Doucet Dakota, Brubaker Connor, Turner Donald, Gregory Carl A
Medical Sciences Program, Texas A&M Health Science Center School of Medicine, Texas A&M University, Bryan, TX, United States.
Department of Statistics, Texas A&M University, College Station, TX, United States.
Front Oncol. 2023 Mar 15;13:1114822. doi: 10.3389/fonc.2023.1114822. eCollection 2023.
The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has the capacity to modulate homeostasis between canonical and non-canonical Wnt pathways and also signal independently of Wnt. The specific effects of Dkk-1 activity on tumor physiology are therefore unpredictable with examples of Dkk-1 serving as either a driver or suppressor of malignancy. Given that Dkk-1 blockade may serve as a potential treatment for some types of cancer, we questioned whether it is possible to predict the role of Dkk-1 on tumor progression based on the tissue origin of the tumor.
Original research articles that described Dkk-1 in terms a tumor suppressor or driver of cancer growth were identified. To determine the association between tumor developmental origin and the role of Dkk-1, a logistic regression was performed. The Cancer Genome Atlas database was interrogated for survival statistics based on tumor Dkk-1 expression.
We report that Dkk-1 is statistically more likely to serve as a suppressor in tumors arising from the ectoderm ( = 0.0198) or endoderm ( = 0.0334) but more likely to serve as a disease driver in tumors of mesodermal origin ( = 0.0155). Survival analyses indicated that in cases where Dkk-1 expression could be stratified, high Dkk-1 expression is usually associated with poor prognosis. This in part may be due to pro-tumorigenic role Dkk-1 plays on tumor cells but also through its influence on immunomodulatory and angiogenic processes in the tumor stroma.
Dkk-1 has a context-specific dual role as a tumor suppressor or driver. Dkk-1 is significantly more likely to serve as a tumor suppressor in tumors arising from ectoderm and endoderm while the converse is true for mesodermal tumors. Patient survival data indicated high Dkk-1 expression is generally a poor prognostic indicator. These findings provide further support for the importance of Dkk-1 as a therapeutic cancer target in some cases.
经典Wnt信号通路抑制剂Dickkopf-1（Dkk-1）能够调节经典和非经典Wnt信号通路之间的稳态，并且还能独立于Wnt进行信号传导。因此，Dkk-1活性对肿瘤生理学的具体影响是不可预测的，有证据表明Dkk-1既可以作为恶性肿瘤的驱动因子，也可以作为抑制因子。鉴于Dkk-1阻断可能是某些类型癌症的潜在治疗方法，我们质疑是否有可能根据肿瘤的组织起源来预测Dkk-1在肿瘤进展中的作用。
检索描述Dkk-1作为癌症生长的肿瘤抑制因子或驱动因子的原始研究文章。为了确定肿瘤发育起源与Dkk-1作用之间的关联，进行了逻辑回归分析。基于肿瘤Dkk-1表达情况，查询癌症基因组图谱数据库以获取生存统计数据。
我们报告称，从统计学角度来看，Dkk-1在由外胚层（P = 0.0198）或内胚层（P = 0.0334）产生的肿瘤中更有可能作为抑制因子，但在中胚层起源的肿瘤中更有可能作为疾病驱动因子（P = 0.0155）。生存分析表明，在Dkk-1表达可以分层的情况下，高Dkk-1表达通常与预后不良相关。这部分可能是由于Dkk-1对肿瘤细胞发挥的促肿瘤作用，也可能是通过其对肿瘤基质中免疫调节和血管生成过程的影响。
Dkk-1作为肿瘤抑制因子或驱动因子具有背景特异性的双重作用。在由外胚层和内胚层产生的肿瘤中，Dkk-1作为肿瘤抑制因子的可能性显著更高，而中胚层肿瘤则相反。患者生存数据表明，高Dkk-1表达通常是不良预后指标。这些发现进一步支持了Dkk-1在某些情况下作为癌症治疗靶点的重要性。
