RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.

Ryo Sato,Ikuko Koya,Jun Kudoh,Takashi Sasaki,Ritsuko Harigai,Hideyuki Okano,Teppei Nakano,Yoshimi Arima,Mari Hosonaga,Oltea Sampetrean,Hideyuki Saya

doi:10.1155/2017/8032910

Ryo Sato, Ikuko Koya + Show 9 more

Open Access

https://doi.org/10.1155/2017/8032910

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Abstract

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

Highlights

Metastasis of cancer cells to the brain occurs in 9% to 17% of cancer patients, with the major sources of these cells being lung adenocarcinoma, breast cancer, and melanoma [1]
We confirmed that both human and mouse mRNAs were present in the isolated total RNA samples by reverse transcription (RT) and real-time polymerase chain reaction (PCR) analysis with primers specific for the human or mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene
We have established mouse xenograft models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines to characterize these interactions

Summary

Introduction

Metastasis of cancer cells to the brain occurs in 9% to 17% of cancer patients, with the major sources of these cells being lung adenocarcinoma, breast cancer, and melanoma [1]. As a result of recent advances in systemic treatment of primary tumors, individuals with cancer are living longer and the incidence of brain metastasis is expected to increase. Radiation, and cytotoxic chemotherapy, molecularly targeted therapies have recently been added to the treatment options for metastatic brain tumors and have improved outcome [2]. Despite the progress in multimodal treatment for brain metastases, the prognosis for affected patients remains poor [3]. For patients with human epidermal growth factor receptor 2– (HER2–) positive breast cancer or epidermal growth factor receptor mutation– positive non–small cell lung cancer, the brain remains a frequent site of disease recurrence regardless of disease control for primary tumors by systemic treatment with molecularly targeted agents such as trastuzumab or gefitinib, respectively [4, 5].

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