ABSTRACT
Mice overexpressing progastrin (PG) in intestinal mucosa (fatty acid-binding protein (Fabp)-PG mice) are at an increased risk of proximal colon carcinogenesis in response to azoxymethane. Here, we report a significant increase in the length of proximal colonic crypts in Fabp-PG mice, associated with potent antiapoptotic effects of PG, which likely contributed to the previously reported increase in colon carcinogenesis in Fabp-PG mice. Phosphorylation of kinase of IkappaBalpha (IKKalpha/beta), inhibitor of kappaB (IkappaB)alpha and p65NF-kappaB was significantly elevated in proximal colonic crypts of Fabp-PG versus wild-type mice, which was associated with degradation of IkappaBalpha and nuclear translocation/activation of p65. Surprisingly, distal colonic crypt cells were not as responsive to elevated levels of PG in Fabp-PG mice. Annexin II, recently described as a high-affinity receptor for PG, strongly co-localized with PG intracellularly and on basolateral membranes of proximal crypt cells, providing evidence that annexin-II binds PG in situ in colonic crypt cells. Proliferative and antiapoptotic effects of PG on proximal crypts of Fabp-PG mice were attenuated to wild-type levels, on treatment with NEMO peptide (an inhibitor of nuclear factor-kappaB (NF-kappaB) activation), demonstrating for the first time a critical role of NF-kappaB in mediating hyperproliferative affects of PG on colonic crypts of Fabp-PG mice, in vivo. Thus, downregulation of NF-kappaB may significantly reduce the increased risk of colon carcinogenesis in response to PG.
Subject(s)
Apoptosis , Colon/pathology , Colonic Neoplasms/etiology , Gastrins/physiology , NF-kappa B/physiology , Protein Precursors/physiology , Animals , Annexin A2/analysis , Cell Proliferation , Colon/metabolism , DNA/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Fatty Acid-Binding Proteins/physiology , Gastrins/analysis , I-kappa B Proteins/metabolism , Mice , NF-KappaB Inhibitor alpha , Phosphorylation , Protein Precursors/analysis , Transcription Factor RelA/analysisABSTRACT
This study sought to determine if weekly X-ray exposure affected breast cancer cell metastasis to bone and to also evaluate the use of bioluminescent imaging (BLI) and microSPECT for detection of metastatic bone lesions. Five week old nude mice were randomly assigned to the CT exposed (n = 7) and no CT exposure (n = 6) treatment groups. Mice received an intracardiac injection of MDA-MB-435 human breast cancer cells transduced with luciferase, or a sham injection (saline). The CT exposed group of mice received CT irradiation once a week for 5 weeks. All mice underwent weekly BLI and select mice received Tc-99m-MDP followed by microSPECT imaging after 5 weeks. Pathological evaluation and histomorphometry were used to assess the affect of CT X-rays on bone metastasis and to evaluate BLI. BLI results found no significant difference in metastasis between animals that received CT and those that did not (P > 0.05); however, histomorphometry of the knee joints revealed a significant increase (P = 0.029) in tumor area of the leg bones in mice that received CT exposure (60% +/- 7%) compared to animals that did not receive CT scans (33% +/- 8%). Compared to histological analysis, BLI of the leg and spine was determined to have excellent sensitivity (100%), good specificity (80-90%) and accuracy (90-96%), a positive predictive value of 81-93% and a 100% negative predictive value. Thus, multi-modality imaging techniques can be very useful for monitoring bone metastasis, however microCT X-rays should be used judiciously in order to limit irradiation that may stimulate increased metastasis to specific regions of the skeleton. MicroSPECT imaging did not detect metastatic lesions in the legs of these young nude mice.
Subject(s)
Bone Neoplasms/diagnostic imaging , Mammary Neoplasms, Experimental/pathology , Animals , Bone Neoplasms/secondary , Bone and Bones/pathology , Cell Line, Tumor , Female , Humans , Luminescence , Mice , Mice, Nude , Neoplasm Transplantation , Organ Specificity , Predictive Value of Tests , Random Allocation , Tomography, Emission-Computed, Single-Photon/methods , Tomography, X-Ray Computed/adverse effects , Tomography, X-Ray Computed/methods , Transplantation, HeterologousABSTRACT
OBJECTIVE: To ascertain the importance rural Australians attribute to different factors of accessibility in their decision to consult a general practitioner. DESIGN: Survey by interview or delivery-and-collection questionnaire (participant's choice) based on the method of paired comparisons. SETTING AND PARTICIPANTS: All residents of 10 small rural communities in north-west New South Wales aged over 16 years in July and August 1996. MAIN OUTCOME MEASURES: Rank order and relative importance of residents' preferences for choosing to consult a particular doctor. RESULTS: Social accessibility or acceptability considerations were more important than geographical proximity in the choices of rural residents to consult a particular doctor. Elderly people, in particular, attributed most significance to acceptability and continuity of care. Geographical proximity ranked most highly for young and middle-aged people and men living in isolated communities. CONCLUSIONS: For rural inhabitants, geographical distance is not the sole or even the most important determinant in their choice of general practice care; rather, they will seek the services of a GP with whom they feel comfortable. Incentives programs designed to recruit and retain more GPs in rural practice must acknowledge the importance of attracting acceptable doctors. This requires that rural doctors acquire suitable clinical and communication skills to meet the diverse needs of their patients, as well as an understanding of rural culture.