Project description:The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease.
Project description:The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non-tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease.
Project description:To determine the influence of primary tumors on pre-metastatic lungs, we have employed whole genome microarray expression profiling as a discovery platform to identify gene signatures of alveolar type II epithelial cells (AT-II) in TLR3 deficient mice (Tlr3-/-) and wide-type (WT) littermates with tumor bearing. We subcutaneously inoculated Tlr3-/- and WT mice with Lewis lung carcinoma (LLC). Two weeks later, lung tissues from Tlr3-/- and WT mice were dissociated and AT-II cells were sorted. AT-II cells from mice without tumor bearing were set as controls. Primary tumor induced gene expression in AT-II cells from Tlr3-/- and WT mice was measured at 2 weeks after tumor inoculation subcutaneously. AT-II cells from mice without tumor bearing were set as controls.
Project description:Age plays a crucial role in the interplay between tumor and host; with further perturbations induced by irradiation. Proton irradiation on tumors induces biological modulations including inhibition of angiogenic and immune factors critical to “hallmark” processes impacting tumor development, in addition to physical targeting advantages. These advantages have provided promising results for proton therapy in cancer. Additionally, protons have implications for carcinogenesis risk of space travel (due to the high proportion of high energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice is altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68 day) versus old (736 day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5Gy (1GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared to old subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74, and RUVBL2 as the key players were involved in the regulatory changes in host environment response (i.e. spleen). These results suggest a significant biological component to proton irradiation, operative through host age, that would indicate a modulation of host’s ability to support carcinogenesis in adolescence and the bestowal of resistance to immunosuppression, carcinogenesis, and genetic perturbation by old age.
Project description:To determine the influence of primary tumors on pre-metastatic lungs, we have employed whole genome microarray expression profiling as a discovery platform to identify gene signatures of alveolar type II epithelial cells (AT-II) in TLR3 deficient mice (Tlr3-/-) and wide-type (WT) littermates with tumor bearing. We subcutaneously inoculated Tlr3-/- and WT mice with Lewis lung carcinoma (LLC). Two weeks later, lung tissues from Tlr3-/- and WT mice were dissociated and AT-II cells were sorted. AT-II cells from mice without tumor bearing were set as controls.
Project description:To investigate the interaction between lung alveolar macrophages and lung cancer cells in vivo, gene expression analysis was performed using orthotopic tumor bearing animal model with C57BL/6 mice and Lewis Lung Carcinoma (LLC) cells. CD45+, F4/80+, Siglec-F+ population was sorted as alveolar macrophage population with fluorescence-activated cell sorting (FACS) technique.
Project description:Edothelial cells were FACS sorted as CD31+CD45- population from LLC transplant tumor bearing WT mice on Day 14 post tumor transplantation
Project description:The objective of this study is to compare transcriptional features in tumor-infiltrating (TI) regulatory T (Treg) cells with TI CD4+ conventional T (Tconv) cells, splenic Treg cells of tumor-bearing mice, splenic Tconv cells of tumor-bearing mice, splenic Treg cells of normal mice, or splenic Tconv cells of normal mice.
