AbstractWhite cell infiltration of solid tumors is an important prognostic indicator in malignant disease. Although macrophage infiltration is associated with good outcome in colorectal cancer, a high macrophage content is associated with poor prognosis in breast cancer. Suppressor macrophages prevent T cell activation in normal tissues such as mucosal linings exposed to continuous antigenic chalenge. Interleukin 10 (IL-10). an immunosuppressive cytokine, inhibits macrophage co-stimulation of T cells.Suppressor macrophage numbers, T cell numbers and T cell activation status were assessed in cell suspensions obtained from fresh specimens of breast and colorectal turnours and matched normal tissues. IL-10 production by both malignant and matched normal tissue was also assessed.This study identified elevated numbers of suppressor macrophages in breast tumors compared to matched normal breast tissue. Colorectal tumors did not contain significant numbers of these cells. Although T cell numbers are increased in breast tumors, these cells do not appear to be fully activated, as assessed by major histocompatability complex class II and Interleukin 2 receptor expression. In contrast, T cells in colorectal tumors exhibit greater expression levels of these markers. Breast tumors produce significantly higher levels of IL-10 than normal breast tissue whereas IL-10 levels in colorectal tumors are similar to normal colon tissue.Our findings of high suppressor macrophage numbers, high levels of IL-10 and poorly activated T cells in breast tumors compared to low suppressor macrophage numbers, low IL-10 and fully activated T cells in colorectal tumors may explain why high macrophage content is associated with poor prognosis in breast cancer and good prognosis in colorectal malignancy.
BRCA1-mutant breast tumors are typically estrogen receptor alpha (ERα) negative, whereas most sporadic tumors express wild-type BRCA1 and are ERα positive. We examined a possible mechanism for the observed ERα-negative phenotype of BRCA1-mutant tumors. We used a breast cancer disease–specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) (the gene encoding ERα), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ERα protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA (siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided. Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors (95% confidence interval [CI] = 2.6-fold to 40.1-fold, P = .0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ERα expression. BRCA1-depleted breast cancer cells expressing exogenous ERα were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector (T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC 40 ] for empty vector versus ERα: >10 −5 versus 8.0 × 10 −9 M [95% CI = 3.1 × 10 −10 to 3.2 × 10 −6 M]; MCF-7 cells, mean IC 40 for empty vector versus ERα: >10 −5 versus 4.9 × 10 −8 M [95% CI = 2.0 × 10 −9 to 3.9 × 10 −6 M]). BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ERα expression.
Oxygen free radical activity has been implicated in carcinogenesis through DNA lysis. This study measured chemiluminescence and superoxide dismutase (SOD) inhibition as an index of oxygen free radical activity in azoxymethane-induced colonic carcinoma. After 3 weeks of acclimatization, ten Fisher 344 rats were injected with azoxymethane (7 mg kg-1 week-1) over 10 weeks. All animals were killed at 37 weeks and colonic mucosa (5-25 mg wet weight) was sampled from sites of histologically confirmed gross tumour and sites 3-5 cm distant from tumour as well as from ten paired normal controls. The samples were processed in buffered luminol and chemiluminescence was measured in a luminometer. Each sample was then placed in a solution of SOD for 3 min before a second chemiluminescence estimation. Mean(s.e.m.) chemiluminescence from control mucosal samples decreased from 8.1(1.0) to 3.9(1.1) mV per 100 mg tissue (P < 0.05) after incubation in SOD, suggesting that oxygen free radical activity was being measured. There was an increase to 20.2(0.9) mV per 100 mg in azoxymethane-treated colon remote from tumour and to 53.9(2.1) mV per 100 mg at tumour sites; both were reduced significantly after incubation with SOD to 6.7(0.7) and 11.0(0.8) mV per 100 mg respectively (P < 0.001). Chemiluminescence was significantly increased in azoxymethane-induced colonic carcinoma, both remote from and maximally at the tumour site, suggesting a field change in carcinogenesis associated with oxygen free radical activity.
Abstract Barrett’s Esophagus is the main pathological precursor to esophageal adenocarcinoma (EAC), dysplasia is known to be one of the principal predictors of progression to malignancy. The RIBBON Registry was established with six academic medical centers in the Republic of Ireland to identify and manage high risk Barrett’s Esophagus (BE) patients. From our database of over 4,000 patients our aim was to establish characteristics of those patients who progressed to dysplasia and furthermore to malignancy. Methods Data was gathered prospectively from December 2007—December 2019. Ethical approval was sought for the database at the time of establishment. Detailed endoscopic, pathological and clinical data was collected via a web-based data capture system at time of initial diagnosis and at each subsequent encounter. A data manager was appointed at each site and a national lead coordinating the project. The Vienna Grading system was used to grade histology. Patients were included if they had an initial or subsequent diagnosis of Specialized intestinal metaplasia (SIM), Indefinite for dysplasia (IND) or Low-Grade Dysplasia (LGD). Results 860 patients were included with a total of 3792 patient years, a male to female ratio of 2.9:1 and a median age at diagnosis of 63. 50 patients had an initial diagnosis of SIM with subsequent episodes of dysplasia while 510 patients had IND or LGD at diagnosis. 158 (18.37%) progressed to High grade dysplasia (HGD) and EAC. The overall incidence of EAC was 1.7% per year, HGD 2.4% per year and a combined rate of 4.2% per year. Median time to progression in SIM was 4.7 years, 1.1 years for IND and 9 months for LGD. Conclusion The overall progression of the group was much higher compared to looking at those who had SIM alone without dysplasia from the same registry (0.9% per year). Time to progression was significantly faster in the groups with initial dysplasia be that IND or LGD. In our centers those patients were followed up with repeat endoscopy as per international guidelines, the above results highlight the importance of this practice given the potential for malignancy.
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