title: An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells.
abstract: Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFβ family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFβ, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFβ strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFβ signaling. Although TGFβ transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFβ, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.|Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Sasahara
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Surgery, Minamimachida Hospital, Machida, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Oncologic Pathology, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kiyokawa
authors.affiliation: Department of General and Digestive Surgery, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Department of General and Digestive Surgery, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Department of Breast and Endocrine Surgery, Showa General Hospital, Kodaira, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kanauchi
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Minato
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Tada
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.|Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D019899:Paracrine Communication
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15
keywords: ERK; TGFbeta; breast cancer; cancer stem cells; tumor spheres