Ontario Cancer Institute/Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, Toronto, Canada.
Radiother Oncol. 2013 Sep;108(3):506-10. doi: 10.1016/j.radonc.2013.06.019. Epub 2013 Jul 12.
Hypoxia can promote tumor metastasis by mechanisms that are believed to result from changes in gene expression. The current study examined the role of putative metastatic genes regulated by cyclic hypoxia in relation to metastasis formation in orthotopic models of cervix cancer.
Orthotopic tumors derived from ME180 human cervix cancer cells or from early generation human cervix cancer xenografts were exposed to cyclic hypoxic conditions during growth in vivo and tumor growth and lymphnode metastases were monitored. Expression of the chemokine receptor CXCR4 and various genes in the Hedgehog (Hh) pathway were inhibited using genetic (inducible shRNA vs CXCR4) small molecule (AMD3100) or antibody (5E1) treatment (CXCR4 and Hh genes, respectively) during tumor growth.
As reported previously, exposure of tumor bearing mice to cyclic hypoxia caused a reduction of tumor growth but a large increase in metastasis. Inhibition of CXCR4 or Hh gene activity during tumor growth further reduced primary tumor size and reduced lymphatic metastasis to levels below those seen in control mice exposed to normoxic conditions.
Blocking CXCR4 or Hh gene expression are potential therapeutic pathways for improving cervix cancer treatment.
缺氧可通过改变基因表达来促进肿瘤转移，这一机制被认为是导致肿瘤转移的原因。本研究通过检测与宫颈癌原位模型转移形成相关的循环缺氧调节的假定转移基因的作用，来研究这一机制。
将源自 ME180 人宫颈癌细胞或早期代人宫颈癌异种移植物的原位肿瘤在体内生长过程中暴露于循环缺氧条件下，并监测肿瘤生长和淋巴结转移情况。在肿瘤生长过程中，使用遗传（诱导性 shRNA 与 CXCR4）、小分子（AMD3100）或抗体（5E1）治疗（分别为 CXCR4 和 Hh 基因）抑制趋化因子受体 CXCR4 和 Hedgehog（Hh）通路中的各种基因的表达。
正如之前报道的那样，使荷瘤小鼠暴露于循环缺氧环境会导致肿瘤生长减少，但转移增加。在肿瘤生长过程中抑制 CXCR4 或 Hh 基因活性会进一步减小原发肿瘤的大小，并将淋巴转移减少到低于在常氧条件下暴露的对照组小鼠的水平。
阻断 CXCR4 或 Hh 基因表达可能是改善宫颈癌治疗的潜在治疗途径。
