Suppression of tropomyosins (TMs), a family of actinbinding, microfilament-associated proteins, is a prominent feature of many transformed cells. Yet it is unclear whether downregulation of TMs occur in human tumors. We have investigated the expression of tropomyosin-1 (TM1) in human breast carcinoma tissues by in situ hybridization and immunofluorescence. TM1 mRNA and protein are readily detectable in normal mammary tissue. In contrast, TM1 expression is abolished in the primary human breast tumors. Expression of other TM isoforms, however, is variable among the tumors. The consistent and profound downregulation of TM1 suggests that TM1 may be a novel and useful biomarker of mammary neoplasms. These data also support the hypothesis that suppression of TM1 expression during the malignant conversion of mammary epithelium as a contributing factor of breast cancer. In support of this hypothesis, we show that the ability to suppress malignant growth properties of breast cancer cells is specific to TM1 isoform. Investigations into the mechanisms of TM1-induced tumor suppression reveal that TM1 induces anoikis (detachment induced apoptosis) in breast cancer cells. Downregulation of TM1 in breast tumors may destabilize microfilament architecture and confer resistance to anoikis, which facilitates survival of neoplastic cells outside the normal microenvironment and promote malignant growth.

BACKGROUND. The objective of the current study was to investigate the clinical usefulness of serum fucose, fucosylated glycoproteins (fucoproteins), fucosyltransferase (FucT), and α‐L‐fucosidase in oral carcinoma. METHODS. Blood samples were collected from 130 patients with untreated oral cancer (OC), from 75 patients with oral precancerous conditions (OPC), and from 100 healthy controls. Cancer patients were followed after the initiation of anticancer treatments, and 75 follow‐up samples were also collected. Serum levels of fucose and α‐L‐fucosidase were measured spectrophotometrically. Fucoproteins were detected by using lectin‐affinity chromatography. FucT activity was analyzed by using radioassay. RESULTS. Serum levels of fucose and fucoprotein were found to be increased significantly in patients with untreated OC compared with controls, patients with OPC, and complete responders (CR) to treatment; whereas the levels were comparable between untreated patients with OC and nonresponders (NR). A similar trend was observed for serum FucT levels, and changes in enzyme activity correlated well with fucose and fucoprotein alterations. The OPC group had significantly increased fucosylation of serum proteins. Furthermore, serum α‐L‐fucosidase activity was markedly higher in patients with untreated OC and in patients with OPC compared with controls. Using receiver operating characteristic curves, a cutoff for α‐L‐fucosidase was determined at >450.6 U/mL, which showed good sensitivity and specificity in OC and OPC compared with controls. The enzyme activity was declined in the CR group but remained higher in the NR group compared with pretreatment levels. Furthermore, various clinicopathologic characteristics were correlated positively with serum fucosylation changes. CONCLUSIONS. The findings of the current study suggest that serum fucosylation has clinical usefulness in the detection of early changes and for monitoring treatment response in patients with OC. Among the markers studied, serum α‐L‐fucosidase was identified as a useful marker for close monitoring of patients during post–treatment follow‐up. Cancer 2008. © 2008 American Cancer Society.

No abstract

Purpose: We reported that in renal cell carcinoma patients with active disease, T-cell reactions to the tumorassociated antigens MAGE-6 and EphA2 are highly skewed toward T H 2-type cytokine responses [interleukin (IL) 5]. Herein, we determined whether tumor-derived products, including gangliosides isolated from renal cell carcinoma patients, participate in the down-regulation of type 1 T-cell responses.Experimental Design: T cells from healthy volunteers or renal cell carcinoma patients were cultured in the presence and absence of supernatants derived from renal cell carcinoma explants or with gangliosides isolated from those tumor supernatants. T cells were stimulated or not with either autologous dendritic cells pulsed with superantigen (Staphylococcus enterotoxin B) or with phorbol 12-myristate 13-acetate and ionomycin and then were assessed for type 1 or type 2 responses (cytokine production and gene expression) and apoptosis. Results: Tumor supernatants efficiently inhibited the T H 1-type responses [interferon (IFN) ␥] of T cells stimulatedwith either S. enterotoxin B or phorbol 12-myristate 13-acetate and ionomycin but had no inhibitory effect on activated T-cell production of type 2 cytokines (IL-4, IL-5, and IL-10). Likewise, IFN-␥ mRNA and protein production were inhibited when T cells were cocultured with either renal cell carcinoma supernatant-derived gangliosides or a commercial source of purified GD1a. It was also determined that gangliosides impair type 1 responses by inducing apoptosis of activated T cells.Conclusions: We propose that renal cell carcinomaderived tumor products such as gangliosides can induce a type 2 bias in antitumor immunity by initiating apoptosis in the IFN-␥-producing type 1 effector cells. This represents a relevant mechanism by which renal cell carcinoma can inhibit protective antitumor immunity.

Our results confirmed the elevations in sialic acid and sialyltransferase levels in OC patients and suggested potential utility of these parameters in prognostication and treatment monitoring of this neoplasm. The alterations in these parameters in circulation were in accordance with the changes in alpha 2-6 sialylated proteins.

Sialic acid, the end moieties of the carbohydrate chains are biologically important and essential for functions of glycoconjugates and are reported to be altered in cancer patients. Two hundred and twenty five breast cancer (BC) patients, 100 patients with benign breast disease (BBD) and 100 healthy females (controls) were enrolled for the study. Eight hundred and twenty four f011ow-up samples of 225 breast carcinoma patients were also evaluated. The association of static acid forms, sialyltransferase and ~-2-6 sialoproteins levels with presence and extent as well as prognosis of breast carcinoma was studie~. Serum sialic acid forms and sialyltransferase revealed significantly elevated levels among untreated breast cancer patients as compared to the controls, patients with BBD as well as cancer patients in remission. Non-responders showed comparable levels of the markers with those found in breast cancer patients at the time of diagnosis. Higher levels of sialic acid forms at diagnosis were associated with poor prognosis. A positive correlation between serum levels of different forms of sialic acids and extent of malignant disease was observed. The changes in serum proteins with terminal a-2-6 sialic acid correlated well with alterations in the levels of sialic acid forms and sialyltransferase. Malignant tissues showed elevated levels of sialic acid and sialyltransferase as compared to surrounding normal tissues.The results suggested potential utility of these markers in evaluation of clinical outcome.

Previous studies from our laboratory demonstrated the role of tumor-derived gangliosides as important mediators of T cell apoptosis, and hence, as one mechanism by which tumors evade immune destruction. In this study, we report that TNF-α secreted by infiltrating inflammatory cells and/or genetically modified tumors augments tumor-associated GM2 levels, which leads to T cell death and immune dysfunction. The conversion of weakly apoptogenic renal cell carcinoma (RCC) clones to lines that can induce T cell death requires 3–5 days of TNF-α pretreatment, a time frame paralleling that needed for TNF-α to stimulate GM2 accumulation by SK-RC-45, SK-RC-54, and SK-RC-13. RCC tumor cell lines permanently transfected with the TNF-α transgene are similarly toxic for T lymphocytes, which correlates with their constitutively elevated levels of GM2. TNF-α increases GM2 ganglioside expression by enhancing the mRNA levels encoding its synthetic enzyme, GM2 synthase, as demonstrated by both RT-PCR and Southern analysis. The contribution of GM2 gangliosides to tumor-induced T cell death was supported by the finding that anti-GM2 Abs significantly blocked T cell apoptosis mediated by TNF-α-treated tumor cells, and by the observation that small interfering RNA directed against TNF-α abrogated GM2 synthase expression by TNF-transfected SK-RC-45, diminished its GM2 accumulation, and inhibited its apoptogenicity for T lymphocytes. Our results indicate that TNF-α signaling promotes RCC-induced killing of T cells by stimulating the acquisition of a distinct ganglioside assembly in RCC tumor cells.

No abstract