The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.

肿瘤和基质细胞之间的动态串扰是癌症侵袭性的主要决定因素。肿瘤抑制因子 DAB2IP（禁用同源物 2 相互作用蛋白）在这方面发挥着重要作用，因为它调节细胞对多种细胞外输入（包括炎症细胞因子和生长因子）的反应。 DAB2IP 是 RasGAP，负控制 Ras 依赖性有丝分裂信号。此外，它还调节其他主要致癌途径，包括 TNFα/NF-κB、WNT/β-连环蛋白、PI3K/AKT 和雄激素受体信号传导。与其肿瘤抑制作用一致，DAB2IP 在癌症中经常通过转录和转录后机制失活，包括启动子甲基化、microRNA 介导的下调和蛋白质-蛋白质相互作用。有趣的是，一些观察结果表明肿瘤基质细胞中 DAB2IP 的下调可以促进促转移微环境的建立。这篇综述总结了 DAB2IP 肿瘤抑制功能及其失活在癌症中的后果的最新见解。特别是，我们探索了旨在重新激活 DAB2IP 或增强其表达水平的潜在方法，作为癌症治疗的新策略。我们认为，DAB2IP 的重新激活或上调将同时减弱癌细胞和肿瘤微环境中的多种致癌途径，这对改善广谱肿瘤的治疗具有重要意义。