Abstract
Hypoxic microenvironment is a common situation in solid tumors. Carbonic anhydrase IX (CA9) is one of the reliable cellular biomarkers of hypoxia. The role of CA9 in colorectal cancer (CRC) remains to be clarified. CA9 inhibitor such as sulfonamides is known to block CA9 activation and reduce tumor growth consequently. Here, we aimed to investigate the CA9 expression in serum and tumor from different stages of CRC patients and utilize sulfonamide derivative with indium-111 labeling as a probe for CRC nuclear imaging detection in vivo. The serum CA9 was correlated with the tumor CA9 levels in different stages of CRC patients. Hypoxia increased cell viability and CA9 expression in colorectal cancer HCT-15 cells. Sulfonamide derivative 5-(2-aminoethyl)thiophene-2-sulfonamide (ATS) could bind with CA9 in vitro under hypoxia. Moreover, tumor tissues in HCT-15-induced xenograft mice possessed higher hypoxic fluorescence signal as compared with other organs. We also found that the radioisotope signal of indium-111 labeled ATS, which was utilized for CRC detection in HCT-15-induced xenograft mice, was markedly enhanced in tumors as compared with non-ATS control. Taken together, these findings suggest that CA9 is a potential hypoxic CRC biomarker and measurement of serum CA9 can be as a potential tool for diagnosing CA9 expressions in CRC clinical practice. The radioisotope-labeled sulfonamide derivative (ATS) may be useful to apply in CRC patients for nuclear medicine imaging.
Highlights
Colorectal cancer (CRC) is one of most common malignancy cancers worldwide [1]
In the present study, we aimed to investigate whether (1) serum CA9 levels are correlated with tumor tissue CA9 levels in clinical CRC patients and can as a CRC reliable biomarker; (2) CA9 can as a biomarker for hypoxic tumor diagnosis; (3) radiolabeled sulfonamide derivative can bind to CA9-overexpressed CRC tumors
The serum CA9 (sCA9) levels were correlated with tissue CA9 expressions in CRC patients (p < 0.05, Figure 1D), considering that detection of sCA9 may be used to reflect the levels of CA9 in tumors as a reference during cancer therapy
Summary
Colorectal cancer (CRC) is one of most common malignancy cancers worldwide [1]. Epidemiological studies have shown that the incidence and mortality of colorectal cancer is increasing over the past several decades [2, 3]. The higher mortality of CRC is due to the disease that is frequently diagnosed in the advanced stage without reliable diagnosis. Accurate detection of cancerous lesions can provide more effective surgical and pharmacological therapies for decreasing in the mortality of CRC [7]. Colonoscopies are considered the most preferred tool for CRC screening in clinical; they are invasive and present a small but significant risk for perforations and limitations in making an accurate diagnosis due to sampling errors or www.impactjournals.com/oncotarget personal skill [8, 9]. The development of high sensitivity and specificity diagnostic methods is urgent and important
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