Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and mature adipocytes, but the role of these fat cells in tumor progression remains unclear. We show that murine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, using an original two-dimensional coculture system. Likewise, adipocytes cultivated with cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by overexpression of proteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6, IL-1b]. In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumor cells. Equally important, we confirm the presence of these modified adipocytes in human breast tumors by immunohistochemistry and quantitative PCR. Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes. Collectively, all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impact surrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior. Our results strongly support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression that might be amplified in obese patients. Cancer Res; 71(7); 2455-65. Ó2011 AACR.

Background: Exosomes can transfer information between cells and facilitate tumor development. Results: PC12 cell-derived exosomes enter into BMSCs through clathrin-mediated endocytosis and macropinocytosis, and decrease the expression of TGF␤RII and TPM1 through miR-21. Conclusion:The results dissect the pathway of exosome internalization and demonstrate their regulation ability. Significance: These findings enhanced our knowledge of the internalization and function of tumor exosomes.

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Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not a-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/b-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. Cancer Res; 73(18); 5657-68. Ó2013 AACR.

Abstract-We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca 2ϩ sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca 2ϩ transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca 2ϩ transient was augmented to compensate for decreased myofilament Ca 2ϩ sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca 2ϩ sensitivity could not be fully compensated by only increasing the intracellular Ca 2ϩ transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca 2ϩ sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca 2ϩ desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca 2ϩ sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations. (Circ Res. 2007;101:185-194.)Key Words: dilated cardiomyopathy Ⅲ troponin Ⅲ mutation Ⅲ calcium sensitivity Ⅲ knock-in mouse D ilated cardiomyopathy (DCM) is a disorder of cardiac muscle characterized by cardiac enlargement and systolic dysfunction and accounts for more than 10 000 deaths annually by heart failure and sudden death in the United States. 1-3 DCM is known to result from nongenetic insults, such as viruses, alcohol, toxins, and immunologic injury; however, recent genetic studies have revealed that mutations in genes for cytoskeletal (dystrophin, desmin, ␦-sarcoglycan), nuclear envelope (tafazzin and lamin A/C), and sarcomeric (cardiac actin, ␤-cardiac myosin heavy chain, ␣-tropomyosin, cardiac myosin-binding protein C, titin/connectin, cardiac troponin [cTn]T, cTnI, and cTnC) proteins are important causes of DCM, 4 and the incidence of the inherited DCM is thought to be 20% to 35%. [5][6][7] Cardiac muscle contraction is regulated through Ca 2ϩ binding to cardiac troponin complex localized on the thin filaments, 8 and DCM-causing mutations in troponin complex are associated with a malignant phenotype with a high incidence of premature cardiac death and heart transplantation. 9 Cardiac troponin complex consists of 3 components of distinct structure and function, cTnT, cTnI, and cTnC. cTnT has a structural role in anchoring troponin complex to the thin filaments through its binding to tropomyosin, cTnI inhibits the interaction ...

Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer.

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This is a meta-analysis of the pooled prevalence of sleep disturbances and its associated factors in Chinese university students. English (PubMed, PsycINFO, Embase) and Chinese (SinoMed, Wan Fang Database and Chinese National Knowledge Infrastructure) databases were systematically and independently searched from inception until 16 August 2016. The prevalence of sleep disturbances was pooled using random-effects model. Altogether 76 studies involving 112 939 university students were included. The overall pooled prevalence of sleep disturbances was 25.7% (95% CI: 22.5-28.9%). When using the screening scales Pittsburgh Sleep Quality Index, Athens Insomnia Scale and Self-Rating Sleeping State Scale, and the diagnostic criteria of the Chinese Classification of Mental Disorders (Second Edition), the pooled prevalence of sleep disturbances was 24.1% (95% CI: 21.0-27.5%) and 18.1% (95% CI: 16.4-20.0%), respectively. The percentages of students dissatisfied with sleep quality and those suffering from insomnia symptoms were 20.3% (95% CI: 13.0-30.3%) and 23.6% (95% CI: 18.9-29.0%), respectively. Subgroup analyses revealed that medical students were more vulnerable to sleep disturbances than other student groups. There was no significant difference between males and females, and across geographic locations. Sleep disturbances are common in Chinese university students. Appropriate strategies for prevention and treatment of sleep disturbances in this population need greater attention.