Is Carbonic Anhydrase IX a Validated Target for Molecular Imaging of Cancer and Hypoxia?

Abstract

The presence of hypoxia is a general feature of most solid malignancies, and hypoxia is considered as one of major factors for anticancer therapy failure. Carbonic anhydrase IX (CAIX) has been reported to be an endogenous hypoxia marker, CAIX monoclonal antibodies, their segments and inhibitors are developed for CAIX imaging. However, growing evidence indicates that CAIX expression under hypoxia condition may be cancer cell lines or cancer-type dependent. Here we review the current literature on CAIX and discuss the advantage and limitation of CAIX as a target for tumor hypoxia imaging. Accordingly, CAIX would be unreliable as a universal target for cancer and tumor hypoxia visualization. KEYWORDS• cancer • carbonic anhydrase IX • hypoxia • molecular imagingIn 2013, approximately 1,660,290 new cancer cases are diagnosed and 580,350 patients are died of cancer in the USA [1]. Hypoxia is a common feature of large primary solid malignancies and is recognized as a negative determinant of clinical outcome [2][3][4][5][6][7][8][9]. It is now established that tumor hypoxia is an important determinant of relapse-free survival and overall clinical outcome [4,[10][11]]. This appears to be largely independent of the treatment modality used and implies that hypoxia is associated with a more aggressive tumor phenotype. There seems to be at least three distinct manifestations of the hypoxic phenotype: Hypoxic cells are more resistant to ionizing radiation and chemotherapy than aerobic cells; The hypoxic environment is selective for genetically unstable tumor cells, and hypoxia is associated with tumors that are more likely to metastasize [10,12-13]; and hypoxia regulates the level of HIF-1α, which controls the expression of genes that are involved in oxygen and glucose supply and utilization [14]. Therefore, it is important to detect the hypoxic status for solid cancers.Recently multiple biomarkers related to tumor hypoxic microenvironment have been discovered and offered as targets for cancer detection, treatment and monitoring, such as HIF-1 [15][16][17], VEGF and VEGF receptors [18][19][20], glucose transporter 1 [21][22][23] and carbonic anhydrase IX (CAIX) [24][25][26][27][28][29]. CAIX is strongly induced by hypoxia through the HIF-1 transcription factor, and has reported to overexpress in some types of cancer [30,31]. Promising results for using anti-CAIX antibodies and CAIX inhibitors for tumor hypoxia imaging have been reported [32][33][34].However, growing evidence indicates that the CAIX expression under hypoxia conditions in cancer cell lines is cancer cell lines or cancer types dependent [30], and some cancer cell lines have undetectable CAIX expression under hypoxia condition [35,36]. In addition, re-oxygenated (previously hypoxic) cancer cells may still show high level of CAIX expression [36]; CAIX has a half-life up to 2-3 days under normoxic condition. In contrast, acute hypoxic cancer cells may not express detectable CAIX. The open question is whether CAIX is a reliable and universal target for canc...

Value of pH regulators in the diagnosis, prognosis and treatment of cancer

“…The variety of studies on the expression of these pH regulators, demonstrated that the expression profile is quite different in normal and tumour samples, where, with few exceptions, a higher expression of these proteins has been found (see Table 1). From the addressed pH regulators, this difference is even more relevant for CAIX, as it is highly expressed in cancer but scarce in normal tissues, being present only in the gastrointestinal tract [175]. Further, with the exception of MCT2, where its upregulation was associated to a more favourable prognosis, in general, the increased expression of pH regulators favours poor prognostic factors such as advanced stage and high grade tumours, increased drug resistance, invasion, metastasis, shorter overall and disease free survival rates, in different cancer types.…”

“…CAIX is regulated by HIF-1␣ and its expression in tumours is associated with hypoxic regions (a common hallmark of solid tumours), being thus a promising biomarker for cancer cells adapted to a hypoxic environment, which normally present a more aggressive phenotype and are associated to a poor outcome [244,245]. However, some studies present controversial results, being the association between CAIX expression and the hypoxic status of the cell, dependent of the cancer type [175,246]. Nevertheless, determination of CAIX expression can be useful, by identifying candidates that can benefit from a CAIX directed treatment.…”

“…Diverse immunohistochemical studies have reported CAIX to be expressed in several cancers, including malignancies of the breast [167,168], colon/rectum, head and neck [19,169], lung [170], brain [171], bladder [172], ovarian [173], and kidney [166] (for review see [174]). Importantly, its expression is scarce in normal human tissues, being only detected in the gastrointestinal tract [175]. This atypical differential expression pattern elects CAIX as a potent tumour hypoxic biomarker that could be useful in the clinic.…”

“…Due to its rare distribution in normal tissues, CAIX has become an attractive biomarker of hypoxia in solid tumours. The development of different radionuclide labelled antibodies [193] or fluorescent labelled compounds [194] targeting CAIX have been designed and tested to validate this molecule as a hypoxic marker for clinical imaging and tumour following [175]. These pre-clinical studies using in vitro and in vivo experiments demonstrated that CAIX, more than CAXII, is a suitable target to trace hypoxic regions and could be used to select candidate patients for anti-CAIX therapies [175].…”

Photosynthetic Tumor Oxygenation by Photosensitizer‐Containing Cyanobacteria for Enhanced Photodynamic Therapy

“…[10] As the dominant reactive oxygen species,singlet oxygen has an extremely short lifespan of several microseconds,capable of oxidizing avariety of organic substances within 200 nm in physiological conditions,r esulting in cytotoxic effects. [11] However,m alignant tumor cells are typically hypoxic with an overall O 2 partial pressure (pO 2 )l ower than 20 mmHg, [12] severely diminishing the efficacies of PDT in clinical tumor therapy.T herefore, effective tumor oxygenation becomes greatly appealing to generalize this clinically promising antitumor methodology. During the past decades,oxygen molecules have been directly transported to tumors using FDA-approved perfluorocarbon (PFC) materials (for example,C 5 F 12 ), [13] yet the short plasma lifespan and the frequent dosing issues associated with the PFC-based tumor oxygenation strategy still remain unsolved.…”