Asunto(s)
Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/inmunología , Lipocalina 2/deficiencia , Macrófagos/inmunología , Neumonía Bacteriana/inmunología , Mucosa Respiratoria/inmunología , Animales , Infecciones por Klebsiella/genética , Infecciones por Klebsiella/patología , Lipocalina 2/inmunología , Macrófagos/patología , Ratones , Ratones Noqueados , Neumonía Bacteriana/genética , Neumonía Bacteriana/patología , Mucosa Respiratoria/patologíaRESUMEN
NGAL/lipocalin-2 is a siderophore-binding protein that is highly expressed in several cancers. It is suggested to confer a proliferative advantage to cancer cells. Its expression has been correlated with aggressiveness of breast cancer as determined both in patients and in mouse breast cancer models. This was recently confirmed in two mouse models of spontaneous breast cancer in wild-type and lipocalin-2-deficient mice. We used a similar strategy using a different mouse strain. Lipocalin-2-deficient mice and mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice were crossed into the same FVB/N background. All mice developed tumors by week 8. The mice were sacrificed on week 13 and tissue was processed for biochemical and histological analysis. The total tumor volume and number of metastases were quantitated in 26 lipocalin-2-deficient mice and 34 wild-type controls. Lipocalin-2 expression in tumors of MMTV-PyMT-positive and wild-type mice was assessed by quantitative real-time PCR and by immunohistochemistry. The expression of the lipocalin-2 receptors 24p3R and megalin and of Mmp-9, transferrin receptor, and Bdh2 (a producer of a mammalian siderophore) were quantitated by real-time PCR. No significant difference was observed between wild-type and lipocalin-2-deficient mice. Lipocalin-2 was highly expressed in tumors from wild-type mice, but the expression did not correlate with tumor size. No effect of lipocalin-2 was observed with respect to time to tumor appearance, total tumor volume, or to the number of metastases. Histology and gelatinolytic activity of the mammary tumors did not differ between wild-type and lipocalin-2-deficient mice. We conclude that NGAL/lipocalin-2 does not invariably affect the aggressiveness of breast cancers as assessed in mouse models, thus questioning the role of lipocalin-2 in cancer development.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Lipocalinas/metabolismo , Proteínas Oncogénicas/metabolismo , Animales , Antígenos Transformadores de Poliomavirus/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Granulocitos/citología , Humanos , Inmunohistoquímica/métodos , Lipocalina 2 , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/biosíntesis , Masculino , Metaloproteinasa 9 de la Matriz/biosíntesis , Ratones , Ratones Noqueados , Receptores de Superficie Celular/biosíntesis , Receptores de Transferrina/biosíntesisRESUMEN
OLFM4 was identified initially as a gene highly induced in myeloid stem cells by G-CSF treatment. A bioinformatics method using a global meta-analysis of microarray data predicted that OLFM4 would be associated with specific granules in human neutrophils. Subcellular fractionation of peripheral blood neutrophils demonstrated complete colocalization of OLFM4 with the specific granule protein NGAL, and stimulation of neutrophils with PMA resulted in corelease of NGAL and OLFM4, proving that OLFM4 is a genuine constituent of neutrophil-specific granules. In accordance with this, OLFM4 mRNA peaked at the MY/MM stage of maturation. OLFM4 was, however, present in only 20-25% of peripheral blood neutrophils, as determined by immunocytochemistry and flow cytometry, whereas mRNA for OLFM4 was present in all MY/MM, indicating post-transcriptional regulation as a basis for the heterogeneous expression of OLFM4 protein.