Expression of carbonic anhydrase IX (CAIX) in malignant mesothelioma. An immunohistochemical and immunocytochemical study
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: Malignant pleural mesothelioma (MPM) is a deadliest and heterogeneous neoplasia, highly refractory to multimodal therapeutic approach consisting of surgery, chemo- and radio-therapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, without fulfilling expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors in MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative models could be exploited in preclinical studies to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible of the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling, that may also be activated by autocrine and paracrine cytokine pathways involved in cell plasticity, invasion and metastasis. Either signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.Current drug targets 08/2015; · 3.02 Impact Factor
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