Fas Expression in Renal Cell Carcinoma Accurately Predicts Patient Survival after Radical Nephrectomy

Abstract

Objectives: To investigate Fas, Fas ligand (FasL) and Bcl-2 expression, which are considered to be important apoptotic regulatory factors in renal cell carcinomas (RCCs). Patients and Methods: mRNA quantification and immunohistochemistry allowed for the determination of the expression of these three factors in surgically resected tumors from 82 patients with RCC. The correlation of protein and gene expression with more than 10 years of survival data following nephrectomy (along with clinical and pathologic parameters) was analyzed using uni- and multivariate statistical models. Results: A significantly poorer outcome was observed in patients with tumors expressing high levels of Fas mRNA in the multivariate analysis (p = 0.0002). In addition, patient survival was significantly worse in FasL mRNA-positive tumor cases when compared with FasL mRNA-negative cases (p = 0.0345). Ten cases relapsed more than 5 years after nephrectomy. Among them, the tumors of 8 cases (80%) did not express FasL mRNA. Analysis of Bcl-2 did not show statistical significance of Bcl-2 expression as a prognostic indicator. Conclusions: The data suggest that pronounced Fas expression is a surrogate biomarker of active cancer cell proliferation. Given the FasL tumor counterattack theory, FasL overexpression in RCC may be one of the host immune deficiencies, consequently leading to poor prognosis.

Regulatory T Cells and Myeloid-Derived Suppressor Cells in the Tumor Microenvironment Undergo Fas-Dependent Cell Death during IL-2/αCD40 Therapy

“…Although tumor-associated Fas/Fas ligand expression has been associated with killing of activated T cells (18, 20) and poor survival in RCC (19), our results highlight the potential for immunotherapeutic strategies capable of harnessing this pathway to elicit the removal of Fas-sensitive immunoregulatory cells specifically within the tumor microenvironment.…”

“…Although tumor-derived Fas expression associates with poorer outcome in RCC patients (19), the contributions of tumor-versus leukocyte-associated Fas ligand expression remains incompletely defined, particularly in the context of immunotherapy. By immunohistochemistry, we found that increased Fas ligand expression was associated with advanced stage RCC (Figure 1).…”

“…However, Fas ligand expression by tumors, including renal cell carcinoma (RCC) (18, 19) can contribute to tumor escape through a process referred to as “tumor counter-attack”, whereby Fas-positive immune cells are killed [reviewed in (20)]. We hypothesized that immunotherapy would alter leukocyte sensitivity to counterattack within the tumor microenvironment and therefore tip the balance toward tumor killing.…”

Comparative analysis of CD4 and CD8 lymphocytes — evidences for different distribution in primary and secondary liver tumors

“…Fas-dependent induced apoptosis of activated T cells may be induced by tumoral cells expressing FasL. Such FasL-counterattack was found in non--small cell lung [48] and kidney cancer [49], but it is also characteristic for metastatic colorectal cancer (CRC) [50]. Since CRC was primary tumor site in most patients with liver metastases we suppose that this tumor-lymphocyte relation may have strong connections with decreased number of intratumoral T lymphocytes in LM in comparison to HCC.…”

An Epigenetic Screen Unmasks Metallothioneins as Putative Contributors to Renal Cell Carcinogenesis

“…Patients with metastatic disease have a median survival of 13 months, the 5-year survival rate is <10% [3]. Poor prognosis and shortened survival rates were recently linked to antiapoptotic events [4] and endoplasmic reticulum stress sensed by glucose-regulated protein 78 (GRP78) [5]. The identification of markers that are linked to renal cell carcinogenesis may improve the detection and diagnosis of RCCs and aid in prognosis as well as in appropriate therapy selection [6].…”