title: Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice.
abstract: Hepatocellular carcinoma (HCC) remains associated with a poor prognosis, but novel targeted therapies in combination with anti-angiogenic substances may offer new perspectives. We hypothesized that simultaneous targeting of tumor cells, endothelial cells, and pericytes would reduce growth and angiogenesis of HCC, which represents a highly vascularized tumor entity. Recently, because of their anti-angiogenic properties, inhibitors of mammalian target of rapamycin (mTOR) have entered clinical trials for therapy of HCC. However, treatment with mTOR inhibitors may lead to paradoxical activation of Akt signaling in tumor cells via insulin-like growth factor-I receptor (IGF-IR)-dependent and IGF-IR-independent mechanisms. Because we have recently identified heat shock protein 90 (Hsp90) antagonists to impair both oncogenic and angiogenic signaling cascades in tumor cells, including Akt and IGF-IR, we sought to investigate whether Hsp90 blockade could improve growth-inhibitory and anti-angiogenic effects of the mTOR inhibitor rapamycin. Human HCC cells, a murine hepatoma cell line, endothelial cells (ECs), and vascular smooth muscle cells (VSMC) were employed in experiments. Results show that dual inhibition of mTOR and Hsp90 leads to effective disruption of oncogenic signaling cascades and substantially improves growth-inhibitory effects in vivo. Importantly, blocking Hsp90 abrogated the rapamycin-induced activation of Akt and of the downstream effector nuclear factor kappa-B (NF-kappaB) in HCC tumors. Furthermore, Hsp90 inhibition reduced the expression of platelet-derived growth factor-receptor-beta (PDGF-Rbeta) on VSMCs, and diminished vascular endothelial growth factor-receptor 2 (VEGFR-2) expression on ECs, which further improves the anti-angiogenic capacity of this regimen.
  
  
  CONCLUSIONS
  Blocking Hsp90 disrupts rapamycin-induced activation of alternative signaling pathways in HCCs and substantially improves the growth-inhibitory effects of mTOR inhibition in vivo. Hence, the concept of targeting tumor cells, ECs, and VSMCs by blocking Hsp90/mTOR could prove valuable for treatment of HCC.
authors.affiliation: Departments of Surgery and Surgical Oncology, University of Regensburg Medical Center, Regensburg, Germany.
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
authors.forename: Christian
authors.initials: C
authors.lastname: Moser
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichnter-Feigl
authors.forename: Philipp
authors.initials: P
authors.lastname: Schachtschneider
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Volker
authors.initials: V
authors.lastname: Schmitz
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoeltzing
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D053938:DNA Fragmentation; D017931:DNA Primers; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus