Esophageal adenocarcinoma microenvironment: peritumoral adipose tissue effects associated with chemoresistance

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 analysed: 1) the peritumoral adipose tissue of rats, following the induction of esophageal carcinogenesis; 2) the peritumoral and distal (omental) adipose tissue of patients affected by EAC; 3) adipose-derived stem cells (ADSCs) 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 VEGF expression increased progressively during EAC development. In patients with EAC, the expression of CD34, CD45, CD90 and Nucleostemin (NSTM) was higher in peritumoral than distal adipose tissue and decreased in the presence of neoadjuvant therapy. Moreover, the expression of NSTM, OCT-4 and VEGF was higher in peritumoral (but not distal) adipose tissue of chemoresistant patients. In ADSCs, the 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 ADSCs treated with distal adipose tissue CM and were partially reduced by a leptin antagonist. Lastly, ADSCs treated with peritumoral CM of chemoresistant patients, displayed increased expression of NSTM, OCT-4, leptin, leptin receptor, α-SMA, CD34 and VEGF. These results suggest that the peritumoral adipose tissue may promote, via paracrine signalling, the expression of depot-specific factors associated with therapeutic resistance.

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