Search

Background: Cancer cells require nutrients to survive in the unfavorable microenvironment of primary solid tumors or metastases before angiogenesis development. Fatty acid synthase (FASN) is a multi-enzyme protein that catalyzes fatty acid synthesis. Expression levels of FASN are low or undetectable in normal human tissues except for the liver and the adipose tissue. In contrast, high levels of FASN expression have been detected in breast cancer tumors and other human carcinomas. Several reports highlight that FASN overexpression in tumor samples correlates with progression, aggressiveness and metastatic potential of the disease. In addition, some studies have suggested the same correlation with serum levels of FASN. Our aim was to analyze the association between the expression of tumor and serum levels of FASN with clinical and pathological prognostic factors in early-stage breast cancer patients. Methods: Fifty-five patients with early-stage breast cancer treated with surgery and postoperative chemotherapy were included in the study. We prospectively measured the levels of FASN in tumor and serum samples. Clinical data included demographic characteristics, menarche, pregnancy, breast feeding, menopausal status and body mass index (BMI). Pathological and molecular data included: pathological state, histological grade, estrogen and progesterone receptors, HER2 status, p53 mutation and Ki 67 levels. FASN tissue expression levels were determined by IHC and circulating FASN levels were determined by ELISA. FASN expression was graded from 0 to 3+, meaning 0--1+ normal amounts of FASN protein compared to non-tumor breast tissue, 2+ moderate amounts and 3+ the highest levels of FASN expression. Baseline characteristics were summarized descriptively. Categorical variables were compared by c² or Fisher's exact. For continuous variables, if the data are approximately normal, the two groups were compared using ANOVA. If the normality assumption is not warranted, then the Kruskall-Wallis test has been used. Results: Median age was 49 (rage 33-77). 51% of the patients were menopausal and median BMI was 24,75. Thirty-four percent of the patients had stage I, 51% stage II and 15% stage III. We observed a statistically significant association between FASN over expression and the lack of progesterone receptors (p = 0.027) in tumor samples. In contrast, we found no relation between FASN and estrogen receptor nor between FASN and HER2 tumor expression in this setting. Menopause and age were strongly related to higher levels of FASN tumor expression (p < 0.001). Patients with higher BMI had higher levels of FASN in tumor tissue although this association was not statistically significant (p = 0.07). Finally, we observed a positive relation between breast cancer stage and the levels of FASN tumor (p = 0.05). In contrast, circulating FASN levels were not associated with any pathological or clinical prognostic factor. Conclusions: Our study suggests that FASN overexpression is significantly related to age, menopausal status, more advanced stages and lack of progesterone receptor expression in early-stage breast cancer patients. However, no relation between serum levels of FASN and the clinical or molecular prognostic factors have been observed. [ABSTRACT FROM AUTHOR]

During adipogenesis, preadipocytes' cytoskeleton reorganizes in parallel with lipid accumulation. Failure to do so may impact the ability of adipose tissue (AT) to shift between lipid storage and mobilization. Here, we identify cytoskeletal transgelin 2 (TAGLN2) as a protein expressed in AT and associated with obesity and inflammation, being normalized upon weight loss. TAGLN2 was primarily found in the adipose stromovascular cell fraction, but inflammation, TGF-β, and estradiol also prompted increased expression in human adipocytes. Tagln2 knockdown revealed a key functional role, being required for proliferation and differentiation of fat cells, whereas transgenic mice overexpressing Tagln2 using the adipocyte protein 2 promoter disclosed remarkable sex-dependent variations, in which females displayed "healthy" obesity and hypertrophied adipocytes but preserved insulin sensitivity, and males exhibited physiologic changes suggestive of defective AT expandability, including increased number of small adipocytes, activation of immune cells, mitochondrial dysfunction, and impaired metabolism together with decreased insulin sensitivity. The metabolic relevance and sexual dimorphism of TAGLN2 was also outlined by genetic variants that may modulate its expression and are associated with obesity and the risk of ischemic heart disease in men. Collectively, current findings highlight the contribution of cytoskeletal TAGLN2 to the obese phenotype in a gender-dependent manner.-Ortega, F. J., Moreno-Navarrete, J. M., Mercader, J. M., Gómez-Serrano, M., García-Santos, E., Latorre, J., Lluch, A., Sabater, M., Caballano-Infantes, E., Guzmán, R., Macías-González, M., Buxo, M., Gironés, J., Vilallonga, R., Naon, D., Botas, P., Delgado, E., Corella, D., Burcelin, R., Frühbeck, G., Ricart, W., Simó, R., Castrillon-Rodríguez, I., Tinahones, F. J., Bosch, F., Vidal-Puig, A., Malagón, M. M., Peral, B., Zorzano, A., Fernández-Real, J. M. Cytoskeletal transgelin 2 contributes to gender-dependent adipose tissue expandability and immune function.

Background/aims: Obesity is characterized by the immune activation that eventually dampens insulin sensitivity and changes metabolism. This study explores the impact of different inflammatory/ anti-inflammatory paradigms on the expression of toll-like receptors (TLR) found in adipocyte cultures, adipose tissue, and blood., Methods: We evaluated by real time PCR the impact of acute surgery stress in vivo (adipose tissue) and macrophages (MCM) in vitro (adipocytes). Weight loss was chosen as an anti-inflammatory model, so TLR were analyzed in fat samples collected before and after bariatric surgery-induced weight loss. Associations with inflammatory and metabolic parameters were analyzed in non-obese and obese subjects, in parallel with gene expression measures taken in blood and isolated adipocytes/ stromal-vascular cells (SVC). Treatments with an agonist of TLR3 were conducted in human adipocyte cultures under normal conditions and upon conditions that simulated the chronic low-grade inflammatory state of obesity., Results: Surgery stress raised TLR1 and TLR8 in subcutaneous (SAT), and TLR2 in SAT and visceral (VAT) adipose tissue, while decreasing VAT TLR3 and TLR4. MCM led to increased TLR2 and diminished TLR3, TLR4, and TLR5 expressions in human adipocytes. The anti-inflammatory impact of weight loss was concomitant with decreased TLR1, TLR3, and TLR8 in SAT. Cross-sectional associations confirmed increased V/ SAT TLR1 and TLR8, and decreased TLR3 in obese patients, as compared with non-obese subjects. As expected, TLR were predominant in SVC and adipocyte precursor cells, even though expression of all of them but TLR8 (very low levels) was also found in ex vivo isolated and in vitro differentiated adipocytes. Among SVC, CD14+ macrophages showed increased TLR1, TLR2, and TLR7, but decreased TLR3 mRNA. The opposite patterns shown for TLR2 and TLR3 in V/ SAT, SVC, and inflamed adipocytes were observed in blood as well, being TLR3 more likely linked to lymphocyte instead of neutrophil counts. On the other hand, decreased TLR3 in adipocytes challenged with MCM dampened lipogenesis and the inflammatory response to Poly(I:C)., Conclusion: Functional variations in the expression of TLR found in blood and hypertrophied fat depots, namely decreased TLR3 in lymphocytes and inflamed adipocytes, are linked to metabolic inflammation., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Objective: Overexpression of fatty acid synthase (FASN), the enzyme involved in the de novo synthesis of fatty acids, has been reported in several human carcinomas, including breast cancer, and has been related to poor prognosis. Our aim was to analyze the association of FASN tumor tissue expression with clinicopathological and anthropometrical features in early-stage breast cancer patients., Methods: We prospectively studied 53 women with early-stage breast cancer who were treated with surgical operation and postoperative chemotherapy., Results: Menopause status and age were strongly associated with higher levels of FASN tumor expression (P < 0.005 and P = 0.038, respectively). Body mass index and pathological stage were also related to FASN tumor expression., Conclusions: Our findings suggest that FASN could be a potential therapeutic target in postmenopausal breast cancer patients. However, further studies are needed.

This paper compares three different methods for performing cancer incidence prediction in an area without a cancer registry under a Bayesian framework, using linear and log-linear age-period models with either age-specific slopes or a common slope across age groups. The three methods assume that a nearby area with a cancer registration has similar incidence and mortality patterns as the area of interest without a cancer registry where the cancer incidence prediction is carried out. The three methods differ in modeling strategies: (i) modeling the incidence rate directly; (ii) modeling the ratio of the number of incident cases to that of mortality cases; and (iii) modeling the difference between the incidence rate and the mortality rate. Strategy (iii) is a new approach in this type of projection. Empirical assessment is made using real data from the cancer registry of Tarragona, Spain, to predict cancer incidence in Girona, Spain, and vice versa. Predictions of short-term (3-4 years) incidence were made for 2001 in Tarragona using observed cancer incidence and mortality data for 1994-1998 from Girona. Short-term predictions were made for 2002 in Girona using Tarragona's 1994-1998 data. Additionally, long-term (10 years) incidence rate predictions were made for 2002 in Girona using data from Tarragona for the period 1985-1992. Our results suggest that extrapolating time-trends of incidence rates minus mortality rates may have the best predictive performance overall. These methods of population-level disease-incidence prediction are highly relevant to health care planning and policy decisions., (Copyright © 2012 John Wiley & Sons, Ltd.)