High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.

Ryotaro Ohkuma,Etsuko Satoh,Koji Tamada,Makoto Watanabe,Kazuyuki Hamada,Tetsuro Sasada,Yutaro Kubota,Shumpei Ishikawa,Nobuyuki Ohike,Masahiko Murakami,Takehiko Yokobori,Masafumi Takimoto,Yuya Hirasawa,Takuya Tsunoda,Hiroo Ishida,Hidenobu Ishizaki,Erica Yada,Tomoko Norose,Kiyohiro Ando,Midori Shida,Masahiko Izumizaki,Daisuke Komura,Kiyoshi Yoshimura,Shinichi Kobayashi,Hirotsugu Ariizumi,Rie Onoue,Satoshi Wada,Takeshi Aoki,Junji Tsurutani

doi:10.1371/journal.pone.0226707

Abstract

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.

Highlights

Pancreatic cancer is the most aggressive human malignancy and the fourth leading cause of cancer-related death in the United States of America (USA) [1] and Japan [2]
hematoxylin and eosin (HE) staining was performed in all cases, in S3 Fig we presented the histological features of nine cases other than the case of Fig 1A
Immunohistological analysis showed that the expression of the human leukocyte antigen (HLA) class I molecule on the tumor cells in patient-derived xenograft (PDX) specimens was retained, even after PDX passaging

Summary

Introduction

Pancreatic cancer is the most aggressive human malignancy and the fourth leading cause of cancer-related death in the United States of America (USA) [1] and Japan [2]. Pancreatic cancer causes more than 200,000 deaths worldwide every year and is associated with an overall 5-year survival rate of less than 6% after diagnosis in the USA [1,3,4]. Only approximately 20% of tumors are resectable at presentation [4], and development of improved methods for early diagnosis is urgently needed. Another reason for the high mortality rates is resistance to chemotherapy and radiotherapy [5,6]. In order to improve the prognosis of patients with pancreatic cancer, novel approaches are needed to overcome chemoresistance to GEM

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Conclusion