Lang Sven A, Moser Christian, Fichnter-Feigl Stefan, Schachtschneider Philipp, Hellerbrand Claus, Schmitz Volker, Schlitt Hans J, Geissler Edward K, Stoeltzing Oliver
Departments of Surgery and Surgical Oncology, University of Regensburg Medical Center, Regensburg, Germany.
Hepatology. 2009 Feb;49(2):523-32. doi: 10.1002/hep.22685.
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.
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.
肝细胞癌（HCC）的预后仍然很差，但新型靶向疗法与抗血管生成物质联合使用可能会带来新的前景。我们假设同时靶向肿瘤细胞、内皮细胞和周细胞会减少HCC的生长和血管生成，HCC是一种血管高度丰富的肿瘤实体。最近，由于其抗血管生成特性，雷帕霉素哺乳动物靶点（mTOR）抑制剂已进入HCC治疗的临床试验。然而，用mTOR抑制剂治疗可能会通过胰岛素样生长因子-I受体（IGF-IR）依赖性和IGF-IR非依赖性机制导致肿瘤细胞中Akt信号通路的反常激活。因为我们最近发现热休克蛋白90（Hsp90）拮抗剂可损害肿瘤细胞中的致癌和血管生成信号级联反应，包括Akt和IGF-IR，所以我们试图研究Hsp90阻断是否能改善mTOR抑制剂雷帕霉素的生长抑制和抗血管生成作用。实验采用了人HCC细胞、小鼠肝癌细胞系、内皮细胞（ECs）和血管平滑肌细胞（VSMCs）。结果表明，mTOR和Hsp90的双重抑制导致致癌信号级联反应的有效破坏，并在体内显著改善生长抑制作用。重要的是，阻断Hsp90消除了雷帕霉素诱导的HCC肿瘤中Akt和下游效应因子核因子κB（NF-κB）的激活。此外，Hsp90抑制降低了VSMCs上血小板衍生生长因子受体-β（PDGF-Rβ）的表达，并减少了ECs上血管内皮生长因子受体2（VEGFR-2）的表达，这进一步提高了该方案的抗血管生成能力。
阻断Hsp90可破坏雷帕霉素诱导的HCC中替代信号通路的激活，并在体内显著改善mTOR抑制的生长抑制作用。因此，通过阻断Hsp90/mTOR靶向肿瘤细胞、ECs和VSMCs的概念可能对HCC治疗具有重要价值。
