title: Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells.
abstract: The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here, we show that cancer cells resistant to Hsp70 inhibitors in vitro remain sensitive to them in vivo, revealing the pathogenic significance of Hsp70 in tumor stromal cells rather than tumor cells as widely presumed. Using transgenic mouse models of cancer, we found that expression of Hsp70 in host stromal cells was essential to support tumor growth. Furthermore, genetic ablation or pharmacologic inhibition of Hsp70 suppressed tumor infiltration by macrophages needed to enable tumor growth. Overall, our results illustrate how Hsp70 inhibitors mediate the anticancer effects by targeting both tumor cells and tumor stromal cells, with implications for the broad use of these inhibitors as tools to ablate tumor-associated macrophages that enable malignant progression. Cancer Res; 76(20); 5926-32. ©2016 AACR.
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. CureLab Oncology, Needham, Massachusetts.
authors: Vladimir L
authors: VL
authors: Gabai
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors: Julia A
authors: JA
authors: Yaglom
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors: Yongmei
authors: Y
authors: Wang
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts.
authors: Le
authors: L
authors: Meng
authors: Department of Pharmaceutical Chemistry and Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors: Hao
authors: H
authors: Shao
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors: Geunwon
authors: G
authors: Kim
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts.
authors: Teresa
authors: T
authors: Colvin
authors: Department of Pharmaceutical Chemistry and Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, California.
authors: Jason
authors: J
authors: Gestwicki
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts. sherma1@bu.edu.
authors: Michael Y
authors: MY
authors: Sherman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects* / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins