Page 7 - Science Focus (Issue 19)

因為 Shh 是一種分級的（graded）訊號，意味著細胞暴露於
不同濃度的 Shh下會有不同的反應，最終會分化為不同的組
織。在胚胎發育的早期階段，只有一個稱為視場（eye field）
的單一結構，該結構會在後期借助 Shh 的特定濃度發展出
兩隻獨立的眼睛。同樣，大腦左右半球的形成亦涉及相同的
原理。Shh 不僅負責大腦和眼睛的發育，而且還負責牙齒，
四肢和肺部的發育。

環巴 胺 是 Shh 訊 息 傳 遞 路 徑 的 抑 制 劑，它 能 夠 與
Smoothened 緊密結合並抑制它。因此，即使 Shh 結合並
抑制 Patched，Smoothened 也無法發揮其誘導基因表達
的正常功能 [1]。如果母羊於妊娠的第 14 天左右攝入了帶毒
性的加州藜蘆 [2]，令胚胎接觸到環巴胺，胚胎的大腦和視
CYCLOPAMINE AND 場便不會分化成左右兩邊，從而導致畸形的情況 [3]。如前
所述，由於大腦兩個半球的適當劃分亦需要 Shh 蛋白 [3]，
THE ONE-EYED SHEEP Smoothened or inactivate Patched [4]. To deal with it, 因此單眼綿羊不僅臉部變形，大腦也會變形，這就是環巴胺
中毒有可能致命的原因。
By Kit Kan 簡迎曦 agents which can inhibit the activity of Smoothened
ᐑˋᶶ ఊ଻ၧϺ (or Smoothened inhibitors) can potentially be used as ੽ߧնݭᖹՑᐖसطᐕ
ၾ
drugs to slower cancer progression. Going from a fatal
poison to a cancer therapy sounds too good to be Shh 訊息傳遞路徑在胚胎發育以後的人生階段也很關
Most people consider one-eyed creatures like there is a single structure called the eye field, which true – although the cyclopamine derivative, saridegib, 鍵。Smoothened 是 原 癌 基 因（proto-oncogene），而
Mike Wazowski from the movie Monster Inc. and the gives rise to two distinct eyes in the later stages failed the clinical trial due to its unsatisfactory efficacy Patched 是腫瘤抑制基因（tumor-suppressor gene）。
cyclopes in Greek mythology to be fictional, because with the help of the concentration gradient of Shh. [5], it has inspired the birth of the two FDA-approved 顧名思義，腫瘤抑制基因可以抑制腫瘤的生長；而原癌基因
they have never seen animals like that in real life. Likewise, the left and right hemispheres of the brain drugs, vismodegib and sonidegib, which are also 在突變後，則可能有利於癌症的發展。基底細胞癌是最常見
Therefore, when sheep in the western United States are formed involving the same mechanism. Shh is not Smoothened inhibitors [2]! 的皮膚癌類型，而髓母細胞瘤是兒童中最常見的原發性腦癌
gave birth to one-eyed lambs in the 1950s, the sheep just responsible for the brain and eye development, While you try to get the disturbing picture of the 類型，這兩種癌症是一些因 Smoothened 和 Patched 突變
ranchers freaked out. After decades of research, but also the tooth, limb, and lung development. cycloptic sheep out of your mind, try to appreciate 而可能形成的癌症種類，當中通常是突變使 Smoothened 過
scientists finally identified the culprit that caused the Cyclopamine is an inhibitor of the sonic hedgehog how innovative and creative scientists are, that they 度激活或使 Patched 失活 [4]。為解決這個問題，使用抑制
disease and the underlying mechanism. literally turn poison into medicine!
signaling pathway. It has a very high affinity to Smoothened 活性的藥物（即 Smoothened 抑制劑）有可
The singular eye deformity is caused by a Smoothened, binding it tightly and inhibiting it. 能減緩癌症進展。從致命毒藥變成癌症療法聽起來太不可思
compound called cyclopamine, which can be found Thus, even when Shh binds and inhibits Patched, 大多數人認為像電影《怪獸公司》中的「大眼仔」米高•華素 議 — 儘管環巴胺衍生物 saridegib 因療效欠佳而未能通過
in the plant Veratrum californicum. Ingestion of the Smoothened cannot execute its normal function of 基（Mike Wazowski）和希臘神話中的獨眼巨人這樣的單
plant at a certain stage during pregnancy hinders inducing gene expression [1]. If an ewe ingests the 眼怪物都是虛構的，因為我們在現實生活中從未見過像這樣 臨床試驗 [5]，但它啟發了兩種 FDA 批准的藥物 vismodegib
the development of the embryo – preventing the toxic plant and expose the embryo to cyclopamine 的生物。因此，當在 1950 年代美國西部有綿羊生下獨眼羔 和sonidegib 的誕生（它們也是 Smoothened 抑制劑） [2]！
primitive, single “eye structure” from developing into at around day 14 of gestation [2], the brain and the 羊時，牧場的主人們都給嚇壞了。經過數十年的研究，科學家
two separate eyes, hence giving rise to only one eye. eye field of the embryo will not separate, resulting in 終於確定了導致該疾病的罪魁禍首及背後的生物學原理。 當你試圖從腦海中刪除那令人不安的單眼綿羊畫面時，也
But how does a single molecule, cyclopamine, cause the deformity [3]. As mentioned previously, since the 可嘗試欣賞科學家的創新精神和創意，因為他們確實將毒藥
such great developmental changes? It all begins with proper division of the two hemispheres of the brain 這種畸形單眼的現象是由一種名為環巴胺（cyclopamine） 變成了抗癌藥物！
a protein called sonic hedgehog. also requires Shh protein [3], the cycloptic sheep not 的化 合 物 引 起 的，這 種 化 合 物 可 以 在 植 物 加 州 藜 蘆
only has a deformed face, but also a deformed brain, （ Veratrum californicum）中找到。在懷孕期間的某個階 References 參考資料：
Sonic Hedgehog and Cycloptic Sheep which is why cyclopamine poisoning is potentially fatal. 段攝入加州藜蘆會阻礙胚胎的發育，它阻止原始單一的眼睛 [1] Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of
The sonic hedgehog protein (Shh) is encoded by 結構分化成兩隻獨立的眼睛，從而只產生一隻眼睛。可是，環 Hedgehog signaling by direct binding of cyclopamine to
Smoothened. Genes Dev. 2002;16(21):2743-2748. doi:10.1101/
the SHH gene and plays an essential role in embryonic From Fatal Poison to Cancer Therapy 巴胺究竟是如何引起如此巨大的發育變化呢？這一切都始於 gad.1025302
development. Shh binds to a receptor on the cell The sonic hedgehog signaling pathway is 一種叫做音速刺蝟（Sonic hedgehog/Shh）的蛋白質。 [2] Chen JK. I only have eye for ewe: the discovery of cyclopamine
and development of Hedgehog pathway-targeting drugs. Nat
membrane called Patched to inhibit it. Since Patched also critical at later stages in life after embryonic Prod Rep. 2016;33(5):595-601. doi:10.1039/c5np00153f
normally inhibits another protein named Smoothened, development. Smoothened is a proto-oncogene while [3] National Library of Medicine. SHH gene. Genetics Home
when Patched is inhibited by Shh, Smoothened is Patched is a tumor-suppressor gene. Tumor-suppressor ࠪ஺Ր㾲ձఊ଻ၧϺ Reference. Updated September, 2010. https://ghr.nlm.nih.gov/
gene/SHH#sourcesforpage.
activated (double negative), which could lead to genes, as the name implies, suppress the growth of 音速刺蝟蛋白（Shh）由 SHH 基因編碼而成，在胚胎發 [4] Taipale J, Chen JK, Cooper MK, et al. Effects of oncogenic
the expression of certain genes. The sonic hedgehog tumor; and proto-oncogenes, when mutated, could 育中扮演相當重要的角色。Shh 會與在細胞膜上的稱為 mutations in Smoothened and Patched can be reversed
signaling is more complicated than that since it is contribute to the development of cancer. Basal cell Patched 的受體結合並抑制它。由於 Patched 通常會抑 by cyclopamine. Nature. 2000;406(6799):1005-1009.
doi:10.1038/35023008
a graded signaling pathway, meaning that cells carcinoma, the most common type of skin cancer, 制另一 種 名 為 Smoothened 的 蛋 白，因 此 當 Shh 抑 制 [5] Levin J. Infinity Stops Phase 2 Trials of Saridegib in
exposed to different concentrations of the Shh respond and medulloblastoma, the most common type of Patched 時，Smoothened 會被激活（雙重否定），這能引 Chondrosarcoma and Myelofibrosis. Fierce Biotech. Updated
in different ways, and will eventually differentiate into primary brain cancer in children, are some cancer June 18, 2012. https://www.fiercebiotech.com/biotech/infinity-
stops-phase-2-trials-of-saridegib-chondrosarcoma-and-
different tissues. In the early stages of development, types that result from mutations that over-activate 發某些基因的表達。但 Shh 的訊息傳導並不是非黑即白的， myelofibrosis.