Separate and not equal: sex differences in JAM-A tumor suppression in glioblastoma.
Separate and not equal: sex differences in JAM-A tumor suppression in glioblastoma.
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独立而不相等：胶质母细胞瘤中 JAM-A 肿瘤抑制的性别差异。
DOI：
10.1093/neuonc/noaa218
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发表时间：
2020
期刊：
影响因子：
15.9
通讯作者：
Ahmed,AtiqueU
中科院分区：
文献类型：
--
作者：
Shireman,JackM;Ahmed,AtiqueU
胶质母细胞瘤（GBM）是一种几乎普遍致命的原发性脑肿瘤。临床发病率数据表明，GBM 在男性中发生率较高，且总体预后较差。 1 尽管男性和女性之间的预后差异已得到充分记录，但直到最近，研究才开始揭示这种性别肿瘤生长和维持差异背后的分子机制。 1-3 Yang 及其同事最近研究了男性和女性之间 GBM 进展的机制差异，并得出结论，由于所有年龄段的患者都存在性别差异，因此一生中的激素波动不太可能是唯一的罪魁祸首。 3 作者发现，不同的信号传导途径可能是男性和女性之间生存差异的基础，女性依赖于整合素信号传导，而男性则依赖于细胞周期调节。 3 这项工作激发了人们更好地了解 GBM 性别差异背后的生物和生理机制的需求。在当前的研究中，Turaga 及其同事研究了连接粘附分子 A (JAM-A) 中性别驱动的机制差异，该差异与 GBM 中癌症干细胞 (CSC) 的维持有关。 4, 5 JAM-A 最初于 2014 年在 GBM 中检测到，是一种富含 CSC 的高表达粘附分子，已被证明可以调节 CSC 生长，同时不会影响正常神经干细胞的增殖。 5 原始研究表明，JAM-A 特异性促进核纤层蛋白特异性细胞粘附，缺乏 JAM-A 的 CSC 无法粘附肿瘤细胞外基质，从而导致细胞干性丧失。 5 JAM-A 随后也被证明对 GBM 具有预后价值，并且与 miR-145 密切相关，miR-145 是一种负责 GBM 肿瘤抑制和 CSC 维持的 microRNA。 6, 7 Turaga 及其同事现在利用当前的这项研究，以之前的 JAM-A 工作为基础，发现了其功能中以前未知的性别依赖性。利用小鼠神经胶质瘤系 GL261，作者注意到雄性和雌性小鼠的存活率存在差异，随后在检查 JAM-A 缺陷的小鼠时，这种差异被逆转。重要的是，当对各组进行一起分析时，这种差异被掩盖，突出了宿主微环境在神经胶质瘤发生过程中以性别特异性方式的重要性。基于他们之前定义神经胶质瘤中骨髓源性抑制细胞的性别特异性差异的工作，2 作者试图对小鼠模型中的肿瘤微环境进行分类，并直接比较雄性和雌性。在此过程中，他们发现雌性小鼠中缺乏 JAM-A 的小胶质细胞表现出增强的吞噬特性。在雌性条件下，这种吞噬性质也与离子钙结合接头分子 1 呈阳性的小胶质细胞相结合，表明小胶质细胞被激活。这种小胶质细胞的激活最终导致抗炎和促肿瘤微环境，导致肿瘤增殖增加。 Turaga 等人在本期《神经肿瘤学》中提出的 GBM 进展中性别依赖性的贡献特别引人注目，因为它是肿瘤细胞外在的，重点是宿主参与建立致癌微环境。通过更深入的探索，作者假设雌激素可能在雌性小鼠的这种反应中发挥作用。通过对野生型和 JAM-A 缺陷小鼠进行卵巢切除术，他们发现这会导致 JAM-A 缺陷组中的肿瘤类型更具侵袭性，但不会显着影响野生型组，这暗示当 JAM-A 时雌激素可能具有保护作用……
Glioblastoma (GBM) is an almost universally fatal primary brain tumor. Clinical incidence data demonstrate that GBM occurs in males at a higher rate and with a poorer overall prognosis. 1 Although prognostic differences among males and females have been well documented, only recently has research begun to shed light on the molecular mechanisms behind such differences in tumor growth and maintenance with regard to sex. 1–3 Yang and colleagues recently examined the mechanistic differences of GBM progression between males and females and concluded that because sex differences are seen in patients across all age brackets, hormone fluctuation throughout life is not likely to be the sole culprit. 3 The authors discover that different signaling pathways may underlie the differences in survival between males and females, with females relying on integrin signaling and males on cell cycle regulation. 3 This work sparked the need for a better understanding of biological and physiological mechanisms that underlie sex differences in GBM. In the current study, Turaga and colleagues examine sexdriven mechanistic differences in junction adhesion molecule A (JAM-A), linked to cancer stem cell (CSC) maintenance in GBM. 4, 5 Initially detected in GBM in 2014 as a highly expressed adhesion molecule enriched on CSCs, JAM-A has been shown to regulate CSC growth while not impacting the proliferation of normal neural stem cells. 5 The original study demonstrates that JAM-A specifically promotes lamin-specific cell adhesion, and CSCs lacking JAM-A fail to adhere tumor extracellular matrix, which results in loss of cellular stemness. 5 JAM-A has also subsequently been shown to have prognostic value in GBM as well as to be intricately tied to miR-145, a microRNA responsible for tumor suppression and CSC maintenance in GBM. 6, 7 Turaga and colleagues now use this current study to build upon the previous JAM-A work and discover a previously unknown sex dependency in its functioning. Utilizing the mouse glioma line GL261, the authors noted a difference in survival between male and female mice, which was subsequently reversed when examining mice deficient for JAM-A. Importantly, this difference was masked when groups were analyzed together, highlighting the importance of host microenvironment during gliomagenesis in a sexspecific manner. Building upon their previous work defining sex-specific differences in myeloid-derived suppressor cells in glioma, 2 the authors sought to categorize the tumor microenvironment in their mouse models and directly compare males and females. In doing so, they discovered that microglia deficient in JAM-A in female mice exhibit increased phagocytic properties. This phagocytic nature was also combined with microglia positive for ionized calcium binding adaptor molecule 1 in the female condition, indicating microglia activation. This microglia activation ultimately resulted in an anti-inflammatory and pro-tumorigenic microenvironment, leading to increased tumor proliferation. The sex-dependent contribution in GBM progression proposed by Turaga et al in this issue of Neuro-Oncology is particularly compelling because it is tumor cell extrinsic, focused on host involvement in establishing an oncogenic microenvironment.Probing deeper, the authors hypothesize that estrogen may play a role in this response in female mice. By conducting ovariectomies across wild-type and JAM-A deficient mice, they discover that this results in more aggressive tumor types within the JAM-A deficient group but does not significantly impact the wild-type group, hinting at a possible protective effect of estrogen when JAM-A …