Enhanced ZAG Production by Subcutaneous Adipose Tissue is Linked to Weight Loss in Gastrointestinal Cancer Patients

Overview

Journal Br J Cancer

Specialty Oncology

Date 2011 Jan 20

PMID 21245862

Citations 52

Authors

T Mracek

N A Stephens

D Gao

Y Bao

J A Ross

M Ryden

P Arner

P Trayhurn

K C H Fearon

C Bing

Affiliations

Soon will be listed here.

Abstract

Background: Profound loss of adipose tissue is a hallmark of cancer cachexia. Zinc-α2-glycoprotein (ZAG), a recently identified adipokine, is suggested as a candidate in lipid catabolism.

Methods: In the first study, eight weight-stable and 17 cachectic cancer patients (weight loss 5% in previous 6 months) were recruited. Zinc-α2-glycoprotein mRNA and protein expression were assessed in subcutaneous adipose tissue (SAT), subcutaneous adipose tissue morphology was examined and serum ZAG concentrations were quantified. In the second cohort, ZAG release by SAT was determined in 18 weight-stable and 15 cachectic cancer patients. The effect of ZAG on lipolysis was evaluated in vitro.

Results: Subcutaneous adipose tissue remodelling in cancer cachexia was evident through shrunken adipocytes with increased fibrosis. In cachectic cancer patients, ZAG mRNA was upregulated (2.7-fold, P=0.028) while leptin mRNA decreased (2.2-fold, P=0.018); serum ZAG levels were found to be unaffected. Zinc-α2-glycoprotein mRNA correlated positively with weight loss (r=0.51, P=0.01) and serum glycerol levels (r=0.57, P=0.003). Zinc-α2-glycoprotein release by SAT was also elevated in cachectic patients (1.5-fold, P=0.024) and correlated with weight loss (r=0.50, P=0.003). Recombinant ZAG stimulated lipolysis in human adipocytes.

Conclusions: Zinc-α2-glycoprotein expression and secretion by adipose tissue is enhanced in cachectic cancer patients. Given its lipid-mobilising effect, ZAG may contribute to adipose atrophy associated with cancer cachexia in human beings.

Citing Articles

Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions.

Wang T, Zhou D, Hong Z MedComm (2020). 2025; 6(1):e70030.

PMID: 39764565 PMC: 11702502. DOI: 10.1002/mco2.70030.

ZAG promotes colorectal cancer cell proliferation and epithelial-mesenchymal transition by promoting lipid synthesis.

Xu M, Jin X, Shen Z Open Life Sci. 2024; 19(1):20221007.

PMID: 39711976 PMC: 11662974. DOI: 10.1515/biol-2022-1007.

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.

Ramos C, Pires J, Gonzalez E, Garcia-Vallicrosa C, Reis C, Falcon-Perez J Extracell Vesicles Circ Nucl Acids. 2024; 5(3):371-396.

PMID: 39697630 PMC: 11648493. DOI: 10.20517/evcna.2024.36.

Cancer cachexia: multilevel metabolic dysfunction.

Diaz M, Rohm M, Herzig S Nat Metab. 2024; 6(12):2222-2245.

PMID: 39578650 DOI: 10.1038/s42255-024-01167-9.

Cancer cachexia: biomarkers and the influence of age.

Geppert J, Rohm M Mol Oncol. 2024; 18(9):2070-2086.

PMID: 38414161 PMC: 11467804. DOI: 10.1002/1878-0261.13590.

References

van den Berg J, Wattimena J, van der Gaast A, Swart G, Wilson J, Dagnelie P . Lipolysis and lipid oxidation in weight-losing cancer patients and healthy subjects. Metabolism. 2000; 49(7):931-6. DOI: 10.1053/meta.2000.6740. View

Hale L . Zinc alpha-2-glycoprotein regulates melanin production by normal and malignant melanocytes. J Invest Dermatol. 2002; 119(2):464-70. DOI: 10.1046/j.1523-1747.2002.01813.x. View

Moses A, Dowidar N, Holloway B, Waddell I, Fearon K, Ross J . Leptin and its relation to weight loss, ob gene expression and the acute-phase response in surgical patients. Br J Surg. 2001; 88(4):588-93. DOI: 10.1046/j.1365-2168.2001.01743.x. View

Albertus D, Seder C, Chen G, Wang X, Hartojo W, Lin L . AZGP1 autoantibody predicts survival and histone deacetylase inhibitors increase expression in lung adenocarcinoma. J Thorac Oncol. 2008; 3(11):1236-44. DOI: 10.1097/JTO.0b013e318189f5ec. View

Trayhurn P, Bing C . Appetite and energy balance signals from adipocytes. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471):1237-49. PMC: 1642696. DOI: 10.1098/rstb.2006.1859. View

Russell S, Zimmerman T, Domin B, Tisdale M . Induction of lipolysis in vitro and loss of body fat in vivo by zinc-alpha2-glycoprotein. Biochim Biophys Acta. 2004; 1636(1):59-68. DOI: 10.1016/j.bbalip.2003.12.004. View

Sanchez L, Chirino A, Bjorkman P . Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science. 1999; 283(5409):1914-9. DOI: 10.1126/science.283.5409.1914. View

Fouladiun M, Korner U, Bosaeus I, Daneryd P, Hyltander A, Lundholm K . Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones. Cancer. 2005; 103(10):2189-98. DOI: 10.1002/cncr.21013. View

Bao Y, Bing C, Hunter L, Jenkins J, Wabitsch M, Trayhurn P . Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes. FEBS Lett. 2004; 579(1):41-7. DOI: 10.1016/j.febslet.2004.11.042. View

10.

Hirai K, Hussey H, Barber M, Price S, Tisdale M . Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients. Cancer Res. 1998; 58(11):2359-65. View

11.

Ceperuelo-Mallafre V, Naf S, Escote X, Caubet E, Gomez J, Miranda M . Circulating and adipose tissue gene expression of zinc-alpha2-glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat. J Clin Endocrinol Metab. 2009; 94(12):5062-9. DOI: 10.1210/jc.2009-0764. View

12.

Todorov P, McDevitt T, Meyer D, Ueyama H, Ohkubo I, Tisdale M . Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res. 1998; 58(11):2353-8. View

13.

Mracek T, Gao D, Tzanavari T, Bao Y, Xiao X, Stocker C . Downregulation of zinc-{alpha}2-glycoprotein in adipose tissue and liver of obese ob/ob mice and by tumour necrosis factor-alpha in adipocytes. J Endocrinol. 2009; 204(2):165-72. PMC: 2807359. DOI: 10.1677/JOE-09-0299. View

14.

Schmitt R, Marlier A, Cantley L . Zag expression during aging suppresses proliferation after kidney injury. J Am Soc Nephrol. 2008; 19(12):2375-83. PMC: 2588107. DOI: 10.1681/ASN.2008010035. View

15.

Tada T, Ohkubo I, Niwa M, Sasaki M, Tateyama H, Eimoto T . Immunohistochemical localization of Zn-alpha 2-glycoprotein in normal human tissues. J Histochem Cytochem. 1991; 39(9):1221-6. DOI: 10.1177/39.9.1918940. View

16.

Gong F, Zhang S, Deng J, Zhu H, Pan H, Li N . Zinc-alpha2-glycoprotein is involved in regulation of body weight through inhibition of lipogenic enzymes in adipose tissue. Int J Obes (Lond). 2009; 33(9):1023-30. DOI: 10.1038/ijo.2009.141. View

17.

Agustsson T, Ryden M, Hoffstedt J, van Harmelen V, Dicker A, Laurencikiene J . Mechanism of increased lipolysis in cancer cachexia. Cancer Res. 2007; 67(11):5531-7. DOI: 10.1158/0008-5472.CAN-06-4585. View

18.

He N, Brysk H, Tyring S, Ohkubo I, Brysk M . Zinc-alpha(2)-glycoprotein hinders cell proliferation and reduces cdc2 expression. J Cell Biochem Suppl. 2001; Suppl 36:162-9. View

19.

Yeung D, Lam K, Wang Y, Tso A, Xu A . Serum zinc-alpha2-glycoprotein correlates with adiposity, triglycerides, and the key components of the metabolic syndrome in Chinese subjects. J Clin Endocrinol Metab. 2009; 94(7):2531-6. DOI: 10.1210/jc.2009-0058. View

20.

Bing C, Russell S, Becket E, Pope M, Tisdale M, Trayhurn P . Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Br J Cancer. 2006; 95(8):1028-37. PMC: 2360696. DOI: 10.1038/sj.bjc.6603360. View