Esophageal adenocarcinoma and obesity: peritumoral adipose tissue plays a role in lymph node invasion

Elisabetta Trevellin; Marco Scarpa; Amedeo Carraro; Francesca Lunardi; Andromachi Kotsafti; Andrea Porzionato; Luca Saadeh; Matteo Cagol; Rita Alfieri; Umberto Tedeschi; Fiorella Calabrese; Carlo Castoro; Roberto Vettor

doi:10.18632/oncotarget.3587

Esophageal adenocarcinoma and obesity: peritumoral adipose tissue plays a role in lymph node invasion

Oncotarget. 2015 May 10;6(13):11203-15. doi: 10.18632/oncotarget.3587.

Affiliations

¹ Department of Medicine, Internal Medicine 3, Endocrine-Metabolic Laboratory, University of Padova, Padova, Italy.
² Surgical Oncology Unit, Veneto Oncological Institute (IOV-IRCCS), Padova, Italy.
³ Department of General Surgery and Odontoiatrics, University Hospital of Verona, Verona, Italy.
⁴ Department of Cardiothoracic and Vascular Sciences, University of Padova, Padova, Italy.
⁵ Department of Molecular Medicine, Normal Anatomy Unit, University of Padova, Padova, Italy.

Abstract

Obesity is associated with cancer risk in esophageal adenocarcinoma (EAC). Adipose tissue directly stimulates tumor progression independently from body mass index (BMI), but the mechanisms are not fully understood. We studied the morphological, histological and molecular characteristics of peritumoral and distal adipose tissue of 60 patients with EAC, to investigate whether depot-specific differences affect tumor behavior. We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients. We treated OE33 cells with conditioned media (CM) collected from cultured biopsies of adipose tissue and we observed increased mRNA levels of leptin and adiponectin receptors, as well as two key regulator genes of epithelial-to-mesenchymal transition (EMT): alpha-smooth muscle actin (α-SMA) and E-cadherin. This effect was greater in cells treated with CM from peritumoral adipose tissue of patients with nodal metastasis and was partially blunted by a leptin antagonist. Therefore, peritumoral adipose tissue may exert a direct effect on the progression of EAC by secreting depot-specific paracrine factors, and leptin is a key player in this crosstalk.

Keywords: adipose tissue; esophageal adenocarcinoma; metastasis obesity; peritumoral microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Adenocarcinoma / complications
Adenocarcinoma / genetics
Adenocarcinoma / metabolism*
Adenocarcinoma / secondary
Adenocarcinoma / therapy
Adipocytes / metabolism
Adipocytes / pathology
Adipose Tissue / metabolism*
Adipose Tissue / pathology
Aged
Antigens, CD
Cadherins / genetics
Cadherins / metabolism
Cell Size
Culture Media, Conditioned / metabolism
Epithelial-Mesenchymal Transition
Esophageal Neoplasms / complications
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / pathology
Esophageal Neoplasms / therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Leptin / genetics
Leptin / metabolism
Lymphangiogenesis
Lymphatic Metastasis
Male
Membrane Glycoproteins / metabolism
Middle Aged
Neovascularization, Pathologic
Obesity / complications
Obesity / genetics
Obesity / metabolism*
Obesity / pathology
Paracrine Communication*
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
RNA, Messenger / metabolism
Receptors, Adiponectin / genetics
Receptors, Adiponectin / metabolism
Signal Transduction
Tissue Culture Techniques
Tumor Cells, Cultured

Substances

ACTA2 protein, human
Actins
Antigens, CD
CDH1 protein, human
Cadherins
Culture Media, Conditioned
Leptin
Membrane Glycoproteins
PDPN protein, human
Platelet Endothelial Cell Adhesion Molecule-1
RNA, Messenger
Receptors, Adiponectin

Supplementary concepts

Adenocarcinoma Of Esophagus