Polysulfide Serves as a Hallmark of Desmoplastic Reaction to Differentially Diagnose Ductal Carcinoma In Situ and Invasive Breast Cancer by SERS Imaging
Akiko Kubo,
Yohei Masugi,
Takeshi Hase,
Kengo Nagashima,
Yuko Kawai,
Minako Takizawa,
Takako Hishiki,
Megumi Shiota,
Masatoshi Wakui,
Yuko Kitagawa,
Yasuaki Kabe,
Michiie Sakamoto,
Ayako Yachie,
Tetsu Hayashida,
Makoto Suematsu
Affiliations
Akiko Kubo
Departments of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Yohei Masugi
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
Takeshi Hase
The Systems Biology Institute, Tokyo 141-0022, Japan
Kengo Nagashima
Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo 160-8582, Japan
Yuko Kawai
Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
Minako Takizawa
Departments of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Takako Hishiki
Departments of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Megumi Shiota
Analysis Technology Center, CTO Office, FUJIFILM Corporation, Minamiashigara-shi 250-0193, Kanagawa, Japan
Masatoshi Wakui
Department of Laboratory Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
Yuko Kitagawa
Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
Yasuaki Kabe
Departments of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Michiie Sakamoto
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
Ayako Yachie
The Systems Biology Institute, Tokyo 141-0022, Japan
Tetsu Hayashida
Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
Makoto Suematsu
Departments of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan
Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.
