Renal cell carcinoma (RCC) is the third most common malignancy of the urinary tract after prostate and bladder cancer. It is a cancer which is particularly difficult to diagnose. Indeed, RCC patients frequently have non-specific symptoms or are completely asymptomatic until a relatively advanced state is reached. Consequently, at the time of diagnosis, 15 to 25 percent of kidney cancer patients already have metastatic RCC. Once metastatic disease develops, the prognosis for long-term survival is poor.
Today, RCC normally is incidentally detected by abdominal ultrasound (US) and computed tomography (CT). It is occasionally suggested by a radioisotope bone or renal perfusion scan. However, these techniques are time consuming and expensive.
A number of efforts are currently performed to characterize RCC using molecular biological, cytogenetic, immunohistochemical as well as proteome-based techniques. In this context, many markers have been evaluated for their potential use as diagnostic or prognostic factors. However, as yet none of them has been validated in vigorous trials. The current state of the matter can be summarized as follows:
Interleukin 6 and its receptor might play a role in tumor proliferation as well as in certain symptom signs associated with metastatic renal cancer (Blay J Y et al., Cancer Res. (1992) 52, 3317-22).
FGF (Fibroblast Growth Factor), an angiogenic factor, may serve as potential prognostic marker of disease progression (Rak J W et al, Anticancer Drugs, (1995) 6, 3-18).
Plasminogen activator inhibitor-1, a specific inhibitor of urokinase, was reported as a prognostic factor in predicting early relapse of renal cell carcinoma. High and low risk groups for disease-free survival can be discriminated by plasminogen activator inhibitor-1 antigen content in the tumor tissue (Hofmann R et al, J. Urol. (1996) 155, 858-62).
Recent studies have described that expression of E-cadherin, which plays a major role in cell-cell adhesion of normal epithelium, is decreased in renal cancer. Its rate may be correlated with tumor aggressiveness (Shimazui T, Cancer Res. (1996) 56, 3234-7).
WO 02/082076 relates to identification of tumor markers which are immunogenic in RCC patients. The authors reported that these proteins are presented at the surface of the tumor cell and therefore are not circulating. The authors describe an immunoassay to detect the presence of circulating antibodies specific to these tumor marker proteins in the serum of an individual. Therefore, the immunoassay is not based on the direct detection of RCC markers in the circulation but on an indirect detection of (circulating) autoantibodies raised against RCC tumor marker proteins present in patients' tissue. Matrix metalloproteinases or antibodies against matrix metalloproteinases are not mentioned.
There is still a need for additional tumor markers for the detection and follow-up of renal cell carcinoma, especially for humoral tumor markers which can be detected in blood samples and serum or plasma samples respectively and which, therefore, can be included in the list of biomarkers determined in routine patient health screening. If it were possible to early diagnose renal tumors, this would have a very high impact on improving the outcome of RCC. The availability of an effective diagnostic assay would make it possible to screen routinely especially high risk populations (i.e. Von Hippel-Lindau, Hemodialysis, transplanted or immunodepressed patients, (N. J. Vogelzang, (1998) The Lancet, 352, 1691-1696)) and to detect asymptomatic tumor. A sensitive humoral renal cell carcinoma marker test would also have high value for detecting tumor recurrence in patients with renal cell carcinoma after total or partial nephrectomy. Such a marker will allow completing the evaluation of the extension of the disease. It may help to limit the use of invasive examination and to adapt therapeutics earlier. Such humoral marker will facilitate the monitoring of tumors during the treatment and allow a better prediction of therapeutic responses and prognosis.