Role of carbonic anhydrases in the progression of renal cell carcinoma subtypes: proposal of a unified hypothesis.

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.