STAT3 Activation-Induced Fatty Acid Oxidation in CD8 T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.
Zhang Chunyan,Yue Chanyu,Herrmann Andreas,Song Jieun,Egelston Colt,Wang Tianyi,Zhang Zhifang,Li Wenzhao,Lee Heehyoung,Aftabizadeh Maryam,Li Yi Jia,Lee Peter P,Forman Stephen,Somlo George,Chu Peiguo,Kruper Laura,Mortimer Joanne,Hoon Dave S B,Huang Wendong,Priceman Saul,Yu Hua
Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8 T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8 T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8 T cells activates STAT3 to increase FAO, inhibiting CD8 T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8 T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8 T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.
Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene.
Eccles D M,van der Luijt R,Breukel C,Bullman H,Bunyan D,Fisher A,Barber J,du Boulay C,Primrose J,Burn J,Fodde R
American journal of human genetics
Desmoid tumors are slowly growing fibrous tumors highly resistant to therapy and often fatal. Here, we report hereditary desmoid disease (HDD), a novel autosomal dominant trait with 100% penetrance affecting a three-generation kindred. Desmoid tumors are usually a complication of familial adenomatous polyposis, a predisposition to the early development of premalignant adenomatous polyps in the colorectum due to chain-terminating mutations of the APC gene. In general, one or more members in approximately 10% of the FAP families manifest desmoid tumors. Affected individuals from the HDD kindred are characterized by multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Osteomas, epidermal cysts, and other congenital features were also observed. We show that HDD segregates with an unusual germ-line chain-terminating mutation at the 3' end of the APC gene (codon 1924) with somatic loss of the wild-type allele leading to tumor development.
Breast cancer, desmoid tumours, and familial adenomatous polyposis--a unifying hypothesis.
Benson J R,Baum M
Lancet (London, England)
There is widespread agreement that epithelial tumours develop as a consequence of primary events within epithelial cells. According to the monoclonal theory, a tumour is caused by genetic change within a single cell, which imparts a selective growth advantage. This simple theory fails to take into account two important concepts. First, tumour generation is likely to involve multiple genetic events, some of which initiate a tumour, and others promote its growth. Second, tumours are usually composed of several tissue components, although they are known by the dominant proliferative cell type. This convention has tended to obscure the importance of "secondary" tissue components in carcinogenesis, despite evidence for the involvement of mesenchymal elements both in the induction and maintenance of transformation. To shift emphasis from the monoclonal theory, we propose a unifying hypothesis accounting for the effect of adjuvant tamoxifen in early breast cancer and the association between gastrointestinal polyps and desmoid tumours.