Carbonic Anhydrase IX: From Biology to Therapy

Abstract

Growing tumor tissues develop a stressful microenvironment characterized by hypoxia and acidosis. Tumor cells can survive these stresses via induction of adaptive transcriptional changes mediated primarily by the hypoxia-inducible factor (HIF), and via stimulation of ion transport machinery maintaining normal intracellular pH. In addition, through these adaptive responses tumor cells acquire new features endowing them with selective advantage in migration, invasion, metastasis, and resistance to therapy. Carbonic anhydrase IX (CA IX), a highly active cancer-related carbonic anhydrase isoform, is linked to both hypoxia, as a direct transcriptional target of HIF, and acidosis, as a component of mechanisms that facilitate ion transport across the plasma membrane and thereby counteract the intracellular accumulation of acidic metabolic products. Expression pattern of CA IX in human tumors reflects the activation of the HIF pathway by physiologic hypoxia, genetic defects, and/or oncogenic events. Moreover, CA IX plays an active role not only in pH regulation but also in cell migration and invasion. Thus, it is often exploited and/or investigated as an intrinsic marker of hypoxia, a prognostic indicator, and a therapeutic target for antibodies or inhibitors of the enzyme activity. It is believed that these CA IXtargeted therapeutic approaches can mediate the selective killing of CA IX-positive cells or sensitize tumor cells to conventional treatment modalities. In addition, both

Carbonic Anhydrase Ix Inhibitors in Cancer Therapy: An Update

“…This cell surface isoform is known to be exclusively associated with hypoxic tumors being present in small amount in normal tissues with almost a total exclusivity in the gastrointestinal tract epithelium [2]. High induction of CA IX in response to hypoxia is observed in many tumors including malignancies of the brain, head/neck, breast, lung, bladder, cervix uteri, colon/rectum and kidney and is generally considered as a poor prognostic indicator [2]. Carbonic anhydrase IX is linked to hypoxia, through a strong transcriptional activation accomplished via the hypoxia inducible factor-1 transcription factor.…”

“…For example, the antibody (Girentuximab) was developed by Wilex AG (München, Germany) and it is currently in Phase III clinical trials, under the trade name RENCAREX ® , for the treatment of metastatic clear cell renal cell carcinoma [2,5].…”

“…This metalloprotein is considered as an integral component of the cancer physiology, acting as both the survival factor and the facilitator of tumor progression [2,3]. Thereby, based on inhibition of their catalytic activity, CA IX has been validated as an imaging and treatment target for hypoxic tumors and metastases hypoxic tumors [4].…”

“…Carbonic anhydrase IX is linked to hypoxia, through a strong transcriptional activation accomplished via the hypoxia inducible factor-1 transcription factor. Carbonic anhydrase IX is a key component of the tumor microenvironment that actively contributes to pH regulation by facilitating ion transport across the plasma membrane and thereby protecting tumor cells from acidosis by counteracting the intracellular accumulation of acidic metabolic products [2,3].…”

“…It is a transmembrane zinc metalloenzyme with an extracellular active site, involved as an efficient catalyst of reversible hydration of carbon dioxide to bicarbonate ions and protons [1]. This cell surface isoform is known to be exclusively associated with hypoxic tumors being present in small amount in normal tissues with almost a total exclusivity in the gastrointestinal tract epithelium [2]. High induction of CA IX in response to hypoxia is observed in many tumors including malignancies of the brain, head/neck, breast, lung, bladder, cervix uteri, colon/rectum and kidney and is generally considered as a poor prognostic indicator [2].…”