Comment on "GRP94 promotes brain metastasis by engaging pro-survival autophagy".
Comment on "GRP94 promotes brain metastasis by engaging pro-survival autophagy".
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DOI：
10.1093/neuonc/noaa017
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发表时间：
2020-03
期刊：
影响因子：
15.9
通讯作者：
G. J. Yoshida
中科院分区：
文献类型：
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作者：
G. J. Yoshida
我怀着极大的兴趣阅读了Santana-Codina等人1的工作，其中作者显示GRP 94（94-kDa糖蛋白），它赋予转移起始癌细胞内质网（ER）应激抗性表型，通过激活保护性Atg 5/7依赖性自噬决定乳腺癌转移的器官特异性性质。鉴于脑中具有低水平葡萄糖的转移前小生境，预期GRP 94过表达通过调节ER应激和促存活自噬对于乳腺癌的脑转移是必不可少的。1脑向性癌症干细胞样细胞（CSC）群体在缺氧和/或低营养素肿瘤微环境（TME）中表现出增强的适应潜力，这就是为什么患有人表皮生长因子受体2阳性或三阴性乳腺癌的患者，其肿瘤含有比其他乳腺癌更多的CSC，更有可能发展为脑胶质瘤。2确实，脑转移患者的病理学检查在图5中显示轻链3-II阳性癌细胞在浸润前沿和坏死周围TME中富集，其中缺氧诱导因子1α阳性CSC激活选择性自噬。1，2然而，严格地说，作者还应进行p62/SQSTM 1的免疫组织化学分析，因为转移性肿瘤细胞中自噬通量可能受损。最近的研究表明，脑中的转移性小生境赋予三脾阴性乳腺癌的存活转移性CSC上增强的原钙粘蛋白7（PCDH 7）表达，其保留自我更新潜力。3从机制上讲，星形胶质细胞和CSC之间的直接相互作用激活PCDH 7-磷脂酶C（PLC）β-Ca 2 + CaMK II/S100 A4轴，以促进转移前小生境中的肿瘤定植。在临床环境中，edelfosine是一种合成的烷基溶血磷脂和选择性PLC抑制剂，已在治疗脑肿瘤的II期临床试验中进行了临床试验，并在预防肿瘤生长方面显示出令人鼓舞的结果。考虑到雷帕霉素/ unc-51的哺乳动物靶点的抑制，如自噬激活激酶1信号传导和Beclin 1-IP 3R-Bcl-2的解离，2复合物负责通过抑制PLCγ1在结直肠癌和肝癌细胞中诱导自噬。4脑中的转移性CSC可能通过依地福新阻断PLCγ1介导自噬细胞死亡（ACD）。ACD伴随着c-Jun N-末端激酶信号过度激活和细胞质中自噬体的过度积累。5与此形成鲜明对比的是，作者显示了羟氯喹（HCQ）对脑转移性病变的预防作用，它抑制自噬体和溶酶体的融合。1事实上，多项临床试验现在已经报道了HCQ与常规化疗相结合的治疗效果，例如在多形性胶质母细胞瘤治疗中，与单独使用替莫唑胺相比，HCQ与替莫唑胺的组合使患者存活时间增加了一倍以上。2重要的是，自噬对于癌细胞是一把“双刃剑”，因为它可以促进或抑制癌细胞的存活和增殖，这取决于TME。此外，作者阐明了MDA-MB-435的脑转移变体表现出线粒体BH 3蛋白，Bcl-2 19千道尔顿相互作用蛋白3（BNIP 3），磷酸酶和张力蛋白同源物（PTEN）诱导的激酶1（PINK 1）/帕金森介导的线粒体自噬所必需。值得注意的是，越来越多的证据表明，线粒体自噬，这是在缺氧和/或低营养素TME下功能失调的线粒体的选择性自噬依赖性降解，通过促进线粒体的更新和限制CSC进行三羧酸循环的能力而使CSC更依赖于有氧糖酵解，（瓦尔堡效应）2.通过过氧化物酶体增殖物激活受体γ共激活因子1-α抑制PINK 1/Parkin介导的线粒体自噬或增强线粒体生物发生，导致乳腺CSC标志物之一CD 44下调，并促进p53易位至细胞核，其中已经报道了它拮抗干细胞基因如Oct 4和Sox2.2的表达。总之，需要进一步的研究来鉴定GRP 94对存在于脑中的转移起始CSC中的线粒体自噬的作用。
I read with great interest the work of Santana-Codina et al1 in which the authors showed GRP94 (94-kDa glycoprotein), which confers endoplasmic reticulum (ER) stress resistance phenotype on metastasis-initiating cancer cells, determines the organ-specific nature of breast cancer metastasis by activating the protective Atg5/7-dependent autophagy. Given the pre-metastatic niche in the brain with the low level of glucose, GRP94 overexpression is expected to be essential for brain metastasis of breast cancer by regulating both ER stress and pro-survival autophagy.1 A brain-tropism cancer stem-like cell (CSC) population exhibits enhanced adaptive potential in the hypoxic and/or hyponutrient tumor microenvironment (TME), which is why patients with human epidermal growth factor receptor 2–positive or triple-negative breast cancer whose tumors contain more CSCs than other breast cancers are more likely to develop brain metastases.2 Indeed, pathological examinations of the patients with brain metastasis showed in Figure 5 that light chain 3-II–positive cancer cells were enriched at the invasive front and in perinecrotic TME, where hypoxia-inducible factor 1α–positive CSCs activate selective autophagy.1,2 Strictly speaking, however, the authors should also perform immunohistochemistry analysis of p62/SQSTM1 because of the possibility of impaired autophagy flux in metastatic tumor cells. It has been recently shown that the metastatic niche in the brain endows an enhanced protocadherin 7 (PCDH7) expression on the survived metastatic CSCs of triplenegative breast cancer, which retains self-renewal potential.3 Mechanistically, the direct interactions between astrocytes and CSCs activate the PCDH7-phospholipase C (PLC) β-Ca2+CaMKII/S100A4 axis to promote tumor colonization in the pre-metastatic niche. In the clinical settings, edelfosine, which is a synthetic alkyl-lysophospholipid and a selective PLC inhibitor, has been clinically trialed in a phase II investigation for the treatment of brain tumor and shown encouraging results in preventing tumor growth.3 However, given that both suppression of mammalian target of rapamycin/ unc-51 like autophagy activating kinase 1 signaling and dissociation of Beclin1-IP3R-Bcl-2 complex are responsible for autophagy induction via PLCγ1 inhibition in colorectal and hepatic cancer cells,4 it is plausible that metastatic CSCs in the brain cause autophagic cell death (ACD) mediated by PLCγ1 blockage by edelfosine. ACD is accompanied by c-Jun N-terminal kinase signal hyperactivation and excessive accumulation of autophagosomes in the cytoplasm.5 By striking contrast, the authors showed a preventive effect of hydroxychloroquine (HCQ), which inhibits the fusion of autophagosomes and lysosome, on brain metastatic lesion.1 In fact, multiple clinical trials have now reported on the therapeutic efficacy of combining HCQ with conventional chemotherapies, such as in glioblastoma multiforme treatment, where HCQ in combination with temozolomide more than doubled patient survival times compared with temozolomide alone.2 Importantly, autophagy is a “double-edged sword” for cancer cells because it can either promote or suppress their survival and proliferation, depending on TME. Furthermore, the authors clarified that the brain metastatic variant of MDA-MB-435 exhibited upregulation of a mitochondrial BH3-only protein, Bcl-2 nineteen-kilodalton interacting protein 3 (BNIP3), essential for phosphatase and tensin homolog (PTEN)–induced kinase 1 (PINK1)/Parkinmediated mitophagy.1 BNIP3 interacts with PINK1 to promote accumulation of full-length PINK1 on the outer membrane of mitochondria and facilitates Parkin recruitment.6 Notably, mounting evidence suggests that mitophagy, which is the selective autophagy-dependent degradation of dysfunctional mitochondria under hypoxic and/or hyponutrient TME, is specifically implicated in maintaining CSC phenotype by promoting the turnover of mitochondria and limiting the capacity of CSCs for the tricarboxylic acid cycle and instead making CSCs more dependent on aerobic glycolysis (Warburg effect).2 Suppression of PINK1/Parkin-mediated mitophagy or enhanced mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α leads to downregulation of CD44, one of the breast CSC markers, and promotes the translocation of p53 into the nucleus, where it has been reported to antagonize expression of stem cell genes such as Oct4 and Sox2.2 Taken together, further investigations are warranted to identify the effect of GRP94 on mitophagy in metastasis-initiating CSCs existing in the brain.