Abstract
Because conventional chemotherapy, radiotherapy, and hormonal therapy have no benefit in terms of prolonging survival in patients with metastatic renal cell cancer (mRCC), almost all mRCC patients eventually succumb to disease. Intriguingly metastatic lesions have been known to disappear after the resectioning of the primary RCC although such cases are very rare (Kavoussi et al. 1986). In addition, immunotherapy, such as the administration of interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), has shown promise, although the efficacy varies among cases and the total response rate reaches only approximately 20% (Krown 1987; Fyfe et al. 1995). Immunotherapy should be performed only in selected responders, because the treatment is sometimes accompanied by severe adverse effects especially with IL-2 (Fyfe et al. 1995). The demography favoring a response to immunotherapy includes a good performance status, prior nephrectomy, metastasis predominantly to the lung (Atkins et al. 1993; Fyfe et al. 1995; Figlin et al. 1997; Rosenberg et al. 1998), and only one site of metastatic disease (Negrier et al. 1998), with a clear cell histological variant (Wu et al. 1998). To date, however, no reliable molecular markers have been identified that can predict susceptibility to immunotherapy.
The present study was performed to elucidate the potential role of the apoptosis-related molecules Bcl-2 and Fas as predictors of the susceptibility of metastatic RCC to immunotherapy. An immunohistochemical examination of tumor tissue from 40 patients with metastatic RCC undergoing postoperative immunotherapy after radical nephrectomy was performed. Patients with progressive disease after immunotherapy had a decreased rate of survival (p = 0.006). Progressive disease correlated with a higher proliferation index (PI) in the primary tumor. All primary tumors in cases of complete response or partial response were negative for Bcl-2, while 40.6% of no change + progressive disease patients, were positive for Bcl-2 (p = 0.0373). Patients in whom the primary tumors were both Bcl-2 and Fas-negative showed significantly better responses to immunotherapy than the remaining group (p = 0.0022). The Bcl-2 and Fas status of the primary lesion may become useful for the selection of patients with metastatic RCC for immunotherapy.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Atkins, M.B., Sparano, J., Fisher, R.I., Weiss, G.R., Margolin, K.A., Fink, K.I., Rubinstein, L., Louie, A., Mier, J.W., and Gucalp, R. (1993) Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J. Clin. Oncol. 11:661–670
Escudier, B., Eisen, T., Stadler, W.M., Szczylik, C., Oudard, S., Siebels, M., Negrier, S., Chevreau, C., Solska, E., Desai, A.A., Rolland, F., Demkow, T., Hutson, T.E., Gore, M., Freeman, S., Schwartz, B., Shan, M., Simantov, R., and Bukowski, R.M. (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356:125–134
Figlin, R., Gitlitz, B., Franklin, J., Dorey, F., Moldawer, N., Rausch, J., deKernion, J., and Belldegrun, A. (1997) Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: an analysis of 203 consecutively treated patients. Cancer. J. Sci. Am. 3(Suppl. 1):S92–S97
Fyfe, G., Fisher, R.I., Rosenberg, S.A., Sznol, M., Parkinson, D.R., and Louie, A.C. (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. 13:688–696
Hara, I., Hara, S., Miyake, H., Arakawa, S., and Kamidono, S. (2001) Bcl-2 modulates Fas-mediated apoptosis in human renal cell carcinoma cell lines. Int. J. Oncol. 18:1181–1185
Herr, I., and Debatin, K.M. (2001) Cellular stress response. and apoptosis in. cancer therapy. Blood 98:2603–2614
Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., Staroslawska, E., Sosman, J., McDermott, D., Bodrogi, I., Kovacevic, Z., Lesovoy, V., Schmidt-Wolf, I.G., Barbarash, O., Gokmen, E., O’Toole, T., Lustgarten, S., Moore, L., and Motzer, R.J. (2007) Temsirolimus, interferon alfa., or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356:2271–2281
Itoi, T., Yamana, K., Bilim, V., Takahashi, K., and Tomita, Y. (2004) Impact of frequent Bcl-2 expression on better prognosis in renal cell carcinoma patients. Br. J. Cancer. 90:200–205
Kavoussi, L.R., Levine, S.R., Kadmon, D., and Fair, W.R. (1986) Regression of metastatic renal cell carcinoma: a case report. and literature review.. J. Urol. 135:1005–1007
Kelly, J.D., Dai, J., Eschwege, P., Goldberg, J.S., Duggan, B.P., Williamson, K.E., Bander, N.H., and Nanus, D.M. (2004) Downregulation of Bcl-2 sensitises interferon-resistant renal cancer cells to Fas. Br. J. Cancer. 91:164–170
Kimura, M., Tomita, Y., Imai, T., Saito, T., Katagiri, A., Tanikawa, T., Takeda, M., and Takahashi, K. (1999) Significance of serum-soluble CD95 (Fas/APO-1) on prognosis in renal cell cancer patients. Br. J. Cancer. 80:1648–1651
Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H., and Peter, M.E. (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo. J. 14:5579–5588
Krown SE (1987) Interferon treatment of renal cell carcinoma. Current status. and future prospects.. Cancer 59:647–651
Maruyama, R., Yamana, K., Itoi, T., Hara, N., Bilim, V., Nishiyama, T., Takahashi, K., and Tomita, Y. (2006) Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma. Br. J. Cancer. 95:1244–1249
Motzer, R.J., Hutson, T.E., Tomczak, P., Michaelson, M.D., Bukowski, R.M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C., Kim, S.T., Chen, I., Bycott, P.W., Baum, C.M., and Figlin, R.A. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356:115–124
Negrier, S., Escudier, B., Lasset, C., Douillard, J.Y., Savary, J., Chevreau, C., Ravaud, A., Mercatello, A., Peny, J., Mousseau, M., Philip, T., and Tursz, T. (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N. Engl. J. Med. 338:1272–1278
Nonomura, N., Miki, T., Yokoyama, M., Imazu, T., Takada, T., Takeuchi, S., Kanno, N., Nishimura, K., Kojima, Y., and Okuyama, A. (1996) Fas/APO-1-mediated apoptosis of human renal cell carcinoma. Biochem. Biophys. Res. Commun. 229:945–951
Reed JC (1998) Bcl-2 family proteins. Oncogene 17:3225–3236
Reed JC (1999) Dysregulation of apoptosis in cancer. J. Clin. Oncol. 17:2941–2953
Rosenberg, S.A., Yang, J.C., White, D.E., and Steinberg, S.M. (1998) Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann. Surg. 228:307–319
Roset, R., Ortet, L., Gil-Gomez G (2007) Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice. Front. Biosci. 12:4722–4730
Szczylik, C., Demkow, T., Staehler, M., Rolland, F., Negrier, S., Hutson, T.E., Bukowski, R.M., Scheuring, U.J., Burk, K., and Escudier, B. (2007) Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. J. Clin. Oncol. 25:5025
Tomita, Y., Bilim, V., Kawasaki, T., Takahashi, K., Okan, I., Magnusson, K.P., and Wiman, K.G. (1996) Frequent expression of Bcl-2 in renal-cell carcinomas carrying wild-type p53. Int. J. Cancer. 66:322–325
Tomita, Y., Bilim, V., Hara, N., Kasahara, T., and Takahashi, K. (2003) Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. Int. J. Cancer. 104:400–408
Tsujimoto, Y., and Shimizu, S. (2000) Bcl-2 family: life-or-death switch. FEBS Lett. 466:6–10
Wu, J., Caliendo, G., Hu, X.P., and Dutcher, J.P. (1998) Impact of histology on the treatment outcome of metastatic or recurrent renal cell carcinoma. Med. Oncol. 15:44–49
Acknowledgements.
The authors thank all members involved RCC projects in the past, Drs. T. Imai, K. Saito, M. Kimura, A. Katagiri, T. Saito, N. Hara, T. Kasahara, T. Itoi, K. Yamana, and K. Takahashi.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Tomita, Y., Maruyama, R., Itoi, T., Bilim, V. (2010). Metastatic Renal Cell Carcinoma: Use of Bcl-2 and Fas to Predict Responses to Immunotherapy. In: Hayat, M. (eds) Methods of Cancer Diagnosis, Therapy, and Prognosis. Methods of Cancer Diagnosis, Therapy and Prognosis, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2918-8_12
Download citation
DOI: https://doi.org/10.1007/978-90-481-2918-8_12
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-2917-1
Online ISBN: 978-90-481-2918-8
eBook Packages: MedicineMedicine (R0)