The etiology of renal-cell carcinoma

Experimental renal-cell carcinoma can be induced by many different chemical carcinogens; dimethyl nitrosoamine has been most studied. The disease so induced in experimental animals closely resembles the spontaneous disease in man in histopathology, course, and other characteristics. Two agents that are probably etiological of renal-cell cancer in man are tobacco and the analgesic, phenacetin; however, these materials can account for only a minority of the cases. The predominance of males in adult renal carcinoma might be explained by the more efficient metabolic activation of carcinogens by renal enzymes that are induced by male hormones. Mouse experiments support this hypothesis. Studies utilizing human kidney tissues that would test the hypothesis in man can and should be done. No obvious clues have emerged to explain the wide geographic differences in incidence of renal carcinoma. No group of industrial workers, or of others with a unique environment, has yet been described that has an especially high incidence of renal-cell carcinoma. A minority of renal carcinomas are familial. They represent a number of different diseases, one of which is associated with the von Hippel-Lindau disease. The hereditary renal-cell carcinoma of the Ecker rat, which is transmitted as an autosomal dominant, provides a useful laboratory model for hereditary carcinoma of man. Recently, two human families with renal-cell carcinoma were described in which there were unique chromosomal abnormalities associated with the disease. Such changes have been linked with oncogene activation in the instance of other tumors. Further studies of chromosomal abnormalities in renal-cell carcinoma will probably define a common pattern of chromosomal rearrangements. While estrogen readily induces renal-cell carcinoma in hamsters other species, including man, appear resistant. An excess of renal-cell carcinoma has not been reported in men on chronic estrogen therapy for prostatic carcinoma, nor has it been associated with the DES syndrome. A virus etiology for renal-cell carcinoma in man comparable to that of the Lucke tumor in frogs is unlikely on epidemiologic, ultrastructural morphologic, and other grounds. There is nothing suggesting horizontal transmission in the human disease, and a unique excess of renal-cell carcinomas in immunosuppressed patients or patients with the acquired immunodeficiency syndrome (AIDS) is not apparent. There is overwhelming evidence that renal adenomas represent early adenocarcinomas, or at least precursor lesions; certainly they are closely related to renal-cell carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)     

Molecular biology of renal-cell carcinoma

Renal-cell cancer (RCC) is an heterogeneous disease consisting of different subtypes that show peculiar histological features and genetic alterations. Although inherited or familial predisposition occurs in less than 4% of renal cancers, most of the available information on the genetic alterations involved in the pathogenesis of RCC derives from the study of the inherited forms of kidney cancer: von Hippel-Lindau (VHL gene), hereditary papillary renal carcinoma (MET proto-oncogene), hereditary leiomyomatosis and renal-cell cancer (fumarate hydratase gene), and Birt–Hogg–Dube (BHD gene) syndromes. Such genetic alterations have also been detected in sporadic RCCs. In particular, inactivation of VHL gene by mutation or hypermethylation has been found in up to 70% of sporadic clear-cell RCC, and it has been associated with increased hypoxia-inducible factor (HIF) activity. The knowledge of these deregulated genes and their downstream pathways provides the rationale for the development of target-based approaches for RCC.     

Choosing the right cell line for breast cancer research

Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research.     

Allogeneic stem-cell transplantation in renal-cell carcinoma

Metastatic renal-cell carcinoma (RCC) remains resistant to nearly all standard cytotoxic therapies, but immune-based cytokine therapies benefit a small minority of patients with advanced RCC. Nonmyeloablative allogeneic stem-cell transplantation is a novel approach to harnessing the immune system to combat this cancer. The strategy relies on a T-cell graft-versus-malignancy effect mediated by donor T cells. Preliminary work in using nonmyeloablative allogeneic stem-cell transplant in RCC has identified a graft-versus-RCC effect and yielded encouraging clinical responses.     

High-dose toremifene in advanced renal-cell carcinoma

 Toremifene (Fareston) – a novel antiestro-genic drug with a triphenylethylene structure – is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35–75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC. Received: 5 May 1996 / Accepted: 5 November 1996     

Sunitinib re-challenge in advanced renal-cell carcinoma

Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment ‘re-challenge'' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re-challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re-challenge.     

Human renal-cell carcinoma tissue contains dendritic cells

Immune surveillance of cancer requires antigen-presenting cells which activate T cells specific for tumor-associated antigens. We show here that substantial numbers of dendritic cells, which are the most potent antigen-presenting cells, emigrate from renal-tumor explants in organ culture. Tumor-derived dendritic cells presented with all characteristics of mature dendritic cells. Dendritic cells could be identified by typical cytoplasmic projections (=veils). They expressed high levels of MHC products and of the co-stimulator CD86 (B7-2). Dendritic cells expressed the CD45RO isoform but not CD45RA. The most important point was that up to 9% of the emigrating leukocytes expressed the CD83 antigen, a specific marker for mature dendritic cells. CD83⁺ cells were approximately 40-fold enriched in the tumor tissue as compared to the peripheral blood. In contrast to cultured blood dendritic cells, tumor-emigrant dendritic cells had a reduced potential to capture soluble antigen, as shown by the exclusion of fluoresceinated Dextran molecules. Finally, in mixed leukocyte reactions, tumor-derived dendritic cells were able to stimulate naive T cells from cord blood, which is a unique feature of dendritic cells. This study demonstrates that genuine dendritic cells reside in or infiltrate renal-cell carcinoma tissue. The failure of patients with renal-cell carcinoma to mount an anti-tumor immune response despite the presence of professional antigen-presenting cells in the tumor tissue suggests that tumor-associated dendritic cells are suppressed in situ, in a similar way to that described for tumor-infiltrating lymphocytes. © 1996 Wiley-Liss, Inc.