Biomedical subjects

Silvia I Gervasoni

Publications and source records attributed to Silvia I Gervasoni.

5 recordsLinked to original sources

PubMed2006

Low-dose cyclophosphamide modulates galectin-1 expression and function in an experimental rat lymphoma model.

In recent years, one of the most important insights into tumor immunity was provided by the identification of negative regulatory pathways and immune escape strategies that greatly influence the magnitude of antitumor responses. Galectin-1 (Gal-1), a member of a family of highly conserved beta-galactoside-binding proteins, has been recently shown to contribute to tumor cell evasion of immune responses by modulating survival and differentiation of effector T cells. However, there is still scarce information about the regulation of Gal-1 expression and function in vivo. Here we show that administration of a single low-dose cyclophosphamide (Cy), which is capable of restraining metastasis in the rat lymphoma model L-TACB, can also influence Gal-1 expression in primary tumor, metastasis, and spleen cells and modulate the effects of this protein on T cell survival. A time-course study revealed a positive correlation between Gal-1 expression and tumor volume in primary tumor cells. Conversely, Gal-1 expression was significantly reduced in spleen cells and lymph node metastasis throughout the period studied. Interestingly, cyclophosphamide treatment was capable of restoring the basal levels of Gal-1 expression in primary tumors and spleens. In addition, this antimetastatic agent rendered spleen T cells from tumor-bearing animals resistant to Gal-1-induced cell death. Our results suggest that, in addition to other well-known functions of cyclophosphamide, this immunomodulatory agent may also modulate Gal-1 expression and function during tumor growth and metastasis with critical implications for tumor-immune escape and immunotherapy.

Animals↗

PubMed2005

The transition to the metastatic phenotype of rat lymphoma cells involves up-regulation of IL-10 receptor expression and IL-10 secretion.

Interleukin 10 (IL-10) is a Th2 anti-inflammatory cytokine that participates in the regulation of the immune response at several levels. Its production has been implicated in the immunosuppression frequently observed in tumor bearing hosts. The broad spectrum of IL-10 biologic activities is mediated by its binding to its cognate receptor (IL-10R). We have already demonstrated the overproduction of IL-10 by B-cell lymphoma tumor bearing rats and, also, that IL-10 could act as a growth factor for metastatic cells. Considering the importance to unravel each feature of the complex biology of metastasis, the goal of the present study was to investigate the expression of IL-10 receptor (IL-10R), at mRNA and protein level, in primary tumor and metastatic cells from a rat B-cell lymphoma, along with the production of IL-10 by both tumor cell types. Our results indicate that IL-10, besides its immunoregulatory effect, would act as an autocrine growth factor for cells with metastatic phenotype. Also, the up-regulation of IL-10 and IL-10R expression would be part of the transition from primary tumor to the metastatic phenotype.

Animals↗

PubMed2003

Hsp25 and Hsp70 in rodent tumors treated with doxorubicin and lovastatin.

Heat shock protein 27 (Hsp27) and Hsp70 have been involved in resistance to anticancer drugs in human breast cancer cells growing in vitro and in vivo. In this study, we examined the expression of Hsp25 (the rodent homologue to human Hsp27) and Hsp70 in 3 different rodent tumors (a mouse breast carcinoma, a rat sarcoma, and a rat lymphoma maintained by subcutaneous passages) treated in vivo with doxorubicin (DOX) and lovastatin (LOV). All tumors showed massive cell death under control untreated conditions, and this massive death increased after cytotoxic drug administration. In this study, we show that this death was due to classic apoptosis. The tumors also showed isolated apoptotic cells between viable tumor cells, and this occurred more significantly in the lymphoma. The tumor type that was more resistant to cell death was the sarcoma, and this was found in sarcomas growing both under control conditions and after cytotoxic drug administration. Moreover, sarcomas showed the highest expression levels of Hsp25 in the viable tumor cells growing under untreated conditions, and these levels increased after DOX and LOV administration. After drug treatment, only sarcoma tumor cells showed a significant increase in Hsp70. In other words, sarcomas were the tumors with lower cell death, displayed a competent Hsp70 and Hsp25 response with nuclear translocation, and had the highest levels of Hsp25. In sarcomas, Hsp25 and Hsp70 were found in viable tumor cells located around the blood vessels, and these areas showed the most resistant tumor cell phenotype after chemotherapy. In addition, Hsp25 expression was found in endothelial cells as unique feature revealed only in lymphomas. In conclusion, our study shows that each tumor type has unique features regarding the expression of Hsp25 and Hsp70 and that these proteins seem to be implicated in drug resistance mainly in sarcomas, making these model systems important to perform more mechanistic studies on the role of Hsps in resistance to certain cytotoxic drugs.

Adenocarcinoma↗

PubMed2002

Differential production of angiostatin by concomitant antitumoral resistance-inducing cancer cells.

The phenomenon by which tumor-bearing hosts are capable of inhibiting secondary tumor implants or metastases, known as concomitant antitumoral resistance (CAR), is presumably due to antiangiogenesis at places distant from the primary tumor. Although angiostatin, a potent inhibitor of angiogenesis, has been reported to be one of the factors responsible for suppressing the growth of secondary tumors in mice bearing previous tumors, it has not been definitively proven yet. With the aim of investigating whether CAR-inducing cancer cells display a differential angiostatin production and to support the role ascribed to that molecule concerning the inhibition of secondary tumor implants, 5 tumor models with different CAR-inducing capacities were studied herein. One of the 2 human lung cancer cell lines analyzed revealed a strong CAR against secondary s.c. tumor implants in nude mice, and 2 of 3 of the murine mammary tumors used exhibited inhibitory effect on secondary s.c. and i.v. tumor inoculations in syngeneic hosts. Since angiostatin is a proteolytic fragment from plasminogen, we examined by Western blot the ability of all conditioned media collected from the tumor cells studied to convert plasminogen to angiostatin. An association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin was found. Since different enzymatic mechanisms were described to explain the generation of angiostatin, we also studied gelatinase and urokinase-type plasminogen activator secretion in conditioned media by zymography. The conversion of plasminogen into angiostatin by conditioned media was mainly inhibited by broad-spectrum serine proteinase inhibitors, suggesting a possible role for 1 or more enzymes of that group in the process. These findings suggest the existence of a differential angiostatin generation by CAR-inducing cancer cells, providing additional support to previous data obtained by other authors.

Angiogenesis Inhibitors↗

PubMed2001

Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model.

Cyclophosphamide (Cy) is an alkylating agent widely used in cancer chemotherapy. It has a bimodal effect on the immune system, depending on the dose and schedule of administration. We have previously demonstrated that a single low dose of Cy has an antimetastatic effect, achieved through immunomodulation, in lymphoma bearing rats. Such a treatment reduced the splenic production of IL-10, TGF-beta, and NO, restoring the lymphoproliferative capacity. A shift from immunosuppression to immunopotentiation induced by low-dose Cy treatment was mainly mediated by a decrease in IL-10 production. The present study focused on the analysis of the modulation of type-1 cytokine levels by treatment with a single low dose of Cy and the effect these cytokines (IL-2 and IFN-gamma) and IL-10 have on primary tumor and metastatic cell growth. Our results suggest that a single low dose of Cy induces a Th2/Th1 shift in the cytokine profile of lymphoma-bearing rats, which may be responsible for its antimetastatic effect. A direct action of IL-10 as a growth factor and IFN-gamma as a cytotoxic factor on metastatic cells is also shown.

Adjuvants, Immunologic↗