RESUMO
Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-beta1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer.
Assuntos
Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/fisiologia , Neoplasias do Colo do Útero/genética , Apoptose/efeitos dos fármacos , Carcinoma/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismoRESUMO
OBJECTIVE: To investigate the expression and regulation of colony-stimulating factor 1 (CSF-1) and its receptor, C-FMS, in endometriosis. DESIGN: In vivo and vitro study. SETTING: University-based academic medical center. PATIENT(S): Reproductive-age women undergoing surgery for benign conditions. INTERVENTION(S): Peritoneal and endometrial tissue samples were obtained. MAIN OUTCOME MEASURE(S): CSF-1 and C-FMS expression. RESULT(S): Significantly higher CSF-1 levels were found in peritoneal fluid of patients with endometriosis compared with control subjects. Ectopic endometriotic tissue had 3.5-fold and 1.7-fold increases in CSF-1 and C-FMS expression, respectively, compared with eutopic tissue. Coculture of endometrial cells from either established cell lines or patient samples with peritoneal mesothelial cells (PMCs) led to increased expression of CSF-1 and C-FMS. A higher but nonsignificant increase in levels of C-FMS and CSF-1 was found in cocultures of endometrial epithelial cells from patients with endometriosis compared with those without endometriosis. CONCLUSION(S): Increased CSF-1 levels may contribute to endometriosis lesion formation and progression. Elevation in CSF-1 after coculture of endometrial cells with PMCs suggests that endometrial tissue may be a source of peritoneal CSF-1. Increased C-FMS expression in endometrial cells from women with endometriosis cocultured with PMCs suggests that endometrial tissue involved in lesion formation is highly responsive to CSF-1 signaling.
Assuntos
Endometriose/imunologia , Endométrio/imunologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Centros Médicos Acadêmicos , Líquido Ascítico/imunologia , Comunicação Celular , Células Cultivadas , Técnicas de Cocultura , Endometriose/genética , Endometriose/patologia , Endométrio/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/genética , Peritônio/imunologia , Peritônio/patologia , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Células Estromais/imunologia , Células Estromais/patologia , Texas , Regulação para CimaRESUMO
A mouse containing an IL-4 promoter linked to the yellow fluorescent protein (YFP) reporter transgene was created to follow aspects of lymphocyte development and function. Following stimulation with phorbol 12-myristate 13-acetate and ionomycin, anti-CD3/CD28, antigen-specific peptide, or allogeneic cells, both CD4 and CD8 T cells expressed the transgene within 24h in a manner that was consistent with cellular activation markers. Transgene induction was inhibited by cyclosporine and FK506, suggesting that its activation occurs in an NFAT-dependent manner. B lymphocytes were also able to express the transgene when stimulated with LPS. This induction was inhibited in part by rapamycin. The results suggest that this transgene can function as an indicator of lymphocyte activation. Because YFP is not toxic and requires no preparation of the cells to view the reporter gene, this system provides a unique tool to follow lymphocyte activation in a number of model systems, such as those involving transplantation, allergy, and vaccine development.