Cancer-Associated Fibroblasts Induce Proliferation and Therapeutic Resistance to Everolimus in Neuroendocrine Tumors through STAT3 Activation.

INTRODUCTION: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET. METHODS: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue. RESULTS: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells. CONCLUSION: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.

Metabolic Syndrome Is Associated with Impaired Survival after Surgery for Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms. Surgery is the only curative treatment option. However, our understanding of predictors of survival after surgery remains incomplete. The aim of the study was to evaluate metabolic syndrome (MetS) as a prognostic factor in pNET. METHODS: In a retrospective single-center cohort study, we examined the influence of MetS in 120 patients with curative intended resection of pNETs on overall survival (OS), recurrence-free survival, and outcome after recurrence. RESULTS: MetS was present in 32 patients (26.6%). Patients with MetS had an impaired OS after curative intended surgery compared to patients without MetS (median OS 72 months [95% CI 13.3-130.7] vs. not reached, p < 0.001). The shortest survival was observed in patients with MetS in the presence of oligometastatic disease at time of surgery. In a multivariable Cox regression analysis, MetS was identified as an independent risk factor for mortality (hazard ratio [HR] = 4.54, 95% CI [1.88-11.00], p = 0.01). In our dataset, MetS was not associated with tumor recurrence or recurrence-free survival. Nevertheless, in patients with recurrence, MetS was associated with shorter time to recurrence (median 3.4 months, 95% CI [2.48-4.24], vs. 20.1 months, 95% CI [10.8-29.49], p < 0.001), and poor outcome (HR = 5.03, 95% CI [1.25-20.20], p = 0.01). CONCLUSIONS: We identified MetS as a negative prognostic factor after curative intended surgery for pNET. In particular, patients with oligometastatic disease might not benefit from extensive surgery in the presence of MetS. Furthermore, MetS had a strong impact on survival after recurrence.