title: Autophagy Inhibition Delays Early but Not Late-Stage Metastatic Disease.
abstract: The autophagy pathway has been recognized as a mechanism of survival and therapy resistance in cancer, yet the extent of autophagy's function in metastatic progression is still unclear. Therefore, we used murine models of metastatic cancer to investigate the effect of autophagy modulation on metastasis development. Pharmacologic and genetic autophagy inhibition were able to impede cell proliferation in culture, but did not impact the development of experimentally induced 4T1 and B16-F10 metastases. Similarly, autophagy inhibition by adjuvant chloroquine (CQ) treatment did not delay metastasis in an orthotopic 4T1, tumor-resection model. However, neoadjuvant CQ treatment or genetic autophagy inhibition resulted in delayed metastasis development, whereas stimulation of autophagy by trehalose hastened development. Cisplatin was also administered either as a single agent or in combination with CQ. The combination of cisplatin and CQ was antagonistic. The effects of autophagy modulation on metastasis did not appear to be due to alterations in the intrinsic metastatic capability of the cells, as modulating autophagy had no impact on migration, invasion, or anchorage-independent growth in vitro. To explore the possibility of autophagy's influence on the metastatic microenvironment, bone marrow-derived cells (BMDCs), which mediate the establishment of the premetastatic niche, were measured in the lung and in circulation. Trehalose-treated mice had significantly more BMDCs than either vehicle- or CQ-treated mice. Autophagy inhibition may be most useful as a treatment to impede early metastatic development. However, modulating autophagy may also alter the efficacy of platinum-based therapies, requiring caution when considering combination therapies.
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.).
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Barnard
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Regan
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.).
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.).
authors.forename: Paola
authors.initials: P
authors.lastname: Maycotte
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado (R.A.B., D.P.R., R.J.H., D.L.G.); and Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado (P.M., A.T.) Daniel.Gustafson@colostate.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D051379:Mice; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D013997:Time Factors; D014199:Trehalose / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002738:Chloroquine; D014199:Trehalose; D002945:Cisplatin