title: Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response.
abstract: Disseminated tumor cells (DTC), which share mesenchymal and epithelial properties, are considered to be metastasis-initiating cells in breast cancer. However, the mechanisms supporting DTC survival are poorly understood. DTC extravasation into the bone marrow may be encouraged by low oxygen concentrations that trigger metabolic and molecular alterations contributing to DTC survival. Here, we investigated how the unfolded protein response (UPR), an important cytoprotective program induced by hypoxia, affects the behavior of stressed cancer cells. DTC cell lines established from the bone marrow of patients with breast cancer (BC-M1), lung cancer, (LC-M1), and prostate cancer (PC-E1) were subjected to hypoxic and hypoglycemic conditions. BC-M1 and LC-M1 exhibiting mesenchymal and epithelial properties adapted readily to hypoxia and glucose starvation. Upregulation of UPR proteins, such as the glucose-regulated protein Grp78, induced the formation of filamentous networks, resulting in proliferative advantages and sustained survival under total glucose deprivation. High Grp78 expression correlated with mesenchymal attributes of breast and lung cancer cells and with poor differentiation in clinical samples of primary breast and lung carcinomas. In DTCs isolated from bone marrow specimens from breast cancer patients, Grp78-positive stress granules were observed, consistent with the likelihood these cells were exposed to acute cell stress. Overall, our findings provide the first evidence that the UPR is activated in DTC in the bone marrow from cancer patients, warranting further study of this cell stress pathway as a predictive biomarker for recurrent metastatic disease.
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. pantel@uke.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Bartkowiak
authors.affiliation: Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kwiatkowski
authors.affiliation: Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Buck
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Gorges
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Nilse
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Assmann
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Andreas
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.affiliation: Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schlüter
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D015153:Blotting, Western; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D046888:Tissue Array Analysis; D056811:Unfolded Protein Response / Q000502:physiology*