hrombospondin, one of the major glycoproteins released from alpha- granules of thrombin-stimulated platelets, is a disulfide-linked trimer of 160,000-dalton subunits. Cultured human monocytes secreted thrombospondin (determined by an enzyme-linked immunosorbent assay) into the culture medium in a time-dependent manner (1.45 micrograms/10(6) cells/24 hr); secretion was totally blocked by cycloheximide (1 microgram/mL). 35S-thrombospondin was isolated from 35S-methionine-labeled human monocyte postculture medium with rabbit polyclonal anti-thrombospondin coupled to protein A-Sepharose. The immunoisolated 35S-thrombospondin migrated in sodium dodecyl sulfate- polyacrylamide gels after reduction with a molecular weight of 159,000. Similar results were obtained using mouse resident peritoneal macrophages. Elicited peritoneal macrophages harvested from mice pretreated with endotoxin, casein, or thioglycollate secreted much less thrombospondin than did resident macrophages harvested from control mice. Thus, monocytes and macrophages from two different species synthesize and secrete thrombospondin, and the rate of synthesis of thrombospondin appears to depend on the state of activation of the cells.
Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer, which may be partly attributable to an inflammation-aromatase axis. Most individuals with elevated BMI harbor white adipose tissue inflammation (WATi), defined by the presence of crown-like structures in the breast (CLS-B). CLS-B are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. This inflammation is associated with activation of NF-κB and elevated expression of aromatase, which could contribute to tumor development. Additionally, WATi correlates with several circulating changes, including hyperinsulinemia, which increase breast cancer risk. Although breast WATi correlates with rising BMI, it is also present in some normal BMI individuals. Beyond inherited germline syndromes, the etiology of breast cancer in individuals with normal BMI is not well understood. Here we examined the impact of breast WATi on breast aromatase expression and circulating factors in women with normal BMI. Methods: Non-tumorous breast tissue and fasting blood were collected from 72 women with BMI < 25 kg/m2 undergoing mastectomy at MSKCC. Breast inflammation was detected by the presence of CLS-B using CD68 immunohistochemistry. The primary objective was to determine if breast WATi in normal BMI individuals correlates with elevated aromatase levels in the breast, measured by qPCR, western blotting, immunofluorescence and enzyme activity. Secondary objectives included assessment of breast adipocyte size and circulating metabolic and inflammatory factors. Results: Breast inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WATi versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=0.04). Aromatase mRNA expression was positively correlated with WATi (CLS-B/cm2; P=0.002). Those with severe WATi had highest aromatase mRNA levels, compared to those with no or mild WATi (P=0.005). Aromatase protein, assessed by measuring adipose stromal cell-specific immunofluorescence or western blotting, and activity were also higher in CLS-B+ cases compared to CLS-B- (P<0.001). Breast WATi correlated with larger adipocytes (P=0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P<0.05). Insulin resistance, characterized by the homeostasis model (HOMA2-IR), correlated with breast WATi (P=0.004). Finally, leptin, a known inducer of aromatase and driver of cancer growth, correlated with higher breast aromatase levels (P=0.02) and larger adipocytes (P<0.01). Conclusions: A metabolically unhealthy state occurs in women with inflamed breast adipose despite having a normal BMI. This subclinical inflammatory state is characterized by elevated aromatase in the breast, insulin resistance, and dysplipidemia. The presence of enlarged adipocytes in the breasts of normal BMI women with inflammation suggests a state of hyperadiposity which could not be predicted based on BMI alone. These findings indicate that normal BMI metabolic obesity may be associated with increased cancer risk. Our results suggest that objective measurements of adiposity rather than BMI may help to identify individuals at increased risk for disease. Citation Format: Iyengar NM, Brown KA, Zhou XK, Subbaramaiah K, Giri DD, Gucalp A, Howe LR, Zahid H, Bhardwaj P, Wendel NK, Falcone DJ, Morrow M, Wang H, Williams S, Pollak M, Hudis CA, Dannenberg AJ. Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-05.
Background: In post-menopausal women, obesity is a risk factor for the development of BC that expresses the estrogen and progesterone receptors (ER/PR). In mouse models of obesity, we previously described crown-like structures (CLS), consisting of macrophages surrounding dead adipocytes in white adipose tissue (WAT) of the mammary gland, which were associated with increased levels of proinflammatory mediators known to be involved in carcinogenesis. We translated these findings to women (n = 30), and provided the first evidence of CLS in the human breast (CLS-B). The presence and severity of CLS-B (CLS-B index) correlated with elevated body mass index (BMI), increased adipocyte size, activation of NF-κB, and increased levels of proinflammatory mediators (TNF-α, IL-1β, COX-2 and PGE2) and aromatase. We expanded our population to prospectively validate these preliminary findings. Methods: We prospectively collected WAT from women undergoing breast and reconstructive surgery. WAT was subjected to immunohistochemistry for CD68, a macrophage marker, to detect CLS-B by light microscopy. Adipocyte diameter was measured on photomicrographs using the Canvas 11 Software. Endpoints were 1) CLS-B presence/absence and 2) CLS-B index (proportion of slides with CLS-B). Associations between CLS-B and clinicopathologic features were analyzed using logistic regression and Fisher's exact test. Results: From 04/2010-02/2012, WAT (100 mastectomy and 5 abdominal reconstructions) was obtained from 101 women; median age 49 (range 26-80). CLS-B were found in 54 (53%) patients (pts). CLS-B were seen in 9/37 (24%) normal weight pts (BMI <25), 23/39 (59%) overweight pts (BMI 25-29.9), and 22/25 (88%) obese pts (BMI ≥30). Pts with CLS-B had significantly larger average adipocyte diameter (106.5 +/- 11.5 microns) compared to those without CLS-B (91.5 +/- 16.1 microns; p<0.001). Consistently, CLS-B index correlated with BMI (p<0.001) and adipocyte size (p<0.001). Breast inflammation was seen in pts with all tumor phenotypes: CLS-B were seen in 24/41 (59%) pts with ER/PR+, HER2- tumors; 7/16 (44%) pts with HER2+ tumors; and 3/10 (30%) pts with ER/PR/HER2- tumors. A higher CLS-B index was seen in WAT from ER+ tumors, but this was not statistically significant (p = 0.08). Regular use of nonsteroidal antiinflammatory drugs was protective against CLS-B (p = 0.17 for association with CLS-B, and p = 0.04 for association with CLS-B index in multivariable analyses). Among 25 pts with bilateral breast WAT, concordant CLS-B findings (+/-) were found in 20 (80%) pts. Among pts with paired breast and abdominal WAT, concordant findings were seen in 4/5 (80%) pts. Conclusions: Findings from this prospective study, the largest reported to date, extend our previous observation that CLS-B are associated with BMI and adipocyte size. These results provide a plausible pathophysiological link between obesity and BC. Breast inflammation occurs in association with all BC phenotypes. Preliminary data suggest concordance between breasts and between abdominal and breast WAT. Hence, abdominal WAT may prove useful as a surrogate for breast WAT; biopsies of abdominal subcutaneous WAT are more easily done, which could prove useful in developing interventions to attenuate WAT inflammation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-03.
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