transcriptional regulation of CAIX in relation to signaling pathways activated in pancreatic cancers. A large part deals with the preclinical evidence supporting the relevance of CAIX in processes leading to the aggressive behavior of pancreatic tumors. Furthermore, we focus on CAIX occurrence in pre-cancerous lesions, and for the first time, we describe CAIX expression within intraductal papillary mucinous neoplasia. Our review concludes with a detailed account of clinical trials implicating that treatment consisting of conventionally used therapies combined with CAIX targeting could result in an improved anti-cancer response in pancreatic cancer patients.

Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

“…The pH e of tumor tissues is often acidic [ 159 ] and this phenomenon is the result of multiple factors such as: (i) increased CO 2 production, which is converted into carbonic acid by membrane Carbonic Anhydrases IX and XII (CAIX and CAXII) [ 160 ]; (ii) increased lactate production as a consequence of high glycolytic flux and aerobic glycolysis [ 161 ]; (iii) extrusion of this lactate by monocarboxylate transporters (MCTs) [ 162 ] and (iv) active translocation of cellular protons into the ECM mainly by sodium-hydrogen exchanger isoform-1 (NHE1) [ 163 ]. Hence, all these mechanisms are altered in tumors and lead to low pH e (~6.7–7.1) compared to normal tissues (7.4) [ 164 ], and to an alkaline intracellular milieu [ 164 ].…”

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives

“…At present, CA IX-targeted drugs have been studied in clinical research. The CA IX inhibitor SLC-0111 combined with gemcitabine for the treatment of metastatic pancreatic ductal cancer in patients overexpressing the CA IX isoform has entered clinical phase II [ 13 , 14 , 15 ].…”

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

“…The effects of CA IX on tumor phenotype can be blunted either by the silencing/suppression of the CA IX expression, or by the small molecule inhibitors of the CA IX catalytic activity, or by the CA IX-specific antibodies as documented in a number of published studies and reviews [61][62][63][64][65][66][67][68]. Moreover, the knowledge obtained in pre-clinical studies of CA IX inhibitors and/or antibodies has opened the window for novel anticancer strategies, some of which have been translated into the clinical trials (reviewed in [69] and listed in https:// clini caltr ials. gov].…”