Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas

Abstract

Background:Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.Methods:Tumour biopsies from patients (n=14) with TNM stage IB–IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations.Results:We identified 520 genes with differential expression (Mann–Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.Conclusions:In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

Adipose tissue, obesity and adipokines: role in cancer promotion

“…Treatment effectiveness is extremely variable in these individuals and greatly affects prognosis and survival [43]. Patients with higher levels of leptin mRNA expression are less responsive to treatment, while those with low levels were more likely to survive [43]. Therefore, leptin levels can be used as an indicator of tumor responsiveness and help guide treatment options to improve a patient's outcome.…”

The potential role of leptin in tumor invasion and metastasis

“…It is known that ICAM-1 or CD54 is a transmembrane glycoprotein of the immunoglobulin superfamily and it can facilitate the metastasis of cancer cells by escaping the recognition and attack of immunocytes [110]. Interestingly, leptin expression in gastric adenocarcinoma cell-lines was reported to be correlated with resistance to the chemotherapeutic agent cisplatin [111]. Furthermore, including a leptin antagonist increased the sensitivity of both the cisplatin-resistant gastric cancer AGS Cis5 and esophageal adenocarcinoma OE33 cell-lines to cisplatin, which greatly illustrated the impact of leptin in the disease course (Table 2 [101,111,112]).…”

Leptin signaling and cancer chemoresistance: Perspectives

“…Ob-R and HIF-1α expression was highly associated in PC tissues. HIF-1α regulated the expression of Ob-R in PC[133]. Leptin binding to Ob-R was earlier found to induce HIF-1α in breast cancer cells.…”