Esophageal adenocarcinoma microenvironment: Peritumoral adipose tissue effects associated with chemoresistance

Amedeo Carraro, Elisabetta Trevellin, Matteo Fassan, Andromachi Kotsafti, Francesca Lunardi, Andrea Porzionato, Luigi Dall'Olmo, Matteo Cagol, Rita Alfieri, Veronica Macchi, Umberto Tedeschi, Fiorella Calabrese, Massimo Rugge, Carlo Castoro, Roberto Vettor, Marco Scarpa

Research output: Contribution to journalArticlepeer-review

Abstract

Peritumoral microenvironment affects cancer development and chemoresistance, and visceral adipose tissue may play a critical role. We aimed to identify depot-specific adipose characteristics associated with carcinogenesis and resistance to neoadjuvant therapy in esophageal adenocarcinoma (EAC). We analyzed: (i) the peritumoral adipose tissue of rats following the induction of esophageal carcinogenesis; (ii) the peritumoral and distal (omental) adipose tissue of patients affected by EAC; (iii) adipose-derived stem cells (ADSC) isolated from healthy patients and treated with conditioned medium (CM), collected from tumoral and adipose tissue of patients with EAC. In peritumoral adipose tissue of rats, CD34, CD31 and vascular endothelial growth factor (VEGF) expression increased progressively during EAC development. In patients with EAC, expression of CD34, CD45, CD90 and nucleostemin (NSTM) was higher in peritumoral than in distal adipose tissue and decreased in the presence of neoadjuvant therapy. Moreover, expression of NSTM, octamer-binding transcription factor 4 (OCT-4) and VEGF was higher in peritumoral (but not in distal) adipose tissue of chemoresistant patients. In ADSC, treatment with peritumoral adipose tissue CM increased the adipogenic potential and the expression of CD34, CD90, NSTM and OCT-4. These effects were similar to those induced by cancer-derived CM, but were not observed in ADSC treated with distal adipose tissue CM and were partially reduced by a leptin antagonist. Last, ADSC treated with peritumoral CM of chemoresistant patients displayed increased expression of NSTM, OCT-4, leptin, leptin receptor, alpha-smooth muscle actin (α-SMA), CD34 and VEGF. These results suggest that peritumoral adipose tissue may promote, by paracrine signaling, the expression of depot-specific factors associated with therapeutic resistance.

Original languageEnglish
Pages (from-to)2393-2404
Number of pages12
JournalCancer Science
Volume108
Issue number12
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • adipose tissue
  • esophageal adenocarcinoma
  • neoadjuvant therapy
  • peritumoral microenvironment
  • stem cell

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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