Abdel Sater Ali H, Bouferraa Youssef, Amhaz Ghid, Haibe Yolla, Lakkiss Ahmed El, Shamseddine Ali
Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon.
Front Oncol. 2022 May 5;12:804983. doi: 10.3389/fonc.2022.804983. eCollection 2022.
Metastasis is a complicated process through which tumor cells disseminate to distant organs and adapt to novel tumor microenvironments. This multi-step cascade relies on the accumulation of genetic and epigenetic alterations within the tumor cells as well as the surrounding non-tumor stromal cells. Endothelial cells constitute a major player in promoting metastasis formation either by inducing the growth of tumor cells or by directing them towards dissemination in the blood or lymph. In fact, the direct and indirect interactions between tumor and endothelial cells were shown to activate several mechanisms allowing cancer cells' invasion and extravasation. On the other side, gastrointestinal cancer development was shown to be associated with the disruption of the gut microbiome. While several proposed mechanisms have been investigated in this regard, gut and tumor-associated microbiota were shown to impact the gut endothelial barrier, increasing the dissemination of bacteria through the systemic circulation. This bacterial dislocation allows the formation of an inflammatory premetastatic niche in the distant organs promoting the metastatic cascade of primary tumors. In this review, we discuss the role of the endothelial cells in the metastatic cascade of tumors. We will focus on the role of the gut vascular barrier in the regulation metastasis. We will also discuss the interaction between this vascular barrier and the gut microbiota enhancing the process of metastasis. In addition, we will try to elucidate the different mechanisms through which this bacterial dislocation prepares the favorable metastatic niche at distant organs allowing the dissemination and successful deposition of tumor cells in the new microenvironments. Finally, and given the promising results of the studies combining immune checkpoint inhibitors with either microbiota alterations or anti-angiogenic therapy in many types of cancer, we will elaborate in this review the complex interaction between these 3 factors and their possible therapeutic combination to optimize response to treatment.
转移是一个复杂的过程，肿瘤细胞通过该过程扩散到远处器官并适应新的肿瘤微环境。这一多步骤级联反应依赖于肿瘤细胞以及周围非肿瘤基质细胞内遗传和表观遗传改变的积累。内皮细胞在促进转移形成方面起着主要作用，其方式要么是诱导肿瘤细胞生长，要么是引导肿瘤细胞在血液或淋巴中扩散。事实上，肿瘤细胞与内皮细胞之间的直接和间接相互作用已被证明可激活多种机制，从而使癌细胞得以侵袭和外渗。另一方面，胃肠道癌症的发展与肠道微生物群的破坏有关。虽然在这方面已经研究了几种提出的机制，但肠道和肿瘤相关微生物群已被证明会影响肠道内皮屏障，增加细菌通过体循环的扩散。这种细菌移位会在远处器官形成炎症性前转移微环境，促进原发性肿瘤的转移级联反应。在这篇综述中，我们讨论了内皮细胞在肿瘤转移级联反应中的作用。我们将重点关注肠道血管屏障在调节转移中的作用。我们还将讨论这种血管屏障与肠道微生物群之间的相互作用如何增强转移过程。此外，我们将试图阐明这种细菌移位通过哪些不同机制在远处器官准备好有利的转移微环境，从而使肿瘤细胞能够在新的微环境中扩散并成功沉积。最后，鉴于在多种癌症中，将免疫检查点抑制剂与微生物群改变或抗血管生成疗法相结合的研究取得了有前景的结果，我们将在这篇综述中详细阐述这三种因素之间的复杂相互作用以及它们可能的治疗组合，以优化治疗反应。
