Harbi Shaghayegh, Park Hannah, Gregory Michael, Lopez Peter, Chiriboga Luis, Mignatti Paolo
1 VasculoTox, Inc. , New York, New York.
2 Department of Epidemiology, University of California , Irvine, School of Medicine, Irvine, California.
Lymphat Res Biol. 2017 Jun;15(2):153-165. doi: 10.1089/lrb.2016.0030. Epub 2017 May 18.
Early-life programming is defined by the adaptive changes made by the fetus in response to an adverse in utero environment. Infantile hemangioma (IH), a vascular anomaly, is the most common tumor of infancy. Here we take IH as the tumor model to propose the stem cell teratogenic hypothesis of tumorigenesis and the potential involvement of the immune system.
Teratogenic agents include chemicals, heavy metals, pathogens, and ionizing radiation. To investigate the etiology and pathogenesis of IH, we hypothesized that they result from a teratogenic mechanism. Immature, incompletely differentiated, dysregulated progenitor cells (multipotential stem cells) are arrested in development with vasculogenic, angiogenic, and tumorigenic potential due to exposure to teratogenic agents such as extrinsic factors that disrupt intrinsic factors via molecular mimicry. During the critical period of immunological tolerance, environmental exposure to immunotoxic agents may harness the teratogenic potential in the developing embryo or fetus and modify the early-life programming algorithm by altering normal fetal development, causing malformations, and inducing tumorigenesis. Specifically, exposure to environmental agents may interfere with physiological signaling pathways and contribute to the generation of IH, by several mechanisms.
An adverse in utero environment no longer serves as a sustainable environment for proper embryogenesis and normal development. Targeted disruption of stem cells by extrinsic factors can alter the genetic program.
This article offers new perspectives to stimulate discussion, explore novel experimental approaches (such as immunotoxicity/vasculotoxicity assays and novel isogenic models), and to address the questions raised to convert the hypotheses into nontoxic, noninvasive treatments.
早期生命编程是指胎儿为应对子宫内不良环境而做出的适应性变化。婴儿血管瘤（IH）是一种血管异常，是婴儿期最常见的肿瘤。在此，我们以IH作为肿瘤模型，提出肿瘤发生的干细胞致畸假说以及免疫系统的潜在参与。
致畸剂包括化学物质、重金属、病原体和电离辐射。为了研究IH的病因和发病机制，我们假设它们是由致畸机制引起的。未成熟、未完全分化、失调的祖细胞（多能干细胞）由于暴露于致畸剂（如通过分子模拟破坏内在因素的外在因素）而在发育过程中停滞，具有血管生成、血管发生和肿瘤发生的潜能。在免疫耐受的关键时期，环境暴露于免疫毒性剂可能利用发育中胚胎或胎儿的致畸潜能，并通过改变正常胎儿发育、导致畸形和诱导肿瘤发生来修改早期生命编程算法。具体而言，暴露于环境因素可能通过多种机制干扰生理信号通路并促进IH的产生。
子宫内不良环境不再是正常胚胎发生和正常发育的可持续环境。外在因素对干细胞的靶向破坏可改变遗传程序。
本文提供了新的视角，以激发讨论、探索新的实验方法（如免疫毒性/血管毒性测定和新的同基因模型），并解决所提出的问题，将假说转化为无毒、非侵入性的治疗方法。
