The incidence of renal cell carcinoma (RCC) is increasing. Radical cure by surgery can only be achieved in patients with early stage tumors. How to precisely use antineoplastic agents after surgery is an important problem to be solved. Most metastatic RCCs are pathologically identified as clear cell RCC (ccRCC), thus to develop agents targeting ccRCC is critical. Most clinically available targeted therapies are based on targeting some spots in specific pathways; or based on targeting new anti-tumor mechanisms, such as programmed death-1(PD-1), antibody-drug conjugates (ADC) and stem cells. There is still no targeted therapy having definite effect to most RCC patients. Only von Hippel-Lindau (VHL) pathway so far has been confirmed to be related to ccRCC development and progression; the inactivation of VHL gene causes many significant downstream gene changes. The key proteins involved in VHL pathway may be potential therapeutic targets for ccRCC. In this article, we review the current progress of targeted therapy for RCC, focus on the molecular characteristics of ccRCC, its relation to VHL pathway, the potential therapeutic targets and future clinical application for metastatic ccRCC.
Antineoplastic Agents ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; Humans ; Kidney Neoplasms ; drug therapy ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Von Hippel-Lindau Tumor Suppressor Protein ; metabolism

Adenoma, Oxyphilic ; classification ; pathology ; Carcinoma, Renal Cell ; classification ; metabolism ; pathology ; Humans ; Kidney ; pathology ; Kidney Neoplasms ; classification ; genetics ; pathology ; therapy ; Molecular Biology ; methods ; trends

OBJECTIVETo study the morphologic features, immunophenotypes, differential diagnoses and prognosis of histiocytic sarcoma (HS).

METHODSThe clinical and pathologic findings of 6 cases of HS were reviewed. Immunohistochemical assay (Elivision staining) was also performed. Follow-up information was available in 4 patients.

RESULTSThere were altogether 3 males and 3 females. The age of patients ranged from 12 to 81 years old (median = 54.6 years). The sites of involvement included lymph node (number = 2 cases) and skin or soft tissue (number = 4 cases). The tumor was composed of sheets of large epithelioid cells with abundant eosinophilic cytoplasm, oval to irregular nuclei, vesicular chromatin and large nucleoli. Binucleated form was not uncommon. Two of the cases showed increased pleomorphism with multinucleated tumor giant cell formation. Focal cytoplasmic with foamy appearance was identified in 3 cases. One case demonstrated foci of spindly sarcomatoid appearance. Hemophagocytosis was identified in 2 cases. Mitotic figures were readily identified. The tumor cells were often accompanied by various numbers of inflammatory cells. Immunohistochemical study showed that all cases were diffusely positive for leukocyte common antigen, CD4, CD68 and CD163. Four of the 5 cases studied also expressed lysozyme. Amongst the 4 patients with follow-up information available, 3 died of the disease at 6 to 11 months interval after diagnosis. One patient, whose lesion was localized at the skin and soft tissue, survived for 3 years, with no evidence of tumor recurrence.

CONCLUSIONSAccurate diagnosis of the HS is based on the combination of morphologic examination and immunohistochemical assay. HS often presents with clinically advanced disease and pursues an aggressive clinical course, with a poor response to therapy. However, a subset of cases presenting with clinically localized lesion may carry a relatively favorable long-term outcome.

Adult ; Aged ; Aged, 80 and over ; Antigens, CD ; metabolism ; Antigens, Differentiation, Myelomonocytic ; metabolism ; Carcinoma, Renal Cell ; metabolism ; pathology ; Child ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Histiocytic Sarcoma ; drug therapy ; metabolism ; pathology ; surgery ; Humans ; Lymphoma, Large B-Cell, Diffuse ; metabolism ; pathology ; Lymphoma, Large-Cell, Anaplastic ; metabolism ; pathology ; Male ; Melanoma ; metabolism ; pathology ; Muramidase ; metabolism ; Prognosis ; Receptors, Cell Surface ; metabolism ; Skin Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Soft Tissue Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Young Adult

Tumor immunology embraces an extensive array of biological phenomena that include interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the center stage because they can be easily demonstrated to specifically recognize autologous cancer cells. However, their role is limited and other components of the immune response are likely necessary for the completion of cancer rejection. Metastatic melanoma and renal cell carcinoma (RCC) are malignancies strongly predisposed to regress in response to the systemic administration of high-dose interleukin (IL)-2. Several clinical Studies in extensive cohorts of patients have shown that this treatment can induce complete or partial clinical regressions of metastatic disease in 15 to 20% of patients who receive this treatment.1-6 Although IL-2 has direct pluri-potent effects on cells with immune and inflammatory function, it remains unexplained which cell subset is implicated in mediating tumor regression. In a quest to characterize the mechanism of action of IL-2 during the course of immunotherapy, we have investigated the early changes in transcriptional profiles of circulating mononuclear cells and microenvironment of melanoma metastases following high dose IL-2 administration (720,000 IU/kg) by serial sampling of blood cells and tumors in the form of fine needle aspirate (FNA).7 Furthermore, studies are currently ongoing to characterize the proteomic profiling of RCC patients undergoing the same treatment using protein arrays (manuscript in preparation). The predominant activation of genes related to inflammation and activation of mononuclear phagocytes lead us to further characterize this cell subset in the context of stimulation with a panel of soluble factors potentially present in the circulation and tumor microenvironment.
Antibody Formation ; Carcinoma, Renal Cell/metabolism/*therapy ; Gene Expression Profiling ; Humans ; *Immunotherapy ; Interleukin-2/*immunology/*therapeutic use ; Lipopolysaccharides/pharmacology ; Melanoma/genetics/immunology/secondary/*therapy ; Phagocytes/drug effects/physiology ; Proteomics

BACKGROUNDOur previous studies have demonstrated potent oncolysis efficacy of the E1A, E1B double-restricted replication-competent oncolytic adenovirus AxdAdB-3 for treatment of bladder cancer. Here, we reported the feasibility and efficacy of AxdAdB-3 alone, or in combination with gemcitabine for treating renal cell carcinoma.

METHODSCytopathic effects of AxdAdB-3 were evaluated in human renal cell carcinoma cell lines TOS-1, TOS-2, TOS-3, TOS-3LN, SMKT-R3, SMKT-R4 and ACHN, and in normal human renal proximal tubule epithelial cells (RPTEC). AxdAdB-3 induced down-regulation of the cell cycle was determined by flow cytometry. Combination therapies of AxdAdB-3 with gemcitabine were evaluated in vitro and in vivo on subcutaneous TOS-3LN tumors in a severe combined immunodeficiency disease (SCID) mouse model.

RESULTSAxdAdB-3 was potently cytopathic against the tested most renal cell carcinoma cell lines including TOS-2, TOS-3, TOS-3LN, SMKT-R3 and SMKT-R4, while normal human RPTEC were not destroyed. AxdAdB-3 effectively induced cell cycle S-phase entry. Combined therapy of AxdAdB-3 with gemcitabine demonstrated stronger antitumor effects in vitro and in vivo compared with either AxdAdB-3 or gemcitabine alone.

CONCLUSIONAxdAdB-3 alone, or in combination with gemcitabine may be a promising strategy against renal cell carcinoma.

Adenoviridae ; genetics ; metabolism ; physiology ; Adenovirus E1A Proteins ; genetics ; Adenovirus E1B Proteins ; genetics ; Animals ; Antimetabolites, Antineoplastic ; pharmacology ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; therapy ; Cell Cycle ; drug effects ; genetics ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Deoxycytidine ; analogs & derivatives ; pharmacology ; therapeutic use ; Flow Cytometry ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Oncolytic Virotherapy ; Receptors, Virus ; genetics ; metabolism ; Xenograft Model Antitumor Assays