難治性(小児)脳腫瘍(膠芽腫)の病因論から治療、予後管理まで

(1:分類、疫学、背景)
原発腫瘍(Primary)
つまり、転移で脳に腫瘍ができたのではなく、
最初に脳に癌細胞ができ、腫瘍組織を発達させる癌の内、
ほとんどがグリア細胞が癌化する神経膠腫(Glima)です。
この神経膠腫は悪性腫瘍であることが多いです。
神経膠腫の「膠(にかわ)」とは
「接着」や「糊」という意味ですが、
グリア細胞は神経細胞(ニューロン)を
支持、保護(絶縁を含む)、栄養供給。修復、再生する機能があり、
それに対して「膠」という和語を与えています。
このグリア細胞の種類は
マイクログリア、星状膠細胞、乏突起膠細胞などがあります。
そのうち、未分化の細胞が癌化する膠芽腫(glioblastoma)は
最も悪性度の高いグレード4に分類されます。
アメリカのニューヨーク
Memorial Sloan Kettering Cancer Centerの報告によれば、
悪性度の高い脳腫瘍の49%は膠芽細胞種(glioblastomas)であるとされています(1)。
神経膠腫(Glioma)は予後が良くありません。
生存値の中間値は12-14カ月で
2年間の生存率は15-26%です(2)。
膠芽腫においては
神経細胞と神経膠腫がシナプスを形成する
「neuron-to-glioma synapse」を持つかどうかにかかわらず
(Both low-neural gliobastoma and high-neural glioblastoma)、
7年生存率は10%を下回ります(3)。
このような予後不良の傾向は
小児が罹患する膠芽腫でも同様です。
5年生存率は8.7%です(4)。
2013年から2019年までの集計結果では
小児がん全体の生存率は85%程度であり、
50年前の1970年代では
その生存率が58%であったため(17)
小児がんに関して確実に医療技術の進歩が
子どもの救命に貢献しています。
しかしながら、
上述した悪性度の高い膠芽腫は
2012年にイランから報告されたのが
子どものケースでの調査で8.7%であり(4)、
アメリカのNational Brain Tumor Societyからの報告では
全年齢の膠芽腫の5年生存率は6.9%であり、
罹患後、平均して8カ月しか生存できないとされています(18)。
アメリカでは10000人が年間で膠芽腫で命を落としているとされています。
日本では全年齢の膠芽腫の
5年生存率が16%であるとされています。
少し5年生存率が高い理由は明らかではありません。
いくつかの因子があるとは推測されますが、
例えば、脳腫瘍に対して神経外科が対応するのが93%と
他の国と比べて高く、
そのうち73%は15年以上の経験を有していると推計されています(19)。
しかしながら、5年以上経っても、
脳腫瘍に関してはグレードに関わらず命を落とすケースが多く、
(参考文献(20) Figure 1)
根治においては大きな課題が残るという現状です。
膠芽腫に罹患した子どもを含めた患者さんの
長期間にわたる生存と健康(Health, Well-being)を実現するためには
劇的かつ系統的なイノベーションが必要な事は自明です。
それの実現の一部に貢献できるか否かはわかりませんが、
罹患する患者さんがいる時点で、
それについて世界で研究されている方々からの報告を引用しながら
独自の視点を含めて考えていく価値はあるテーマです。
脳腫瘍の治療を考えるという事は
他の難治性の脳神経系の疾患、精神疾患の治療にも
派生する可能性がありますし、
私が集中的に提唱している
細胞種薬物送達システムと脳神経系のシステムは
細胞種特異的な振る舞いが強く見られる点で親和性があるため、
優先度を上げて追究していく事に意義を見出しています。
このような背景から脳腫瘍の報告を複数立ち上げています。
小児がんが最も重要なテーマである事には変わりありませんが、
脳腫瘍について考える時点で
その対象は子どもに限るものではありません。
1年あたり、小児が膠芽腫に罹患する人数は
世界で約1000人と推計されています。
おおよそ人口10万人当たり0.85人です。
日本では2023年の出生数は約73万人なので、
この割合から計算するとおおよそ6人です。
国際連合が制定した2030アジェンダであるSDGsの骨子は
「誰一人取り残さない」
「最も遅れているところに第一に手を伸ばす」
これらがあります。
この中に全員が親や社会から支援を多く必要とする
立場の弱い子どもが含まれます。
そのうち世界でたった年間1000人、日本では6人しか罹患しない
脳腫瘍の内、最も治療が難しいとされる膠芽腫について
様々な資源を利用して考えるという事は
少なくとも国際連合の指針に従うことにもなります。
特に予防、早期発見の観点から言うと遺伝子的な理解が重要です。
また、それに加えて効果的な治療を考えていく際には
細胞の振る舞いを含めた生物学的な理解も必要です。

(2:膠芽腫の細胞生物学と突破口)
膠芽腫がどの細胞種を起源としているか？
一般的には星状膠細胞と考えられているようですが(21)、
実際には神経幹細胞(Neural stem cell)から
細胞種特異的な発がん性の遺伝子変異を受ける事で
異種的な特徴を持つ膠芽腫に分化すると考えられます。
神経幹細胞から神経細胞、乏突起膠細胞、星状膠細胞に
それぞれ分化する事が決定している前駆細胞
(Unipotent progenitors (UPP))まで
膠芽腫に分化しうることが遺伝子操作によって示されています。
(参考文献(6) Figure 1)
アメリカの
スタンフォード大学が中心となる膠芽腫の研究から示された
重要な生物学的事実は
神経細胞と膠芽腫を形成する癌細胞がネットワークを
築いているということです(3,7)。
その連結部を「Neuron-to-glioma synapse」と言います。
上述したように膠芽腫に分化する細胞種は
星状膠細胞に限定されない可能性が示唆されますが、
Richard Drexler(敬称略)らによる研究によっても
神経前駆細胞的、星状膠細胞的、乏突起膠前駆細胞的に
トランスクリプトーム解析から分類できるとされています(3)。
それ以外に間葉系用の細胞種も存在すると報告されています(22)。
一つ重要なのは星状膠細胞、間葉系は「前駆細胞ではない」ということです。
これは世界保健機関(WHO)の2014年のレポートの中で示される
膠芽腫が星状膠細胞から生じる事と一致します(21)。
膠芽腫からなる腫瘍組織が空間的にどのように形成されているか？
それが膠芽腫の中でも予後に関わる可能性があります。
より予後が悪い傾向にあるのは
星状膠細胞的な癌細胞が塊(クラスター)を作っている場合です(23)。
従って、星状膠細胞がどのように中枢神経系の疾患に関わっているか？
それについて深堀して考える重要性が浮かび上がります(Chapter3)。
現時点で言えることは、
星状膠細胞のみが成熟した状態で癌化して膠芽腫になりますから、
膠芽腫の細胞タイプの内、星状膠細胞は
他の細胞に触手できる枝の構造を多く有しているとも言えます。
星状膠細胞同士が相互作用している可能性もありますし、
上述したようにシナプス形成して
通常の神経細胞と連結している可能性もあります。
膠芽腫がどのように細胞同士結合、連携しているか？
その様式はギャップ接合に基づくと想定されています(7)。
このギャップ接合はイオンなどの
分子の細胞間の供給、受容に関わります(8,10)。
そのイオンは膜電位に影響を与え、
神経細胞の信号伝達である発火に関わります(9)。
このような信号伝達は神経栄養因子(BDNF)の生成に関わります(7)。
この神経栄養因子が膠芽腫依存的に傍分泌様で生成されることは
脳内の組織を膠芽腫が組織形成の為に浸潤するときに
神経系性のメカニズムを「利用する(Hijacking)」する(3)ことに
関連しているかもしれません。
星状膠細胞はAlexei Verkhratsky(敬称略)らがFig.2で示すように(24)
脳内の野(region)特異的な形状を取ります。
実際に単一細胞の解析で脳内の野特異的な
星状膠細胞のサブタイプが存在し、分類できる事は報告されています(25)。
ここで重要な細胞生物学を再確認します。
上述したように星状膠細胞、間葉系細胞だけが成熟した状態で
膠芽腫に分化し、神経細胞や乏突起膠細胞は前駆状態であると分析されています。
星状膠細胞に脳の野ごとに細かくサブタイプが存在する事は
発現遺伝子群も同様に特異的である事を含みますから
その中で特異的な標的を見つける事ができる可能性があります。
言い換えれば、脳のある任意の部分に膠芽腫ができた時、
その任意の部分の星状膠細胞のサブタイプの形質を色濃く反映している
可能性があり、そこから領域特異的な薬物送達ができる可能性があります。
この点からも星状膠細胞について詳しく調べる意義が生じます。


(3:中枢神経系疾患における星状膠細胞)(Ref.(24))

(4:星状膠細胞を利用した細胞種特異的薬物送達論)

<<English.ver>>
(1:Epidemiology)
Most primary malignant brain tumor is glioma (49%: glioblastoma(1)), and glioma exhibits dismal prognosis, in which medial survival of 12 to 14 months and a 2-year survival of 15 to 26%(2) and a 7-yeaar survival rate is below 10% in both low neural glioblastoma and high neural glioblastoma indicating poor prognosis regardless of neural-glioma interaction(3). This dismal tendency is similar in the pediatric glioblastoma (aa 5-year survival rate of 8.7%(4)). The onset number of pediatric glioblastoma per a year is approximately 1,000 (0.85/100,000) in the world(5) and glioblastoma takes 900 children life despite the current developed medical treatment. Therefore, the further development of medical treatment for the malignant glioma is needed for not only pediatric patients but also adults. For significant improvement of survival rate in whole life, the detail analysis of the patient exhibiting complete remission is prerequisite. Furthermore, understanding biological feature of glioma is also required. 

(2:Cell biology of glioblastoma)
The cellular origin of glioma is neural stem cell which can differentiate several neural cells such as neuron, oligodendrocyte, astrocyte, so glioma may have several cellular traits like neural-like, glia-like glioma(6), but this remains unclear. Why is this cellular feature of glioma important issue? The recent two reports shows that neural-glioma interaction named glioma synapse is associated with biology and malignancy (clinically prognosis in the patients) of this tumor (3,7). In neural-glioma interactions, whether neural like trait with axon and synapse is conferred to glioma remains elusive, but the connection to neural synapse through gap junction mediates molecular interactions like ion (8,10). At least, in the part of gliomas, the connection for neural activity that the sodium(Na+) ion channel of glioma cell membrane is opened for depolarization which initiates signal transduction (9) is driven through paracrine signal similar to general neural connections such as neuroligin-3 and brain-derived neurotrophic factor 1-3 (BDNF) and the electrophysiologically functional receptors like AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (7). Generally, rigid neural connection confers strong synaptic strength and plasticity of neuron associated with long-term potentiation (11), but how does active signal transduction to glioma affect tumor trajectory? The previous report indicates that glioma prolificates through neuron-to-glioma (ionic molecule) interaction, and this synaptic interaction of glioma is based on gap junction (7). Due to generality of synaptic signal transduction through gap junction including astrocyte (12), we cannot assume the cellular type of glioma (more concretely whether some types of glioma include neural-like axon or not) through only this biological fact. However, neuroligin 3 is one of neural-related cell adhesion molecules, and this type neuroligin is also expressed in glia cell (13,14) whose fact confers the possibility of the nature of glial(astrocyte)-like glioma in glioma synapse. For delivery specific to high neural glioblastoma, finding this cell-type specific cell adhesion molecules associated with high neural nature is crucial, because binding to this specific cell adhesion molecules simultaneously realizes the specific drug delivery and inhibition of neural connectivity between neuron and glioma cell. This connective feature is related to poor prognosis (3), so the deactivation of this neural connectivity with efficient local drug delivery leads to novel approach for significant improvement of malignant glioma. It is confirmed that neuroligin 3 is associated with glioma synapse (7) and high-neural glioblastoma exhibits hypomethylation of CpG site (5’ end) whose genomic region triggers promoter and enhances upregulation gene associated with synaptic integration. Therefore, discerning genes with overexpression based on hypomethylation and confirming whether these genes are associated with expression level of neuroligin 3 are the part of the important issues. Furthermore, whether there are novel molecular structure in neuroligin 3 (meaning mutation named neuroligin 3-2) or not like claudin 18-1, 18-2 related to gastric caneer (15) and the other specific surface protein related to glioma synapse from gene information or/and the other methods need to be carefully investigated. Cellular connectivity of malignant cells faces threat, on the other hand, this “adhesive” connectivity give us the great opportunities for the cell-type specific delivery system owing to (probably) nature of neural connectivity in a reginal-specific manner and the mechanism of tropism important to drug delivery and natural delivery like integrin (16).

(3:Astrocyte-related etiology in human diesases and glioblastoma)
In human brain and spinal cord classified as central nervous system, there are mainly two types of parenchymal cells (neuron and neuroglia). Astrocyte mainly described in this chapter is one cell type of neuroglia. Neuron is vulnerable to environmental stress including nutrient deficiency, inflammatory signals, radiational stress, and so on. For example, by only three minutes of oxygen deprivation, neuron suffer more extensive damage, so maintaining sustained respiratory health and cardiac health suppling oxygen also to central nervous system is crucial for preserving human life, which is obvious in our knowledge. However, we experientially understand neuron quite susceptible to these stresses, we have not been less likely to consider about the reason why neuron is weak against stress. When we understand the functional importance of astrocyte in human health, this neuronal biology is worth investigating as one of backgrounds. When considering the stress-related vulnerability of neuron, biological information process of axon is one of the important components. One of the main functions of axon in information processing is to transport action potential from the site near cell body to terminal(26). The physical mechanism of transportation of action potential is based on up or down regulation of membrane potential of ionic leakage channel between myelin(27). Therefore, the energy for opening and closing of many ionic channel is needed for information processing of neuronal network. Axon length is widely different between neuronal cell-types from less than a millimeter to over a meter, but at least, this range is significantly longer scale than normal cellular scale. Except for ionic transportation, neuronal network has dynamics of many kinds of molecules. In principle, these biological traits may lead the higher energy demand per one neuron. In metabolic trait of neuron, neurons predominantly rely on oxidative phosphorylation for cellular energy(ATP) production, on the other hand, this cellular type has a relatively low capacity for anaerobic glycolysis. Therefore, sustained and proper oxygen supply from vascular system is crucial, and these physical and metabolic traits could rationally explain neuronal death only at 3 minutes discontinuation of oxygen supply. In genetic and cell biological perspectives, neuron cannot make cell division, so generally, this cells don’t enter S phase having DNA repair mechanisms against various DNA damages(28). Therefore, genetic dysfunction doesn’t have recovery process in neuron. In biologically negative background related to neuronal vulnerability against damages, neuroglia like microglia, astrocyte and oligodendrocyte has protective functions for neuron. The glial cells make up at most 50% of all brain cells, and the composition ratio of astrocytes to all glial cells is different among species including a human and among the brain regions, but astrocytes are the most common cell types in the brain. The main function of astrocytes is to maintain homeostasis of central nervous system through the broad pathway such as molecular pathway (ions homeostasis, regulation of pH metabolites, water transport and neurotransmitter(glutamate, GABA, Adenosine, monoamines), and so on), network(regulation of synaptic connectivity including regulation of myelination, axon growth, axon guidance synaptogenesis, synaptic plasticity, synaptic maturation and synaptic extinction(30)), circulation system (formation and maintenance of blood brain barrier glymphatic clearance system, glial-vascular interface) and metabolic system(sensing of oxygen, Na ion, carbon dioxide (CO2), glucose, regulation of (energy balance, food intake and sleep), metabolic support, regulation of glycogen(synthesis and storage)(24). Glioblastoma forming cluster of astrocyte-like cell-type exhibits extremely dismal prognosis and astrocytes is major cell-type and have the close relation on homeostasis central nervous system through the broad pathways, so if glioblastoma has abnormal function of astrocyte, in principle, astrocyte-like cell types in glioblastoma results in the various malfunction including molecular one, network, circulation system, metabolic system. There are several kinds of malfunction in astrocyte such as reactive astrocyte (gain of function), genetically specific dysfunction of astrocyte classified to germline mutation and somatic mutation, astrocyte atrophy (loss of function), decreasing number of astrocyte(death)(24). According to transcriptional analysis, genetic trait of reactive astrocyte linked to JAK/STAT pathway activation is found from glioblastoma(31). Including the report(31), as important viewpoints of biological traits related to glioblastoma, we need to investigate the relation between above listed functions of astrocytes for central nervou system and glioblastoma.
(3-1:Ionic function in glioblastoma)
Takeshi Takayasu et al. explains that malignant glioma including glioblastoma may have aberrant regulation of ion channel, leading cell volume change affecting migration and invasion into brain tissue. Cell volume change stems from aberrant water flux to glioblastoma through abnormal ionic interaction which is resulted from the function of ionic channels(32).
(3-2: The regulation of pH in glioblastoma)
Generally, glioblastoma shows more acidic value than the normal tissue. This pH is changed at the specific tissue zone in glioblastoma. “Necrotic zone”, which is surrounded by “pseudo-palisading cell”(see ref.(33) Figure.1), exhibits pH values ≤3.4, “pseudo-palisading cell zone” exhibits pH values<5.5, “cellular tumor zone” with pH values of 6.2 to 7.0, “leading edge zone” with normal pH values of 7.2 to 7.4(34). pH of endolysosomes is controlled in acidic condition by v-ATPases which is enzyme transporting H ion and affecting H ion gradient determining pH value (acidic level) and this molecular behavior is affected by the other ion like K+, Na+, Ca+, Cl-. Importantly, reactive astrocyte experiences metabolic switch to upregulated glycolysis in accordance with energy demand from damaged surrounding tissue(35), resulting enhancement of proton export(36) and acidic condition of surrounding. Therefore, the biological fact of acidic environment surrounding glioblastoma and favor glycolysis of reactive astrocyte also indicates that glioblastoma may be reflected by the metabolic trait of reactive astrocytes.

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