To date there have been no specific tumor markers available for the differential diagnosis of renal cell carcinoma (RCC). In an earlier study we identified high RNA expression of CD70 in clear cell RCC. CD70 is a type II transmembrane protein belonging to the tumor necrosis factor family. It represents the ligand for CD27, a glycosylated transmembrane protein of the tumor necrosis factor receptor family. To our knowledge the function of CD70 in solid tumors is not known. In the current study we analyzed CD70 protein expression in different RCC subtypes.
A total of 68 tumor samples of different histopathological subtypes were investigated by immunochemistry, including 41 clear cell, 19 papillary and 5 chromophobe RCCs, and 3 oncocytomas as well as their normal tissue counterparts. Immunochemistry was performed on frozen tissue samples using monoclonal antibody against CD70.
None of the normal kidney tissues showed CD70 expression. In contrast, all clear cell RCCs expressed CD70 at a high level. Positive immunostaining was observed in 1 papillary (5%) and in 1 chromophobe (20%) RCC. Five papillary tumor samples (26%) showed focal staining in less than 5% of cells. All other samples were negative for CD70.
Our study identified CD70 as a new specific tumor marker for clear cell RCC. This new marker can be used for differential diagnosis in cases of uncertain histological classification. The function of this protein in tumorigenesis and its use as a diagnostic marker in serum and urine or as a therapeutic tool must be investigated in further studies.
"CD70 is a type 2 transmembrane surface antigen belonging to the tumor necrosis factor super family 7.3 CD70 is upregulated in the cancer cells of several malignancies, which could induce cytotoxic effects on B- and T-lymphocytes, and then lead to immune escape.4 Recently, aberrant high CD70 expression in cancer cells has been observed in ovarian carcinomas, and CD70 is regarded as an ideal immunotherapeutic target.5 Ryan et al6 reported that cancerous CD70 was positive in the cancer cells of ovarian cancer tissues, and ovarian cancer cell lines were also demonstrated to be sensitive to the auristatin-based anti-CD70 antibody-drug conjugate, SGN-75, in vitro and in vivo. "
[Show abstract][Hide abstract] ABSTRACT: CD70 has been regarded as a novel potential therapeutic target for multiple cancers. In this study, we characterized the expression of the CD70 protein in ovarian carcinomas and assessed its clinical-pathological prognostic value.
The expression of CD70 in advanced ovarian cancer specimens was assessed by immunohistochemistry. Our results indicated that 16 out of 92 (17.4%) advanced ovarian serous carcinoma tumors showed a high level of CD70 expression. Furthermore, CD70 overexpression was significantly associated with cisplatin-based chemotherapy responses. The high CD70 expression subgroup demonstrated a higher incidence of chemotherapy resistance than the low CD70 subgroup (68.8% versus 25.0%, P = 0.001). Furthermore, univariate analysis conducted on subsets of ovarian carcinoma indicated that high CD70 expression was also associated with decreased survival rates; retained significance was observed on multivariate analysis.
Given the elevated expression of CD70 and its relationship with drug resistance and poor prognosis, our findings suggest that a minor proportion of ovarian carcinomas with CD70 overexpression might be a candidate for the emerging anti-CD70 antibody drug conjugates or therapeutic anti-CD70 antibodies.
OncoTargets and Therapy 06/2013; 6:615-9. DOI:10.2147/OTT.S44445 · 2.31 Impact Factor
"While CD70 is found on over 60% of ccRCC samples tested, its expression in metastatic ccRCC samples approaches a remarkable 100% . Importantly, CD70 is mostly undetectable in normal kidney tissue and highly-restricted in its expression in other normal tissues, making it an ideal antigen for immunocytokine targeting strategies in RCC , , , . "
[Show abstract][Hide abstract] ABSTRACT: Metastatic renal cell carcinoma (RCC) is an incurable disease in clear need of new therapeutic interventions. In early-phase clinical trials, the cytokine IFN-γ showed promise as a biotherapeutic for advanced RCC, but subsequent trials were less promising. These trials, however, focused on the indirect immunomodulatory properties of IFN-γ, and its direct anti-tumor effects, including its ability to kill tumor cells, remains mostly unexploited. We have previously shown that IFN-γ induces RIP1 kinase-dependent necrosis in cells lacking NF-κB survival signaling. RCC cells display basally-elevated NF-κB activity, and inhibiting NF-κB in these cells, for example by using the small-molecule proteasome blocker bortezomib, sensitizes them to RIP1-dependent necrotic death following exposure to IFN-γ. While these observations suggest that IFN-γ-mediated direct tumoricidal activity will have therapeutic benefit in RCC, they cannot be effectively exploited unless IFN-γ is targeted to tumor cells in vivo. Here, we describe the generation and characterization of two novel 'immunocytokine' chimeric proteins, in which either human or murine IFN-γ is fused to an antibody targeting the putative metastatic RCC biomarker CD70. These immunocytokines display high levels of species-specific IFN-γ activity and selective binding to CD70 on human RCC cells. Importantly, the IFN-γ immunocytokines function as well as native IFN-γ in inducing RIP1-dependent necrosis in RCC cells, when deployed in the presence of bortezomib. These results provide a foundation for the in vivo exploitation of IFN-γ-driven tumoricidal activity in RCC.
PLoS ONE 04/2013; 8(4):e61446. DOI:10.1371/journal.pone.0061446 · 3.23 Impact Factor
"One confirmed way for RCC to induce apoptosis in lymphocytes is through FasL expression . Another potential immune-regulatory gene, CD70, a member of the tumor necrosis superfamily, has been identified in earlier studies to be specifically overexpressed in clear cell RCC  . "
[Show abstract][Hide abstract] ABSTRACT: Tumors can escape immune recognition and destruction through the induction of apoptosis in lymphocytes. Although renal cell carcinoma (RCC) is able to prevent immune recognition, only a few genes (such as FasL) that are relevant for RCC immune escape have been identified so far. We have previously shown that some apoptosis-inducing genes are overexpressed in RCC. We hypothesized that these genes could be part of the immune-escape strategy of these tumors. Here we report that CD70, a cytokine overexpressed in RCC, promotes lymphocyte apoptosis through interaction with its receptor CD27 and with the intracellular receptor-binding protein SIVA. Apoptosis increased after cocultivating lymphocytes with the RCC cell lines A498 and CAKI2. The addition of recombinant soluble CD70 to both native lymphocytes and a T-cell cell line resulted in increased lymphocyte apoptosis as well. Furthermore, induced apoptosis could be partially blocked with anti-CD27 and anti-CD70 antibodies. Our results strongly indicate a role for CD70 and CD27 receptor in lymphocyte apoptosis within the tumor environment. Apoptosis mediated by exposure to the CD70 secreted by tumor cells may contribute to the failure of RCC patients to develop an effective lymphocyte-mediated antitumor response.
Neoplasia (New York, N.Y.) 12/2006; 8(11):933-8. DOI:10.1593/neo.06451 · 4.25 Impact Factor
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