Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models.

Signe Adamberg,Concetta Panebianco,Paolo Graziano,Kaia Kolk,Kaarel Adamberg,Anna Di Chio,Raivo Vilu,Chiara Saracino,Madis Jaagura,Valerio Pazienza

doi:10.3390/nu9040331

Abstract

Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

Highlights

As the fourth leading cause of death for cancer worldwide, adenocarcinoma of the pancreas is a highly lethal tumor [1]
We evaluated the effects of an engineered resistant-starch (ERS) diet treatment in a xenograft pancreatic cancer mouse model
Since it is known that intestinal microbiota can be manipulated by a diet that selectively enriches specific microbial groups [12,13,14], and that changes in gut microflora can affect the development of several diseases [15,16,17,18] including pancreatic cancer [21], we investigated the effects of an ERS diet on the composition and metabolism of mouse fecal microbiota

Summary

Introduction

As the fourth leading cause of death for cancer worldwide, adenocarcinoma of the pancreas is a highly lethal tumor [1]. Poor survival rates are due to cancer aggressiveness and chemo-resistance, which make existing systemic therapies ineffective. Despite both intrinsic and acquired resistance mechanisms that decrease drug efficacy [3], gemcitabine, alone or in combination with other drugs, has long been considered the first-line option in the therapy of pancreatic cancer (PC) [4]. Short-term (24 h) starvation achieved with fasting-mimicking medium increases the uptake of gemcitabine by tumor cells, rendering them more susceptible to drug-induced cell death. In an in vivo model of xenograft pancreatic cancer, gemcitabine administered to 24 h-fasted mice significantly decreased tumor volume, as compared to control mice [5].

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