Ali Eman Amin M, Altaie Alaa Muayad, Talaat Iman M, Hamoudi Rifat
Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
Cancers (Basel). 2025 Aug 30;17(17):2856. doi: 10.3390/cancers17172856.
Colorectal cancer (CRC) is a major global health burden and a leading cause of cancer-related mortality, with metastasis representing the primary cause of death. Angiogenesis plays a critical role in this process, and macrophages within the tumor microenvironment (TME) are its key regulators. Among these, Tie2-expressing macrophages (TEMs) constitute a distinct pro-angiogenic subset that localizes to perivascular regions and responds to angiopoietin2 (Ang2) signaling. Moreover, TEMs contribute to vessel destabilization and the formation of permissive niches for cancer cell intravasation, linking them to both angiogenic and non-angiogenic modes of malignant tumor progression. The significance of TEMs in CRC remains controversial. This controversy, as we noticed, stems from a confluence of methodological challenges, lack of standardized markers, small-scale studies, inconsistent findings across studies, and the inherent complexity of both CRC biology and macrophage biology. Evidence from preclinical models and patient samples highlights the correlation between Ang2/Tie2 activity, TEM infiltration, and poor prognosis in CRC. This review summarizes current knowledge on the role of TEMs and the Ang/Tie2 axis in CRC angiogenesis, metastasis, and resistance to anti-angiogenic therapies. Advancing our understanding of TEMs may enable novel macrophage-focused strategies to inhibit CRC progression and improve patient outcomes.
结直肠癌（CRC）是一项重大的全球健康负担，也是癌症相关死亡的主要原因，转移是主要死因。血管生成在此过程中起关键作用，肿瘤微环境（TME）中的巨噬细胞是其关键调节因子。其中，表达Tie2的巨噬细胞（TEMs）构成一个独特的促血管生成亚群，定位于血管周围区域并对血管生成素2（Ang2）信号作出反应。此外，TEMs有助于血管不稳定和形成允许癌细胞内渗的微环境，将它们与恶性肿瘤进展的血管生成和非血管生成模式联系起来。TEMs在CRC中的意义仍存在争议。正如我们所注意到的，这种争议源于一系列方法学挑战、缺乏标准化标志物、小规模研究、各研究结果不一致以及CRC生物学和巨噬细胞生物学固有的复杂性。临床前模型和患者样本的证据突出了Ang2/Tie2活性、TEM浸润与CRC预后不良之间的相关性。本综述总结了目前关于TEMs和Ang/Tie2轴在CRC血管生成、转移及抗血管生成治疗耐药性方面作用的知识。加深我们对TEMs的理解可能会催生以巨噬细胞为重点的新策略，以抑制CRC进展并改善患者预后。
