Kilmister Ethan J, Tan Swee T
Gillies McIndoe Research Institute, Wellington, New Zealand.
Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Lower Hutt, New Zealand.
Front Surg. 2022 Apr 27;9:868187. doi: 10.3389/fsurg.2022.868187. eCollection 2022.
Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) - a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.
在血管异常（VAs）、癌症和纤维增生性疾病中已证实存在具有胚胎干细胞（ESC）特征的细胞，这些疾病通常由整形外科医生处理，且在很大程度上仍未得到解决。mTOR抑制剂西罗莫司以及在多种癌症和VAs中阻断Ras/BRAF/MEK/ERK1/2和PI3KCA/AKT/mTOR通路的靶向疗法的疗效，进一步支持了类ESC细胞在这些疾病发病机制中的关键作用。VAs、癌症和纤维增生性疾病中的类ESC细胞表达肾素-血管紧张素系统（RAS）的成分，RAS是一种调节具有ESC特征细胞的稳态内分泌信号级联反应。类ESC细胞受Ras/BRAF/MEK/ERK1/2和PI3KCA/AKT/mTOR通路影响，这些通路直接调节细胞增殖和干性，并在多个点与RAS相互作用。在许多已用靶向疗法成功治疗的癌症和VAs类型中，已鉴定出影响这些通路的功能获得性突变。在癌症中，RAS促进肿瘤进展、治疗耐药性、复发和转移。RAS调节细胞侵袭、迁移、增殖和血管生成。它还通过对组织微环境的直接影响以及与免疫系统的相互作用间接调节类ESC细胞。研究表明，RAS抑制在不同实验模型中可抑制癌症的特征。大量流行病学研究表明，服用RAS抑制剂的患者癌症发病率降低，生存结果改善，尽管一些研究未显示出这种效果。在婴儿血管瘤（IH）中发现表达RAS成分的类ESC细胞，突显了对其程序性生物学行为以及β受体阻滞剂和血管紧张素转换酶抑制剂诱导的加速消退的理解上的范式转变。R-普萘洛尔抑制SOX18的研究结果表明，在不进行β肾上腺素能阻断及其相关副作用的情况下，有可能靶向IH中的类ESC细胞。本文概述了目前关于VAs、癌症和纤维增生性疾病中类ESC细胞和RAS的知识。它还强调了新的研究方向以及针对整形外科中这些未解决问题的潜在新治疗方法，即通过使用现有的低成本、常用且安全的口服药物，通过操纵RAS、其旁路环和汇聚信号通路来靶向类ESC细胞。
