Volume 50, Issue 1, Pages 23-25 (July 2006)

Although it has been associated with a range of premalignant and malignant lesions of epithelial origin such as colon, lung, breast, prostate, bladder, stomach, and esophagus, the underlying mechanisms of this elevated COX-2 expression in cancer is not known. In view of strong experimental evidence, selective COX-2 inhibitors were tested in the context of sporadic colorectal cancer and in patients with familial adenomatous polyposis (FAP). This demonstrated a 40–50% reduction in colorectal cancer in individuals who take nonsteroidal anti-inflammatory drugs (NSAIDs; the inhibitors of COX activity), a clear indication of the importance of COX in carcinogenesis, and emphasizes its potential as therapeutic target [1].

In the current issue of European Urology, Mungan et al. [2] describe COX-2 upregulation in premalignant lesions (renal intraepithelial neoplasia, RIN) found in radical nephrectomy specimens as well as expression in renal cancer (clear cell and nonclear cell types). Based on an immunohistochemical assessment, COX-2 expression in RCC was heterogeneous. The observation that increased COX-2 was seen in premalignant tissue illustrates that activation of COX-2 may be an early event during tumorigenesis. The molecular events that lead to conventional or clear cell RCC (ccRCC), which account for 70–80% of renal tumors, differ from those in nonclear cell RCC. ccRCC, the most common form of kidney cancer, is associated with mutation in the Von Hippel Lindau (VHL) tumor suppressor gene. The hereditary form of Type I papillary RCC is associated with an activating mutation in the c-met oncogene, and a hereditary form of Type II papillary RCC is associated with a mutation in the fumarate hydratase gene [3]. Thus, the genetic changes that lead to ccRCC and papillary RCC are at the two extremes of the molecular spectrum: inactivation of a tumor suppressor gene and activation of an oncogene. Activation of COX-2 as seen in RIN may therefore precede molecular events that lead to ccRCC and papillary RCC. This is in line with the supposition that upregulation of COX-2 may prolong the survival of abnormal cells and thereby favor the accumulation of sequential genetic changes, which increases the risk of tumorigenesis.

In this context the lifetime risk for RCC in VHL-affected individuals is >70% by the age of 60. As these patients increasingly survive other VHL manifestations—most notably cerebellar hemangioblastoma—RCC is expected to increase in relative importance of cause of morbidity. Metastatic RCC has historically caused about one-third of deaths among VHL patients. Hence, one area of particular interest may be the use of COX-2 inhibitors in chemoprevention for VHL patients, analogous to FAP patients. One drawback is that long-term use of COX-2 inhibitors leads to increased cardiovascular and thrombotic adverse effects. Nevertheless, although this may change the utility of selective COX-2 inhibitors in low-risk populations, they may still be useful in high-risk populations such as VHL families. This will require carefully planned studies. There is a well-organized VHL network that may facilitate these complicated trials. Distribution of lifestyle questionnaires may already tell us whether COX-2 inhibition can influence the occurrence of RCC in VHL patients.

Molecular events that lead to elevated COX-2 expression in RIN and RCC have not been studied. The promoter region of COX-2 consists of many transcription factor binding sites such as nuclear factor kappaB (NF?B), nuclear factor interleukin-6 (NF-IL-6), and hypoxia inducible factor-1 (HIF-1). Considering that renal cells produce IL-6, there is an autocrine loop in renal tissue, and constitutive IL-6 expression by renal tubular cells may therefore explain COX-2 expression in normal kidney specimens, although NF-IL-6 alone probably cannot activate COX-2 expression. In ccRCC important transcription factors are readily available: HIF-1 is stabilized as a consequence of mutations in the VHL gene, and NF-IL-6 is available through RCC produced IL-6. Whether COX-2 is advantageous for successful tumor establishment is unclear. Although it can also induce an angiogenic response in endothelial cells, a vital event in tumor formation, this component may be of minor importance, because VHL mutations also lead to high expression of vascular endothelial growth factor (VEGF), a strong angiogenic growth factor. Nevertheless, collectively the results indicate that COX-2 might be a sensible therapeutic target in RCC.

In RCC, many new molecular targeted therapies, including tyrosine-kinase inhibitors (TKI) and monoclonal antibodies, are coming of age [4]. As already briefly discussed, the VHL gene is inactivated most ccRCC. The VHL gene product (pVHL) is the substrate-recognition component of a complex that targets the transcription factor HIF-1a for proteolysis. Nonfunctional pVHL or hypoxia leads to HIF-1a stabilization and increased transcription of hypoxia-inducible genes, including VEGF and platelet-derived growth factor (PDGF). Indeed, studies have confirmed VEGF overexpression (mRNA or VEGF protein) in most RCC [5]. Thus, VEGF became an obvious attractive therapeutic target once the fundamental biology of ccRCC was unraveled. Inhibition of VEGF in RCC has included binding of VEGF protein by Bevacizumab (alone and in combination with Erlotinib, a small molecule epidermal growth factor inhibitor) and blockade of VEGF receptor signaling through TKI (most notably SU11248 and BAY 43-9006). Impressive clinical responses were observed in RCC, which is resistant to conventional therapies, particularly with TKI treatment. The latter have the added advantage of oral administration. At present comparison of anti-VEGF agents is not possible because they have been tested in separate studies with different patient selection, methods, and outcome criteria.

Although the new development in ccRCC treatment is exciting, a significant proportion of patients do not respond to these new treatment modalities, and treatment may be restricted to clear cell histology. This means that approximately 20% of patients are excluded from treatment. Can COX-2 serve as a possible therapeutic target in renal cancer? In this context COX-2 expression must be examined under physiological conditions. Mice in which COX-2 was “knocked out” have a moderately high rate of still births caused by severe renal dysplasia, which indicates that COX-2 is critical for kidney development [6]. More importantly, COX-2 expression appears to be crucial in kidney function: it can salvage renal medullary interstitial cells under hypertonic stress and COX-2 specific inhibition impaired renal function in newborn rabbits. Thus, COX-2 inhibition may lead to renal side effects [7].

Despite this possible drawback, animal experiments in a colorectal cancer model demonstrated that combination of a COX-2 inhibitor with an epidermal growth factor receptor TKI (ZD1839) was superior to the individual treatments, a clear rationale for COX-2 combination treatment in colorectal cancer [8]. However, because the effect of COX-2 expression resembles the effects of nonfunctional pVHL (increased expression of VEGF, PDGF, and bFGF) the additive value of specific COX-2 inhibition in combination with TKI that principally targets the same molecules needs to be established. Certainly this hypothesis can be adequately addressed in animal models. The additive value of COX-2 combination treatment may lie in RCC tumors with functional pVHL. There, COX-2 inhibition may lead to a release of COX-2-linked inhibition of apoptosis [9].

References

1. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J. Clin Oncol. 2005;23:2840–2855.
2. Mungan MU, Gurel D, Canda AE, Tuna B, Yorukoglu K, Kirkali Z. Expression of COX-2 in normal and pyelonephritic kidney, renal intraepithelial neoplasia and renal cell carcinoma. Eur Urol. 2006;50:92–97.
3. Linehan WM, Vasselli J, Srinivasan R, et al.. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10:6282S–6289S.
4. Rini BI, Sosman JA, Motzer RJ. Therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: biology, clinical results and future development. Br J Cancer. 2005;96:286–290.
5. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapyin renal cell carcinoma. J Clin Oncol. 2005;23:1028–1043.
6. Dinchuk JE, Car BD, Focht RJ, et al.. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase 2. Nature. 1995;378:406–409.
7. Breyer MD, Hao C, Qi Z. Cyclooxygenase-2 selective inhibitors and the kidney. Curr Opin Crit Care. 2001;7:393–400.
8. Tortora G, Caputo R, Damiano V, et al.. Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clin Cancer Res. 2003;9:1566–1572.
9. Dempke W, Rie C, Grothey A, et al.. Cyclooxygenase-2: a novel target for cancer chemotherapy?. J Cancer Res Clin Oncol. 2001;127:411–417.

Egbert Oosterwijk, Peter F.A. Mulders,
University Medical Center Nijmegen, St Radboud, The Netherlands

published online 23 January 2006.

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