RESUMO
Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection.
Assuntos
Caquexia/imunologia , Tolerância Imunológica , Células Mieloides/imunologia , Neoplasias Experimentais/imunologia , Animais , Caquexia/etiologia , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/patologia , Neoplasias Experimentais/patologiaRESUMO
Previous studies have suggested that neonates rely heavily on innate immunity for their antimicrobial response to bacterial infections. However, the innate immune response by neonates to bacterial infection remains poorly characterized. Here, we show that in a murine model of neonatal polymicrobial sepsis, CXC ligand 10 (CXCL10) concentrations increase in the blood and peritoneum concordant with the peritoneal recruitment of granulocytes and macrophages. Additionally, CXC receptor 3 (CXCR3) expression on elicited peritoneal macrophages and granulocytes increases following sepsis. Blockade of CXCL10 worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival. Deletion of CXCR3 also significantly increases mortality to a septic challenge. Finally, we demonstrate that the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist to neonatal sepsis is dependent on an endogenous CXCL10 response and that pretreatment of neonates with CXCL10 can also significantly improve macrophage and granulocyte function and modestly improve outcome to polymicrobial sepsis. Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis.
Assuntos
Infecções Bacterianas/imunologia , Quimiocina CXCL10/imunologia , Receptores CXCR3/metabolismo , Sepse/imunologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Infecções Bacterianas/metabolismo , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/sangue , Feminino , Citometria de Fluxo , Granulócitos/imunologia , Granulócitos/metabolismo , Imunidade Inata , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Receptores CXCR3/sangue , Receptores CXCR3/deficiência , Receptores CXCR3/genética , Sepse/metabolismo , Sepse/microbiologia , Receptor 4 Toll-Like/imunologiaRESUMO
The CD117 (KIT) protein is overexpressed in many human neoplasms including adenoid cystic carcinoma of salivary glands. To evaluate the function of c-kit-activating mutations in adenoid cystic carcinoma of the salivary gland, we studied 14 cases (13 primary, 1 cervical lymph node metastasis) from our institution. KIT protein expression was evaluated by immunohistochemistry using formalin-fixed paraffin-embedded tissue. Mutational analyses of c-kit extracellular (exon 9), juxtamembrane (exon 11) and tyrosine kinase domains (exons 13 and 17) were performed by polymerase chain reaction, clonal selection and DNA sequencing. All 14 cases demonstrated strong KIT expression by immunohistochemistry. Molecular analysis was successful in 8 of 14 cases, and c-kit missense point mutations were detected in seven of eight cases (88%) including seven in exon 11, two in exon 9, two in exon 13 and two in exon 17. Eight silent point mutations were detected in five cases. Two cases contained missense mutations in more than one exon. Different mutations were found in the primary tumor and the cervical lymph node metastasis of one patient. Point mutations in domains similar to those described in gastrointestinal stromal tumors were detected, including Pro551Leu and Lys558Glu (5' end of exon 11), Leu576Phe (3' end of exon 11), Val643Ala (exon 13) and Asn822Ser (exon 17). Additional novel point mutations in exons 9, 11, 13 and 17 were also identified. This study is the first to report c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Identification of such potential gain-of-function mutations in exon 11, and less frequently in exons 9, 13 and 17, suggests that KIT may be involved in the pathogenesis of adenoid cystic carcinoma of salivary glands. Our study raises a prospect of correlation of c-kit mutation and a potential treatment of adenoid cystic carcinoma with tyrosine kinase inhibitor (imatinib).
Assuntos
Carcinoma Adenoide Cístico/genética , Regulação Neoplásica da Expressão Gênica , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias das Glândulas Salivares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/química , Carcinoma Adenoide Cístico/secundário , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-kit/análise , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/secundárioRESUMO
CONTEXT: Human epidermal growth factor receptor 2 (HER2/neu) is overexpressed in a proportion of gastroesophageal (GE) adenocarcinomas, and trastuzumab treatment results in significant improvement in overall survival in patients with HER2/neu-overexpressing GE tumors. Grading of HER2/neu expression in GE tumors and its clinical application is different from that of breast cancer. HER2/neu immunohistochemistry (IHC) image analysis (IA), widely used in breast cancer, has not been studied in GE tumors. OBJECTIVE: To evaluate the correlation between manual HER2/neu IHC scoring and HER2/neu IHC image analysis in GE adenocarcinomas with characterization of associated clinicopathologic features. DESIGN: Tumor grade, growth pattern, and stage were evaluated in 116 cases of primary GE adenocarcinoma biopsy and resection specimens. Using anti-HER2/neu antibody and the proposed HER2/neu scoring system for gastric cancer, HER2/neu IHC expression was recorded after manual scoring and automated IA interpretation. RESULTS: HER2/neu overexpression (IHC 3+) was detected in 19% (10 of 54) of gastric tumors, and overall correlation between manual HER2/neu IHC interpretation and IA interpretation was 78% (42 of 54). HER2/neu overexpression (IHC 3+) was detected in 26% (16 of 62) of GE junction tumors, and the overall correlation between manual HER2/neu IHC interpretation and IA interpretation was 84% (52 of 62). CONCLUSIONS: The HER2/neu IHC scoring system for GE adenocarcinomas differs from that of breast carcinoma. Automated IA, validated for scoring of HER2/neu IHC in breast cancer, has a low correlation between HER2/neu IHC 2+ and IHC 3+ cases scored by conventional light microscopy and cannot be reliably used in the interpretation of HER2/neu IHC expression in GE adenocarcinomas.
Assuntos
Adenocarcinoma/metabolismo , Receptores ErbB/metabolismo , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/metabolismo , Genes erbB-2 , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Humanos , Imuno-Histoquímica , Microscopia , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Changes in mitochondrial matrix [Ca2+] evoked by trains of action potentials were studied in levator auris longus motor terminals using Ca2+-sensitive fluorescent indicator dyes (rhod-2, rhod-5F). During a 2500 impulse 50 Hz train, mitochondrial [Ca2+] in most wild-type terminals increased within 5-10 s to a plateau level that was sustained until stimulation ended. This plateau was not due to dye saturation, but rather reflects a powerful buffering system within the mitochondrial matrix. The amplitude of this plateau was similar for stimulation frequencies in the range 15-100 Hz. Plateau amplitude was sensitive to temperature, with no detectable stimulation-induced increase in fluorescence at temperatures below 17 degrees C, and increasing magnitudes as temperature was increased to near-physiological levels (38 degrees C). When stimulation ended, mitochondrial [Ca2+] decayed slowly back to prestimulation levels over a time course of hundreds of seconds. Similar measurements were also made in motor terminals of mice expressing the G93A mutation of human superoxide dismutase 1 (SOD1-G93A). In mice > 100 days old, all of whom exhibited hindlimb paralysis, some terminals continued to show wild-type mitochondrial [Ca2+] responses, but in other terminals mitochondrial [Ca2+] did not plateau, but rather continued to increase throughout most of the stimulus train. Thus mechanism(s) that limit stimulation-induced increases in mitochondrial [Ca2+] may be compromised in some SOD1-G93A terminals.