Transcriptomic Analysis of LNCaP Tumor Xenograft to Elucidate the Components and Mechanisms Contributed by Tumor Environment as Targets for Dietary Prostate Cancer Prevention Studies.

Lu Yu,Quynhchi Pham,Thomas T Y Wang,Haiqiu Huang,Robert W Li,Liangli Yu

doi:10.3390/nu13031000

Abstract

LNCaP athymic xenograft model has been widely used to allow researchers to examine the effects and mechanisms of experimental treatments such as diet and diet-derived cancer preventive and therapeutic compounds on prostate cancer. However, the biological characteristics of human LNCaP cells before/after implanting in athymic mouse and its relevance to clinical human prostate outcomes remain unclear and may dictate interpretation of biological efficacies/mechanisms of diet/diet-derived experimental treatments. In this study, transcriptome profiles and pathways of human prostate LNCaP cells before (in vitro) and after (in vivo) implanting into xenograft mouse were compared using RNA-sequencing technology (RNA-seq) followed by bioinformatic analysis. A shift from androgen-responsive to androgen nonresponsive status was observed when comparing LNCaP xenograft tumor to culture cells. Androgen receptor and aryl-hydrocarbon pathway were found to be inhibited and interleukin-1 (IL-1) mediated pathways contributed to these changes. Coupled with in vitro experiments modeling for androgen exposure, cell-matrix interaction, inflammation, and hypoxia, we identified specific mechanisms that may contribute to the observed changes in genes and pathways. Our results provide critical baseline transcriptomic information for a tumor xenograft model and the tumor environments that might be associated with regulating the progression of the xenograft tumor, which may influence interpretation of diet/diet-derived experimental treatments.

Highlights

Understanding the biology of prostate cancer is critical for developing successful diet/diet-derived compound preventive and therapeutic strategies for this disease
The current study seeks to use the next generation sequencing (NGS) approach coupled with complementary in vivo and in vitro models to (1) provide molecular information on the progression of human prostate cancer cells in vivo, (2) identify possible tumor microenvironmental signals that lead to these molecular changes, and (3) facilitate molecular target identification to elucidate the mechanism of action for dietary prostate cancer prevention studies
We identified greater than 1000 genes that changed 2× or greater in the tumor xenograft vs. culture cells

Summary

Introduction

Understanding the biology of prostate cancer is critical for developing successful diet/diet-derived compound preventive and therapeutic strategies for this disease. To this end, rodent models are often used to simulate human prostate cancer initiation and development processes and to test diet/diet-derived compound prevention and treatment modalities [1]. Among the numerous rodent prostate cancer models, genetically engineered mouse (GEM) [2], chemical-induced carcinogenesis [3], and tumor xenograft models [4] are extensively used to investigate the molecular and cellular mechanisms underlying prostate cancer progression [5,6].

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