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Antigens associated with tumors have proven valuable in cancer immunotherapy. Their insufficient expression in the majority of tumors, however, limits their potential value as therapeutic markers. Aiming for a noninvasive approach applicable in clinical practice, we investigated the possibility of using focused shock waves to induce membrane expression of hidden intracellular tumor markers. Here, we studied the in vitro effect of a thousand focused shock waves at 16 MPa overpressure on the membrane expression of a cytosolic glycosphingolipid, monosialosyl-galactosyl-globoside (MSGG). Double-staining flow cytometry with propidium-iodide and monoclonal antibody RM1 revealed an immediate increase in MSGG expression on renal carcinoma cells (18% ± 0.5%) that reached its peak value (20.73% ± 0.4%) within one hour after the shock waves. The results of immunoelectron microscopy confirmed the incorporation of MSGG into newly formed cytosolic vesicles and their integration with the cell membrane. Based on the enzymatic nature of MSGG production that is not controlled directly by genes, the immediate upregulation of MSGG membrane expression implies that a chain of mechanochemical events affecting subcellular structures are responsible for the shock-wave-induced antigenic modification. Physically unmasking hidden tumor antigens and enhancing their expression by focused shock waves presents a potential noninvasive method of boosting tumor immunogenicity as a theranostic strategy in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Human renal cell carcinoma (RCC) has been characterized by remarkable changes in ganglioside composition. TOS1 cells, typical of metastatic RCC, are characterized by predominance of GM2 as monosialoganglioside, and β1,4GalNAc disialyl-Lc4 (RM2 antigen) as disialoganglioside [J. Biol. Chem. 276 (2001) 16695]. In order to observe the functional role of gangliosides in RCC malignancy, TOS1 cells were transfected with short interfering RNA (siRNA) based on open reading frame sequence of β1,4GalNAc transferase (β1,4GalNAc-T), and its disordered sequence of siRNA (dsiRNA) as control. In siRNA transfectant, β1,4GalNAc-T mRNA level and GM2 expression were greatly reduced, whereby GM3 expression appeared. In contrast, RM2 antigen level was unchanged, even though it has the same β1,4GalNAc epitope at the terminus. dsiRNA transfectant showed no change of β1,4GalNAc-T mRNA and did not express GM3. Concomitant with reduction of GM2 and appearance of GM3, siRNA transfectant showed greatly reduced motility and invasiveness, although growth rate was unaltered. Both transfectants with siRNA and dsiRNA expressed the same level of tetraspanin CD9. Since CD9/GM3 complex is known to reduce integrin-dependent motility and invasiveness [Biochemistry 40 (2001) 6414], it is plausible that motility and invasiveness of siRNA transfectant of TOS1 cells may be reduced by enhanced formation of such complex. [Copyright &y& Elsevier]

Sarcomatoid renal cell carcinoma (SRCC) is associated with an aggressive course, high incidence of bone metastasis, and an extremely poor prognosis. There are a few case reports concerning the effectiveness of chemotherapy on metastasis in SRCC. To our knowledge, however, there are no reports describing its effectiveness on bone metastasis. We report a 22-year-old woman with an 8-cm × 7-cm left renal mass. Left nephrectomy was done. The pathological diagnosis was SRCC, INF-β, pT3aN2. Although, she received continuous infusion of interferon α-2a (INFα-2a) and interleukin-2 (IL-2) as adjuvant therapy, liver metastasis appeared 2 months later. Resection of the liver metastasis was done. After resection of the metastasis, multiple bone metastases appeared, in both humeri, the left chest wall, the left fourth rib, and the left iliac bone. The patient was treated with gemcitabine, 1000 mg/m2 (days 1, 8), docetaxel 80 mg/m2 (day 1), and carboplatin 300 mg/m2 (day 1). A computed tomography (CT) scan after the first cycle revealed that the multiple osteolytic bone tumors had significantly decreased in size. Her ability of daily life (ADL) improved and this continued for almost 2 months. A second course of chemotherapy, with gemcitabine and IL-2 was given, but it was ineffective, and the patient died approximately 16 months after the initial diagnosis of SRCC. Combination chemotherapy with gemcitabine, docetaxel, and carboplatin was effective for the bone metastasis of SRCC. [ABSTRACT FROM AUTHOR]

Abstract Background: The present study provides data from clinical experience with gamma-knife radiosurgery (GK) in patients with brain metastasis from renal cell carcinoma (RCC) and shows the value of this less invasive treatment modality. Methods: Forty-two patients received GK. Twenty of the 42 cases had multiple brain metastases. Extracranial metastases were observed in the lung (38 cases), bone (12 cases), liver (9 cases), lymph node (5 cases) and skin (6 cases). Results: Neurological symptoms seen in 40 patients were rapidly improved after GK in 32 patients (80%). Magnetic resonance imaging (MRI) evaluation after GK in 32 patients showed the disappearance of brain tumor in 9 patients (28%). Complete response was obtained by GK in tumors up to 30 mm in diameter. Repeated GK for newly developed lesions was conducted in 11 patients. Extracranial tumor resection was conducted in 7 cases (lung: 3, skin: 2, liver: 1, adrenal: 1). Chemo-radiotherapy or immunotherapy was effective in 8 cases (lung: 5, liver: 2, bone: 1). The actual one-, two- and three-year survival rates were 44.9%, 16.8%, and 11.2%, respectively. The median survival time was 12.5 months. In univariate analysis, the patients with successfully treated extracranial metastases had significantly better prognosis. In multivariate analysis, the patients with Karnofsky performance scale (KPS) ≥ 80%, who were treated by GK more than once and obtained complete response (CR) or partial response (PR) by GK, had significantly better prognosis. Conclusion: Gamma-knife radiosurgery for RCC is an effective non-invasive modality of treatment. It offers a high local control rate and an improved quality of life and survival rate. [ABSTRACT FROM AUTHOR]

Abstract Background : The present study examined adrenal metastasis resulting from renal cell carcinoma (RCC), with the aim of assessing the need for routine ipsilateral adrenalectomy during radical nephrectomy. Methods : Ipsilateral and contralateral adrenal metastases were investigated in 256 patients with RCC who had undergone radical nephrectomy from 1977 to 1996 at the Tohoku University School of Medicine. Results : Twelve of the 256 patients (4.7%) had adrenal metastasis. Ten of these 12 patients had progressed to disseminated disease with very poor prognosis. Two patients who had solitary adrenal metastases remained disease-free for 21 and 7 years. Four patients showed metastases to the contralateral adrenal gland. Adrenal metastases in seven of 12 patients were identified by pre- or postoperative computed tomography (CT), and in another five macroscopically during surgery. Conclusions : Adrenalectomy was regarded as a possible curative treatment for patients with solitary adrenal metastasis. However, the incidence of this kind of metastasis was minimal and contralateral adrenal metastases may occur in RCC cases. We therefore believe that adrenalectomy should only be performed if radiographic evidence reveals metastases in the adrenal gland or if gross disease is present at the time of nephrectomy. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) has been characterized by high expression of three types of disialogangliosides: two based on lacto-series type 1 structure (disialosyl Lc4, GalNAc disialosyl Lc4), the other based on globo-series structure (disialosyl globopentaosylceramide; disialosyl Gb5). The present study established a mAb, 5F3, directed to disialosyl Gb5. 5F3 was established after immunization with RCC cell line ACHN. The major disialoganglioside antigen isolated from ACHN cells, showing specific reactivity with 5F3, was characterized unequivocally as disialosyl Gb5 (V3NeuAcIV6NeuAcGb5) by identification of the core structure as globopentaosylceramide (Gb5) after enzymatic and acid hydrolysis, and by 2-dimensional 1H-NMR spectroscopy. 5F3 does not react with monosialosyl Gb5 (V3NeuAcGb5), Gb5, or any lacto-series structures. 5F3 strongly stained 19 of 41 cases of primary RCC tissue. It reacted with proximal tubules (but not distal tubules) of kidney, microglial cells of cerebrum and cerebellum, goblet cells of stomach and intestine, smooth muscle of various organs. It did not react with parenchymatous cells of various organs, except for kidney epithelia and prostate stroma. Immunostaining of RCC tissue by mAb 5F3, in combination with staining by other antibodies directed to globo-series and lacto-series structures, has prognostic significance in defining metastatic potential of RCC. [ABSTRACT FROM AUTHOR]

Human plasma membrane-associated sialidase (NEU3), specifically hydrolyzing gangliosides, plays crucial roles in the regulation of cell surface functions. Here we demonstrate that NEH3 mRNA level are increased in renal cell carcinomas (RCCs) compared with adjacent non-tumor tissues, significantly correlating with elevation of interleukin-6 (IL-6), a pleiotropic cytokine that has been implicated in immune responses and pathogenesis of several cancers, including RCCs. In human RCC ACHN cells, IL-6 treatment enhanced NEU3 promoter luciferase activity 2.5-fold and the endogenous sialidase activity significantly. NEU3 transfection or IL-6 treatment resulted in both suppression of apoptosis and promotion of cell motility, and the combination had synergistic effects. NEU3 scarcely affected MAPK- or IL-6-induced STAT3 activation but promoted the phosphatidylinositol 3-kinase (PI3K)/Akt cascade in both IL-6-dependent and -independent ways. Consistent with these data, NEU3 markedly inhibited staurosporine-induced caspase-3 activity and enhanced IL-6-dependent inhibition, which was abolished by LY294002, a PI3K inhibitor. Furthermore, IL-6 promoted Rho activation, and the effect was potentiated by NEU3, leading to increased cell motility that was again affected by LY294002. NEU3 silencing by siRNA resulted in the opposite: decreased Akt phosphorylation and inhibition of Rho activation. Gycolipid analysis showed a decrease in ganglioside GM3 and increase in lactosylceramide after NEU3 transfection, with these lipids apparently affecting cell apoptosis and motility. The results indicate that NEU3 activated by IL-6 exerts IL-6-mediated signaling, largely via the PI3K/Akt cascade, in a positive feedback manner and contributes to expression of a malignant phenotype in RCCs. NEU3 thus may be a useful target for RCC diagnosis and therapy. [ABSTRACT FROM AUTHOR]