Role of Carbonic Anhydrases in the Progression of Renal Cell Carcinoma Subtypes: Proposal of a Unified Hypothesis

Abstract

Renal cell carcinoma (RCC) has the highest rate of occurrence within the US when compared with other countries. Recent advances in the basic research and molecular diagnostics of this malignancy have revealed that RCC is not a single disease, but it is a mixture of several types of malignancies with unique molecular mechanisms and pathological attributes. RCC is now divided into clear cell carcinoma (80% of all kidney cancers), papillary type 1 and papillary type 2 neoplasms (10-15% of all RCC patients) and RCC with chromophobic and oncocytic features, called the Birt-Hogg-Dube (BHD) subtype, in roughly 5% of all patients. Apart from these, neoplasms such as the tuberous sclerosis (TSC) syndrome may occur with a mixed pathological features with a renal presentation. In this review, molecular evidence, both direct and indirect, published so far on all these RCC subtypes have been analyzed to find out whether there is any common thread that could run through these disparate malignancies that happen to occur in a single organ, i.e., the kidney. We believe that the role played by the expression and certain non-traditional activities of the cabonic anhydrase (CA) family members, along with the differing levels of hypoxia induced within these tumors may be the most common denominators. Evidence is presented focusing on how the CA family members could participate in the genesis and progression of each and every one of these RCC subtypes and how their function could be influenced by hypoxia, activities of receptor type protein tyrosine kinases and certain other pre-disposing factors. These rationalizations point towards a unified hypothesis that may help explain the occurrence of all these RCC subtypes in a molecular manner. We hope that these analyses would a) stimulate further studies aimed toward a better understanding of the role played by carbonic anhydrases in RCC subtypes and b) would pave way to a better and rationally designed therapies to interfere with their function to benefit patients with RCC and possibly other cancers.

Searching for Hif1-α interacting proteins in renal cell carcinoma

“…The fact that Hif1-α showed a positive correlation with VEGF in our study corroborates the idea that Hif1-α accumulation leads to enhanced transcription of the respective DNA segments [23]. Carbonic anhydrases are transmembrane enzymes that play a crucial role in the regulation of pH by catalysing the reversible reaction of carbonic acid to carbon dioxide and water [27]. Both hypoxia and VHL inactivation lead to increased cellular levels of Hif1-α, and subsequently, to an increase in carbonic anhydrases, especially CAIX [28].…”

Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma

“…In fact, Ihnatko et al (45) recently described that CAIX expression in human glioblastoma cells was increased via a hypoxia-independent mechanism. Similar or other mechanisms can be assumed in RCC (42). It is therefore possible that CAIX expression in metastatic RCC reflects VHL status, whereas HIF-1a expression might be more complex and be regulated by additional mechanisms and molecular pathways.…”

“…Carbonic anhydrases are transmembrane enzymes that play a crucial role in the regulation of the pH value by catalyzing the reversible reaction of carbonic acid to carbon dioxide and water (42). Both hypoxia and VHL inactivation lead to increased cellular levels of HIF-1a, and subsequently, to an increase of carbonic anhydrases, especially of CAIX (43,44).…”

Selective Inhibition of Carbonic Anhydrase IX Decreases Cell Proliferation and Induces Ceramide-Mediated Apoptosis in Human Cancer Cells

“…Several clinical studies have shown a clear relationship between high CA IX levels and poor prognosis (Chia et al, 2001;Giatromanolaki et al, 2001). A possible role for this enzyme has been suggested in the adaptation of tumor cells to hypoxic conditions and in tumor cell progression (Dorai et al, 2006;Chiche et al, 2010). In particular, CA IX has been proposed to promote tumor cell growth by counteracting hypoxia-induced acidosis through the alkalinization of the intracellular pH (pH i ) (Chiche et al, 2009).…”