UCD School of Medicine, University College Dublin, Dublin 4, Ireland.
UCD Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
EMBO Mol Med. 2020 Sep 7;12(9):e11416. doi: 10.15252/emmm.201911416. Epub 2020 Jul 20.
Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
传统的最大耐受剂量（MTD）化疗依赖于周期性的、大量的癌细胞消融事件，随后是无治疗间歇期，典型地导致耐药性、复发和死亡。此外，MTD 化疗可以通过激活依赖缺氧诱导因子（HIF）-1α和（HIF）-2α（以下简称 HIFα）的转录程序促进转移扩散。相反，频繁的低剂量节拍（LDM）化疗在保留显著临床前抗癌活性的同时，显示出较少的不良反应。因此，我们在此比较了 MTD 或 LDM 化疗对晚期转移性结肠和乳腺癌模型中 HIFα的影响。我们的结果表明，LDM 化疗可以抵消在肝脏和肺部扩散的结肠癌中，MTD 依赖性的 HIFα诱导，同时限制乳腺癌肺转移中的 HIFα和缺氧。此外，我们通过开发两个紧凑的 11 个基因转录组特征来评估 HIFα活性在结直肠癌和乳腺癌 TCGA/微阵列数据中的转化意义，这些特征允许对可能受益于 LDM 和/或 HIFα靶向治疗的患者进行分层/鉴定。总之，这些结果表明 LDM 化疗作为一种潜在的维持策略，可以阻止肿瘤微环境中的 HIFα诱导。
