To drive their growth, many tumors hijack nervous system signals, including those needed for brain plasticity. Stanford Medicine discoveries are opening a promising new branch of oncology research.
為了驅動生長，許多腫瘤劫持神經系統信號，包括那些大腦可塑性所需的信號。美國史丹佛大學醫學院的發現，正在開啓一種有指望之腫瘤學研究的新分支。
Michelle Monje's team has found that brain tumors can exploit the biological machinery of brain plasticity to drive their own growth.
Michelle Monje的團隊已經發現，腦腫瘤能利用大腦可塑性的生物機制，來驅動自身生長。
Cancer cells hijack normal biological processes, allowing them to multiply. For example, tumors spur construction of new blood vessels, building themselves “highways” to supply nutrients.
癌細胞劫持正常的生物進程，使其得以增殖。譬如，腫瘤刺激新血管的構築，為自身建造供應養分的“高速公路”。
Researchers have known about cancer’s blood vessel infiltration for decades, but it was only in the past few years that Stanford Medicine scientists and their colleagues discovered that tumors don’t just tap the body’s highway system; they can also infiltrate and exploit its “telecommunications.”
研究人員們知曉癌腫的血管滲透性，已經達數十年。不過，僅在過去幾年，美國史丹佛大學醫學院的科學家及其同僚們才發現，腫瘤不只私接人體的高速公路系統，也會滲透及利用其“電信”。
To put it in physiologic terms, tumors don’t just grow blood vessels; they also wire themselves into the nervous system. Certain brain cancers form working electrical connections with nearby nerves, then use the nerves’ electrical signals for their own purposes, the research has shown.
用生理學術語來說，腫瘤不僅生長血管;它們也將自己連接到神經系統中。該項研究已經證實，某些腦癌腫與附近的神經，形成有作用的電氣連接。然後，利用神經的電氣信號，供其自身目的使用。
The latest findings, published Nov. 1 in Nature, demonstrate that these tumors can even hijack the biological machinery of brain plasticity — which enables learning — to drive their own growth.
此些(2023年)11月1日，發表於《自然》期刊的最新研究結果證實，這些腫瘤甚至能劫持大腦可塑性的生物機制(這使能學會)，以驅動自身生長。
The discoveries have opened a novel field of medicine called cancer neuroscience. It offers new opportunities to target some of the deadliest forms of cancer, including brain tumors that are almost always lethal.
此些發現已經開啟一個，被稱為癌腫神經科學的新醫學領域。這提供了，鎖定一些最致命癌腫類型的新機會，包括幾乎總是致命的腦腫瘤。
Scientists are especially intrigued by the cancer treatment potential of FDA-approved drugs developed for other neurological disorders, such as epilepsy. It turns out that several such medications interrupt neural signals now understood to fuel certain cancers.
科學家們特別被，美國食品暨藥物管理局(FDA：Food & Drug Administration)批准之其他神經系統疾病(諸如癲癇)藥物的癌腫治療潛力所迷住。這顯然是，幾種此類藥物阻斷目前，被瞭解激起某些癌腫的神經信號。
“Since 2015, when we first published that neuronal activity actually drives the growth of cancer in multiple brain tumor types, there has been a very exciting explosion of studies on these interactions,” said Michelle Monje, MD, PhD, a professor of neurology and neurological sciences and senior author of the new Nature study, whose team’s discoveries form the foundation of cancer neuroscience. “This is clearly a major set of interactions crucial to tumor biology that we had missed.”
該發表於《自然》期刊的新研究資深撰文人，神經病學及神經科學教授，其團隊的發現形成了，癌腫神經科學基礎的Michelle Monje博士宣稱：「打從2015年，我們首次發表神經元活動，實際上於多種腦腫瘤類型中，驅動癌腫生長以來。諸多有關此些交互作用的研究，一直有極令人振奮的迅猛發展。顯然，這是對我們已經錯過之有關腫瘤生物學，至關重要的一組重要交互作用。」
Why did cancer’s ability to twine into the nervous system stay hidden from researchers for so long? A focus on how malignant and healthy cells differ may provide an explanation.
為何癌腫以纏繞方式插入神經系統的能力，對研究人員隱藏了這麼久？ 著重於惡性細胞及健康細胞的差異，可能提供一種解釋。
“People tend to think of cancer as more like an infectious disease, something that’s occurring but has nothing really to do with our body,” said Kathryn Taylor, PhD, lead author of the Nature study and a postdoctoral scholar in neurology and neurological sciences. “Whereas really, particularly in pediatric tumors, it’s a developmental disease.”
該發表於《自然》期刊的研究首要撰文人，神經學及神經科學領域的博士後學者，Kathryn Taylor博士宣稱：「人們傾向認為，癌腫更像是一種正在發生，不過沒有真正與我們身體有關的傳染病。」
Small missteps in development underlie some of the worst childhood tumors, Monje’s team has shown.
Monje的團隊已經證實，於發育中的諸多小錯誤，引發一些最惡劣的兒童腫瘤。
This is true of one especially horrible type of brain cancer, diffuse intrinsic pontine glioma. Known as a high-grade glioma, DIPG arises in the brainstem that controls essential body functions such as breathing and heartbeat. It entwines with healthy cells, meaning it can’t be removed surgically. The five-year survival rate is 1%.
一種特別可怕類型的腦癌腫，瀰漫、內源性的腦橋膠質瘤(DIPG)，就是如此。被通稱為一種上等神經膠質瘤，DIPG發生於控制諸如呼吸及心跳等，基本身體功能的腦幹。它與健康細胞糾纏在一起，意味著它無法手術性移除。五年存活率是1%。
In 2011, Monje showed that DIPG arises from a type of healthy brain cells called oligodendrocyte precursor cells. Normally, OPCs develop into brain cells that produce insulating myelin, a substance that coats nerves and speeds up their electrical signals.
於2011年，Monje證實DIPG源自一種，被稱為少突膠質細胞前身細胞(OPCs)的健康腦細胞。通常，OPCs發育成，產生絕緣髓磷脂(又稱為髓鞘質)的腦細胞。絕緣髓鞘質是一種，覆蓋神經表面且加速其電氣信號的物質。
This “neuron maintenance” job requires the healthy cells to stay in close communication with adjacent neurons, receiving and responding to neurons’ electrical and chemical signals.
此“神經元維護”工作需要健康的細胞，來與鄰近的神經元保持密切溝通，接收並對神經元的電氣及化學信號作出反應。
DIPG cells respond to the same signals, but use them to fuel malignant growth, Monje’s team has demonstrated. “The cancer is diffusely and widely invading the nervous system because that’s advantageous for it,” Monje said. “It integrates into neural circuits.”
Monje的團隊已經證實，DIPG細胞對相同的信號作出反應。不過，利用它們來激發惡性生長。Monje宣稱：「這種癌腫擴散且廣泛侵入神經系統，因為對它那是有利的。它整合到神經迴路中。」
In 2019, Monje’s team published a groundbreaking study showing that DIPG and similar cancers form working synapses with neurons. Synapses are the nervous-system widgets that allow electrical signals to cross the gaps between one cell and the next.
於2019年，Monje的團隊發表了一項，證實DIPG及相似的癌腫與神經元形成，起作用之突觸的開創性研究。突觸是神經系統，使電氣信號得以跨越一個細胞與下一個細胞之間間隙的小部件。
Via these connections and additional means of electrical signaling, about half of all glioma cells in a given tumor have some type of electrical response to signals from healthy neurons, the research showed.
該項研究證實了，經由此些連接及額外電氣發信號的方法，在一種已知的腫瘤中，所有神經膠質瘤細胞，大約一半對來自健康神經元的信號，有某種類型的電氣反應。
Adjacent brain cells also signal to each other with proteins that cross the space between cells to trigger complex intracellular responses. Such responses include molecular signals that underlie the neural plasticity needed for learning and memory. (The brain physically changes as we learn; these signals are part of that change.)
鄰接的腦細胞也使用，穿過細胞間之空間的蛋白質，相互發出信號，以觸發複雜的細胞內反應。此類反應包括，引發學習及記憶所需之神經可塑性的分子信號。(當我們學習時，大腦發生物理性變化；此些信號是那變化的一部分。)
The new study investigates tumor responses to brain-derived neurotrophic factor, or BDNF, a protein that helps enable brain plasticity. With BDNF, the brain can strengthen synaptic connections between cells, enforcing a neural circuit that’s built as we learn.
該項新研究調查研究了，腫瘤對腦源性神經養分因子(BDNF)的反應。BDNF 是一種，有助於為大腦可塑性提供條件的蛋白質。由此BDNF，大腦能增強細胞之間的突觸連接，加強我們學習時，建立的神經迴路。
The tumors use BDNF the same way healthy brain cells do, the researchers showed: BDNF travels from neurons to tumor cells to trigger a chain reaction inside the tumor that ultimately helps the tumor form more and stronger synapses.
此些腫瘤使用BDNF的方式與健康腦細胞使用的相同方式，此些研究人員證實了：BDNF從神經元行進到腫瘤細胞，來觸發腫瘤內部的一種，最終有助於腫瘤，形成更多且更強突觸的連鎖反應。
During the studies of BDNF, which Taylor led, one key experiment showed that when the cell machinery triggered by BDNF was activated more strongly, the tumor cells responded with stronger electrical currents, which then fueled their growth. In other words, cancer uses the brain’s learning machinery to grow.
在由Taylor領導的諸多BDNF研究中，一項關鍵實驗證實了，當由BDNF觸發的細胞機制，被更強烈激活時，腫瘤細胞隨著較強的電流作出了反應，之後激發了它們的生長。換言之，癌腫利用大腦的學習機制，來生長。
“We looked at the electrophysiological recordings and seeing this increase was … I will never forget that. It was pretty incredible,” Taylor said. “What was so striking about that finding was that not only can the cells connect, they also dynamically respond to input from healthy brain cells. The tumor cell is not only plugging into the network, it’s increasing its connection to that plug.”
Taylor宣稱：「我們檢視了電生理學的記錄，發現此種增加是…我永遠不會忘記那種。有關那發現如此引人矚目的是，此些細胞不僅能連接，它們也動態地對來自健康腦細胞的信息，作出反應。此腫瘤細胞不僅插入神經網絡中，而且增加其與那插頭的連接。」
Prior research by Monje’s team showed that another mechanism involved in neural plasticity, driven by a signaling molecule called neuroligin 3, works independently of BDNF to also increase neuron-to-glioma synapses.
由Monje團隊先前進行的研究證實了，另一種涉及神經可塑性的機制，由一種被稱為Neuroligin(I型膜蛋白，是一種後突觸膜上，介導形成及維持神經元間之突觸的細胞黏附蛋白) 3的發信號分子所驅動，獨立於BDNF起作用，也增加神經元到神經膠質瘤的突觸。
It’s unsettling that tumors use brain activity to grow, Taylor admits. “It’s the same electrical activity that helps us think, move, feel, touch and see,” she said. “Cancer is plugging into that and using that to grow, invade and even occur in the first place.”
Taylor承認，腫瘤利用大腦活動來生長，這是令人不安的。她宣稱：「這是幫助我們思考、移動、感覺、觸摸及認知的相同電氣活動。癌腫插入其中並利用那，來生長、侵入及甚至存在於最早的處所。」
But understanding these unsettling interactions between tumors and the healthy nervous system presents new options for cancer treatment.
不過，瞭解腫瘤與健康神經系統之間，此些令人不安的交互作用，為癌腫治療提供了，諸多新的選擇。
In the Nature study, Taylor, Monje and their team showed that medications aimed at the BDNF receptor, which were developed for other forms of cancer that have mutations affecting the receptor, work surprisingly well at slowing the growth of DIPG and other gliomas that do not typically have genetic alterations in that receptor.
在該發表於《自然》期刊的研究中，Taylor、Monje及其團隊證實了，諸多針對BDNF受體的藥物(為具有影響該受體之突變的其他形式癌腫開發的)，在減緩瀰漫、內源性腦橋膠質瘤(DIPG)及，在那受體中，通常沒有遺傳改變之其他神經膠質瘤的生長上，令人訝異地起了適切作用。
Other drugs, including certain painkillers, anti-seizure medications and blood pressure medications also have potential as cancer fighters. A detailed understanding of how the tumors tap nerve signals to grow provides a huge leg up in cancer treatment research, as scientists can match what’s in the “medicine cabinet” of FDA-approved neuroactive drugs with their new knowledge of how cancers operate.
其他藥物，包括某些止痛藥、抗癲癇藥物及血壓藥物，也具有作為抗癌物的潛力。有關腫瘤如何利用神經信號來生長的詳細瞭解，在癌腫治療研究上，提供了莫大的幫助。因為，科學家們能將美國食品暨藥物管理局(FDA：Food & Drug Administration)批准的神經活性藥物之“藥櫃”中的藥物，與他們有關癌腫如何運作的新知識進行匹配。
Stopping the worst gliomas, including DIPG, will require a mixture of tactics, from cancer neuroscience and from other oncology specialties, Monje said. Perhaps doctors can start treatment with neurological medications that slow the tumors’ growth, then give immunotherapies — such as specially engineered immune cells called CAR-T cells, which her team is also studying as a treatment for DIPG — as a second line of attack.
Monje表示，阻止包括DIPG在內，最嚴重的神經膠質瘤，需要癌腫神經科學及其他腫瘤學專業的綜合策略。或許，醫生們能開始使用，減緩腫瘤生長的神經藥物進行治療，之後進行免疫療法。諸如，其團隊也正在進行研究，被稱為嵌合抗原受體T (CAR-T：Chimeric Antigen Receptor-T)細胞，經特殊工程改造的免疫細胞，供作為第二道攻擊DIPG之線的一種治療方法。
Such a strategy might give immunotherapy treatments enough of a head start to enable them to outpace the rapidly growing tumors.
這樣的策略可能賦予免疫療法足夠的領先優勢，使其能超越快速生長的腫瘤。
Monje’s team also plans to learn more about how electrical currents prompt tumor growth. “As we uncover granular details of those voltage-sensitive mechanisms, that will open up a whole additional realm of potential therapeutic targets,” she said.
Monje的團隊也計劃，瞭解更多有關電流如何激發腫瘤生長。她宣稱：「當我們揭露那些電壓敏感之機制的細密詳情時，那將開啟一個全新潛在治療標地的領域。」
Cancer neuroscience is also offering clues about how to tackle tumors outside the brain. Nerves normally send signals to stem cells that help regulate healthy organ development and repair, and research is increasingly documenting that these signals can fuel cancer.
癌腫神經科學也正在提供，有關如何對付大腦外腫瘤的線索。通常，神經發信號到，協助調節健康器官發育及修復的幹細胞。不過，研究正日益證實，此些信號會激發癌腫。
“There are critically important roles for the nervous system in pancreas, prostate, breast, colon, gastric, skin, and head and neck cancers — a very long list,” Monje said, adding that there’s also evidence that tumors that began outside the nervous system can piggyback on normal nerve signals once they invade the brain.
Monje宣稱：「神經系統在胰腺癌、前列腺癌、乳腺癌、結腸癌、胃癌、皮膚癌及頭頸癌等，極長清單中，有極為重要的角色。」補充說，也有始於神經系統外的腫瘤，一旦侵入大腦，會依附正常神經信號的證據。
For Monje, who was inspired to study DIPG more than 20 years ago, at a time when the biology of the disease was completely unknown, the new options are heartening. The old way of trying to treat the deadly tumor — a sort of throw-the-spaghetti-at-the-wall approach, using drugs not fitted to how the tumor grows — is obsolete, she said.
對20多年前受到啟發，研究DIPG的Monje而言，在該種疾病的生物學完全未知時，此些新的選擇是令人振奮的。她表示，嘗試治療致命腫瘤的舊方法(一種把義大利麵丟到牆上，也就是進行大量的嘗試或猜測，希望其中一個能夠成功的方法)是過時的。
“This is a connected tumor; it’s connecting to the entire nervous system. We have to disconnect it,” she said. “We understand enough about this disease now to have lots of really rational ways to try to fight it.”
她宣稱：「這是一種連接在一起的腫瘤；它連接到整個神經系統。我們必須斷開它。目前，有關此種疾病，我們的瞭解足夠有諸多真正合理的方法，來嘗試對抗它。」
Researchers contributed to the new study from the Weizmann Institute of Science in Rehovot, Israel; Massachusetts General Hospital; Harvard Medical School; and the Broad Institute of the Massachusetts Institute of Technology.
來自以色列雷霍沃特魏茨曼科學研究所；美國馬薩諸塞州總醫院；哈佛醫學院；及麻省理工學院布羅德研究所的研究人員，為該項新研究做出了貢獻。
網址：https://med.stanford.edu/news/all-news/2023/11/cancer-neuroscience.html
翻譯：許東榮
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