生命的叛逆:癌症(續)
生命的終結：老化
周成功
長庚大學生命科學糸
99年3月22日
本著作除另有註明外，採取創用CC「姓名標示－非商業性－相同方式分享」台灣2.5版授權釋出
癌症的興起
一連串的基因突變和在身体內部
長期優生劣敗的天擇
生命的叛逆:癌症
對付叛逆的策略：防範於未然
征剿、安撫、矯正
癌症是可以預防的嗎?
•減少與環境中的致癌物接觸.
–物理及化學致癌物(突變劑)
–病毒
•及早發現
人類癌症会傳染嗎?
•大部份人類癌症中沒有找到會致癌的病毒.
•但有些人類癌症可能與病毒的感染有關
– HBV，HCV與肝癌
– EBV 與鼻咽癌
– AIDS 病毒 與 Caposi sarcoma
• Papilloma virus 與子宮頸癌
• HTLV 與 T cell leukemia
如何及早發現或預防人類癌症?
• 大部份人類癌症中沒有找到會致癌的病毒.
– 尋找檢驗標記？
– 全身檢查 (生化檢查；內視鏡；超音波等等)
– 全身掃描 (CT；MRI；PET etc)
• 但有些人類癌症可能與病毒的感染有關
– HBV，HCV與肝癌(疫苗)
– EBV 與鼻咽癌(尋找檢驗標記？)
– AIDS 病毒 與 Caposi sarcoma (疫苗)
• Papilloma virus 與子宮頸癌 (抹片與疫苗)
• HTLV 與 T cell leukemia (疫苗)
生命的叛逆:癌症
對付叛逆的策略：防範於未然
征剿、安撫、矯正
癌症腫瘤的治療
•外科手術.
•放射線照射.
•化學藥物
–殺死快速增生的細胞.
–誘導癌細胞的分化.
–抑制新生血管的形成.
• 免疫治療
• 基因治療
致癌基因成癮假說
B,C,D,…
A,B,C,D,…..
B,C,D,…
尋找癌細胞的罩門？
用藥物抑制生長因子受體的活性是否就
能抑制癌細胞的生長？
藥
物
周成功
Thomas J. Lynch et. al. (2004) N Engl J Med 350:2129-2139
用藥物抑制生長因子受體的活性是否就
能抑制癌細胞的生長？
藥
物
周成功
Feb. 24 2005
Wild type
T790M mutation
生命的叛逆:癌症
對付叛逆的策略：防範於未然
征剿、安撫、矯正
癌細胞源起於失去了正常細胞分化的能力
死亡(Apoptosis)
老化
(Senescence)
休眠
細胞
分化
(Differentiation)
(Quiescent)
生長與分裂
(Growth & Division)
生命的叛逆:癌症
對付叛逆的策略：防範於未然
征剿、安撫、矯正
人生的必經之路：生、老、病、死！
“老”是一種病嗎？
老是整體生理功能逐漸减退，並伴隨而來生殖
能力的喪失與死亡率的增加。
但它不是病，因為它沒有特定致病的原因！
“老” 是由身體中一個有目的的“遺傳程式”
在指揮進行嗎？
• Yes！
– 鮭魚產卵後即老死！
– 限制族群的人口，保留有限的資源給年青的
後代、、、、
• But、、、
在非洲野外看不到老的斑馬！
只有在動物園裡オ能看到老的斑馬。
老化是文明的產物！
Survival
Protected
Wild
Age
生物為什麼會演化出產生老化現象的機制？
(Why we age?)
老化是由那些機制的運作而顯現？
(How we age?)
生物為什麼會演化出產生老化的機制？
Why we age?
為什麼小鼠的壽命年限只有２-３年，
而人可以超過一百歲？
如何從演化的觀點來瞭解「老化」？
Accumulation of germ-line mutations with late-acting deleterious effects
在平均年齡30歲的族群中累積了許多60歲才會發作的基因突變
…the forces of natural selection
weakens with increasing age …. If a
genetical disaster… happens late
enough in individual life, its
consequences may be completely
unimportant. Even in such a crude
and unqualified form, this
dispensation may have a real bearing
on the origin of innate deterioration
with increasing age.
Medawar, 1952
杭丁頓舞蹈症:遺傳到突變的基因所產生神經的病變。
４０歲以後才會發病、死亡！
如果１０歲就發病、死亡，情況會如何？
以電腦病毒為例 George Sumner Huntington
Frank Gaillard
同一個基因，在年青個體身上的
作用和在老年個体體身上的作用
恰恰相反！
Survival
只有在動物園裡オ能看到老的斑馬。
老化是文明的產物！
Good
Bad
Age
A
Young animal
mutant gene action
B
Elderly animal
mutant gene action
Increased fitness
Reduced fitness
Young animal
Elderly animal
mutant gene action
Latent damage
unmasked
到老年時才發作
Increased fitness
Reduced fitness
Latent damage 潛在的傷害
李承維
Survival
只有在動物園裡オ能看到老的斑馬。
老化是文明的產物！
Effective maintenance and repair
Age
如果你是小鼠，你的投資抉擇是什麼？
如果老化的投資抉擇理論是對的，
那麼我們可以在實驗室裡作些什麼
樣的預測？
老化的模式動物
Wild-type (left specimen)and long-lived dwarf (right
specimen) yeast, flies and mice with mutations that
decrease glucose or insulin/IGF-I signaling.
長期在死亡率高或低的環境中繁殖，
會演化出什麼樣的族群？
投資在修補保養：體型較大
投資在及早生育：生殖成熟較早
老化現象產生的分子機制是什麼?
How we age?
•染色體端粒子的限制？
•都是氧化壓力惹的禍？
細胞會老嗎？
給予充分的營養，細胞在體外能無
限期的生長分裂嗎？
不能！體外培養的細胞也會老。
Cellular senescence
Human diploid fibroblast has limited replicative
life span, termed replicative senescence or
cellular senescence. Human diploid fibroblasts
can divide ~60-80 times.
周成功
Young vs. senescent fibroblasts
• Senescent cells are generally
larger, less motile, decreased
saturation density.
• Senescent cell is different from
the quiescent cell in G0.
Senescence is irreversible
process whereas G0 cells can
reenter cell cycle upon induction.
• Senescent cells resist apoptosis,
this may explain why senescent
cells are not cleared and thus
accumulate with age.
Aging is an autonomous property of normal cells
Hayflick and
Moorhead
40th population doubling
10th population doubling
Male control Male, female Mixture Female control
Male control
230
……
李承維
……
……
230
230
Female cell remain Female control
Telomere: in Greek, Telos means end; meros, part
AGGGTTAGGGTTAGGG-3’
TCCC-5’
李承維
染色體端粒子：由端粒酵素製造出的一個
特殊結構來保護染色體的端點。而端粒酵
素在正常細胞中很早就消失了！
端粒子,細胞的老化與癌症
Cell divisions
Cell divisions
Cell cycle arrest (M1)
Catastrophe (M2)
李承維
細胞逐漸失去分裂
的能力(老化)，終
致走向死亡！
Human telomere shortening during replication
Is cellular senescence the same as biological aging?
• Cells cultured from old donors tend to senesce after fewer
population-doublings than cells from young cell.
• Interspecies comparison suggests that cell replicative life span and
biological life span is genetically related.
Correlation between telomere length and human aging
Cells from long-lived species are capable of
replicating more times
Sci Am. 1968 Mar;218(3):32-7
What is the cause of Dolly’s death?
• Dolly was cloned in 1997.
• Analysis of telomere lengths
in Dolly indicates that Dolly’s
telomere length is similar to
normal six-year-old sheep
(1999).
• Dolly die on 14 Feb, 2003
Toni Barros
Dolly, 1997-2003
Werner Syndrome
• Autosomal recessive; Life Span in Years: 60
• Loss of WRN, a RecQ family helicase.
• Reduced replicative life span of cultured cells. Increased mutation rate,
particularly DNA deletions. Rapid telomere shortening during cellular
replicative life span.
細胞永生的祕密：端粒酵素的重新活化
Cell divisions
Cell divisions
端粒酵素
的活化
Cell cycle arrest (M1)
是禍害？還是福氣？
Catastrophe (M2)
李承維
Telomerase is expressed in immortal and cancer cells
老化現象產生的分子機制是什麼?
How we age?
•染色體端粒子的限制？
•都是氧化壓力惹的禍？
版權標示頁
作品
授權條件
作者/來源
Susumu Kobayashi et al, EGFR Mutation and
Resistance of Non–Small-Cell Lung Cancer to
Gefitinib, N Engl J Med, 352:786-792; 2005
Thomas J. Lynch et. al. (2004) Activating Mutations in the
Epidermal Growth Factor Receptor Underlying
Responsiveness of Non–Small-Cell Lung Cancer to
Gefitinib. N Engl J Med 350:2129-2139
Susumu Kobayashi et al, EGFR Mutation and
Resistance of Non–Small-Cell Lung Cancer to
Gefitinib, N Engl J Med, 352:786-792; 2005
Zhi-Xiang Shen et al, All-trans retinoic acid/As2O3
combination yields a high quality remission and
survival in newly diagnosed acute promyelocytic
leukemia, Proc Natl Acad Sci U S A , 101(15):5328-35;
2004
Douglas Hanahan and Robert A. Weinber, The
Hallmarks of Cancer, Cell 100, 57-70; 2000
作品
授權條件
作者/來源
Kelloggs&Comstock
http://commons.wikimedia.org/wiki/File:11-stageswomanhood-1840s.jpg 2010/09/29 visited
Rory Curtis et al, Ageing and metabolism: drug discovery
opportunities , Nature Reviews Drug Discovery 4, 569-580;
July 2005
Xtreambar
http://commons.wikimedia.org/wiki/File:Peter_Brian_Meda
war.jpg 2010/09/29 visted
Frank Gaillard
http://commons.wikimedia.org/wiki/File:Huntington.jpg
2010/09/30 visited
http://commons.wikimedia.org/wiki/File:George_Sumner_
Huntington.jpg 2010/09/30 visited
A
B
Young animal
Elderly animal
mutant gene action
mutant gene action
Increased fitness
Reduced fitness
Young animal
Elderly animal
mutant gene action
Latent damage
unmasked
到老年時才發作
Increased fitness
Reduced fitness
Latent damage 潛在的傷害
臺灣大學動物所 李承維
作品
授權條件
作者/來源
Valter D. LONGO, Caleb E. Finch, Evolutionary Medicine:
From Dwarf Model Systems to Healthy Centenarians?,
Science Vol.299, pp 1342 – 1346; 2003
Hayflick and P. S. Moorhead , The serial cultivation
of human diploid cell strains, Experimental Cell
Vol.25 585-621;Dec 1961
L. Hayflick and P. S. Moorhead , The serial cultivation
of human diploid cell strains, Experimental Cell
Vol.25 585-621;Dec 1961
長庚大學
周成功
G. A. McFarland and R. Holliday (1994) Experimental Cell
Research 212, p167-175
40th population doubling
10th population doubling
Male control Male, female Mixture Female control
臺灣大學動物所 李承維
230
……
Male control
……
……
230
230
Female cell remain Female control
作品
授權條件
作者/來源
臺灣大學動物所 李承維
AGGGTTAGGGTTAGGG-3’
TCCC-5’
Cell divisions
Cell divisions
臺灣大學動物所 李承維
Cell cycle arrest (M1)
Catastrophe (M2)
Calvin B. Harley, A. Bruce Futcher & Carol W. Greider,
Telomeres shorten during ageing of human
fibroblasts, Nature 345, 458 – 460; May 1990
Calvin B. Harley, A. Bruce Futcher & Carol W. Greider,
Telomeres shorten during ageing of human
fibroblasts, Nature 345, 458 – 460; May 1990
Nicholas D. Hastie et al,Telomere reduction in human
colorectal carcinoma and with ageing , Nature 346,
866 – 868; Aug 1990
Nicholas D. Hastie et al,Telomere reduction in human
colorectal carcinoma and with ageing , Nature 346,
866 – 868; Aug 1990
作品
授權條件
作者/來源
L Hayflick (1968) Human cells and aging. Sci Am. 218:327.
Toni barros
http://commons.wikimedia.org/wiki/File:Dolly_face_closeu
p.jpg 2010/09/30 visted
Genes and Genetics, National Library of Medicine發行。
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&
part=wernersyndrome
Fiona S. Wyllie et al, Telomerase prevents the
accelerated cell ageing of Werner syndrome
fibroblasts, Nature Genetics 24, 16 – 17; 2000
Kim NW et al, Specific association of human
telomerase activity with immortal cells and cancer,
Science 23, 266; Dec 1994
Kim NW et al, Specific association of human
telomerase activity with immortal cells and cancer,
Science 23, 266; Dec 1994
作品
授權條件
作者/來源
Kim NW et al, Specific association of human
telomerase activity with immortal cells and cancer,
Science 23, 266; Dec 1994