RESUMO
During normal bone remodeling, the receptor activator of nuclear factor-kappaB (RANK) interacts with its ligand RANKL, which is present on pre-osteoclasts, resulting in bone resorption and initiation of new bone formation. When breast cancer metastasizes to bone, normal bone remodeling is disturbed by invasion of tumor cells, resulting in osteolytic lesions. We have studied the expression of both RANK and RANKL in 10 nonneoplastic breast samples, 58 infiltrating ductal carcinoma (IDC), and 43 breast cancer bony metastases (BTM). RANK seemed to be present in all samples tested. However, whereas RANKL expression was observed in 90% of nonneoplastic breast, RANKL expression was only observed in 62% of nonmetastatic IDC, 31% of metastatic IDC, and 2% of osteolytic BTM lesions. This decreased or absent expression of RANKL in the tumor cells may allow RANK, which is normally expressed as a receptor on the cell surface, to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone. Stimulation of the normal osteoblasts and stromal cells by the tumor cells may then lead to secondary osteoclastogenesis, resulting in the osteolytic phenotype common to breast metastases.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Remodelação Óssea , Osso e Ossos/metabolismo , Humanos , Imuno-Histoquímica , Metástase Neoplásica , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoprotegerina , Fenótipo , Fatores de TempoRESUMO
The lymphomagenic action of myc genes in conjunction with Epstein-Barr virus nuclear antigen-1 (EBNA-1) have been examined using transgenic mice in several separate tests. Synergy between Myc and EBNA-1 in lymphomagenesis was revealed in a cross breed study where co-expression of transgenic myc and EBNA-1 led to a tumor latency period reduced significantly in some crosses. In the resulting bitransgenic tumors, expression of the Emu-myc genes was not affected by EBNA-1 expression. MoMLV was utilized as a transposon tag to activate cellular oncogenes by infection of EmuEBNA-1 mice. Rearrangement at the c-myc locus in B cell tumors from these mice again suggests a cooperative action between myc and EBNA-1. Tumors arising in EmuEBNA-1 mice typically showed a trisomy of chromosome 15, upon which the c-myc locus resides. Bitransgenic tumors (EBNA-1/c-myc) did not show trisomy 15. This raises the possibility that amplification of c-myc is factorial in the selection of trisomy 15 in these tumors. These data indicate that myc and EBNA-1 act cooperatively and are not redundant in lymphomagenesis. Expression of EBNA-1 by EBV may provide a selection pressure in addition to translocation of the c-myc locus in the genesis of endemic Burkitt's lymphoma (BL).
Assuntos
Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/fisiologia , Herpesvirus Humano 4/fisiologia , Linfoma de Células B/virologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Animais , Linfócitos B/virologia , Southern Blotting , Western Blotting , Cromossomos/genética , Cruzamentos Genéticos , Infecções por Vírus Epstein-Barr/patologia , Feminino , Amplificação de Genes , Rearranjo Gênico , Humanos , Cariotipagem , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma de Células T/química , Linfoma de Células T/patologia , Linfoma de Células T/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Translocação Genética , TrissomiaRESUMO
Previous analysis of tumor-specific constitutional LOH had identified a putative tumor-suppressor gene (LOH18CR) active in osteosarcoma tumorigenesis, which mapped to a subregion of chromosome 18q linked to both familial Paget's disease and FEO. Using 9 new polymorphic loci within the previous minimal region of LOH, we have reduced the minimal region of LOH in osteosarcoma tumors to localize the LOH18CR locus to the distal end of chromosome 18q21.33. This new region is approximately 500 kb and contains at least 7 known genes; however, it excludes 2 previous candidate genes: TNFRSF11A (RANK) and BCL2.