Expression of carbonic anhydrase IX (CAIX) in malignant mesothelioma. An immunohistochemical and immunocytochemical study
ABSTRACT Malignant mesothelioma is an aggressive tumor with a poor prognosis. Carbonic anhydrase IX (CAIX) is a membranously located metalloenzyme involved in pH homeostasis with influence on regulation of cell proliferation, oncogenesis and tumor progression. Much attention has been paid recently to carboanhydrases and their inhibitors as they offer an opportunity for both developing novel anticancer drugs, as well as diagnostic and prognostic tools. This study was designed to assess the expression of CAIX in malignant pleural and peritoneal mesotheliomas, their benign counterparts, and in pleural effusions from patients with malignant mesothelioma, metastatic carcinoma or a benign disease. Tissue blocks from 51 malignant mesotheliomas of pleura (47 cases; 41 epithelioid, 2 biphasic, 4 sarcomatoid) and peritoneum (4 cases; all epithelioid), 14 cases with normal or reactive pleural tissue, and 19 cell blocks were analyzed. CAIX expression was determined using immunohistochemistry and its membranous immunoreactivity was semiquantitatively evaluated. Specimens were divided into five subgroups according to the staining pattern and intensity.Overall, 92.2% (47/51) of mesotheliomas expressed CAIX. All epithelioid mesotheliomas showed CAIX positivity, which was predominantly strong and diffuse (73.3%, 33/45). Sarcomatoid mesotheliomas and sarcomatoid areas in biphasic mesotheliomas were negative. A strong diffuse staining was observed in all cases of normal mesothelia. In pleural effusions, CAIX expression was observed in malignant cells as well as in benign mesothelial cells. In conclusion, CAIX is expressed virtually in all mesotheliomas except for sarcomatoid subtype, and in benign mesothelia. There are probably more mechanisms of CAIX overexpression than hypoxia-induced in malignant mesothelioma, with the influence of other tissue specific transcription or growth factors depending on the type of the cell lineage. CAIX immunoreactivity is not a reliable diagnostic marker for distinguishing malignant cells from benign mesothelia in pleural effusions. Nevertheless, our data support the potential use of therapeutics targeting CAIX in patients with advanced mesothelioma. Keywords: carbonic anhydrase IX, CAIX, malignant mesothelioma, pleura, immunohistochemistry, immunocytochemistry.
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ABSTRACT: The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease.The Oncologist 08/2007; 12(7):850-63. DOI:10.1634/theoncologist.12-7-850 · 4.54 Impact Factor
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ABSTRACT: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.Nature reviews. Cancer 02/2002; 2(1):38-47. DOI:10.1038/nrc704 · 37.91 Impact Factor
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ABSTRACT: Most patients affected by malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of the disease, as single modality treatment or within the context of a multimodality approach. Following the results of a large phase III trial, the combination of cisplatin and pemetrexed has become the preferred first-line chemotherapy, although there is also evidence for the activity of the combination with carboplatin based on phase II studies. Unfortunately, nearly all MPM patients progress during or after first-line treatment. Second-line therapies are being increasingly used in the clinical practice because patients are frequently still healthy at the time of disease progression. However, the role of these treatments in MPM is unproven, and the optimal regimens still remain to be defined. In pemetrexed-naïve patients, data from a randomized trial vs. best supportive care suggest the use of single-agent pemetrexed as a standard second-line treatment. This evidence is supported also by the results of the Expanded Access Programs. To date, there is still no standard approach for the growing population of pemetrexed-pre-treated patients. In selected cases with a prolonged response to first-line pemetrexed-based chemotherapy, re-treatment with a pemetrexed-based regimen should be considered. When a trial is not available or patients are not eligible for an experimental approach, single-agent vinorelbine can be a reasonable option for palliation. However, second-line therapy in MPM remains an ideal field in which to test new chemotherapy agents as well as new therapeutic strategies, including anti-angiogenic compounds, small molecules or monoclonal antibodies that target different molecular pathways.Cancer Treatment Reviews 10/2009; 36(1):24-32. DOI:10.1016/j.ctrv.2009.09.003 · 6.47 Impact Factor