title: MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation.
abstract: Overweight and obesity is linked to increased incidence and mortality of many cancer types. Of all cancers, oesophageal adenocarcinoma (OAC) displays one of the strongest epidemiological links with obesity, accounting for up to 40% of cases, but molecular pathways driving this association remain largely unknown. This study aimed to elucidate mechanisms underpinning the association of obesity and cancer, and to determine if visceral obesity is associated with aggressive tumour biology in OAC. Following co-culture with visceral adipose tissue explants, expression of genes involved in tumour cell invasion and metastasis (matrix metalloproteinase (MMP)2 and MMP9) were upregulated between 10-fold (MMP2) and 5000-fold (MMP9), and expression of tumour suppressor p53 was downregulated 2-fold in OAC cell lines. Western blotting confirmed these results at the protein level, while zymographic analysis detected increased activity of MMPs in OAC cell lines following co-culture with adipose tissue explants. When OAC cell lines were cultured with adipose tissue conditioned media (ACM) from visceral adipose tissue, increased proliferative, migratory and invasive capacity of tumour cells was observed. In OAC patient tumour biopsies, elevated gene expression of MMP9 was associated with visceral obesity, measured by visceral fat area, while increased gene expression of MMP9 and decreased gene expression of tumour suppressor p53 was associated with poor tumour differentiation. These novel data highlight an important role for visceral obesity in upregulation of pro-tumour pathways contributing to aggressive tumour biology, and may ultimately lead to development of stratified treatment for viscerally obese OAC patients.
authors: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors: Emma H
authors: EH
authors: Allott
authors: Joanne
authors: J
authors: Lysaght
authors: Mary Clare
authors: MC
authors: Cathcart
authors: Claire L
authors: CL
authors: Donohoe
authors: Robert
authors: R
authors: Cummins
authors: Sarah A
authors: SA
authors: McGarrigle
authors: Elaine
authors: E
authors: Kay
authors: John V
authors: JV
authors: Reynolds
authors: Graham P
authors: GP
authors: Pidgeon
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000273:Adipose Tissue / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000150:complications / Q000201:enzymology*; D015203:Reproducibility of Results; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D016159:Tumor Suppressor Protein p53; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9