癌是生命程序的缺省设置，而非随机突变疾病

sunsong7

% b  b$ y; R- e* q5 `  q( Z0 \6 j7 z9 C  F( @
Bioessays. 2012 Jan;34(1):72-82. doi: 10.1002/bies.201100049. Epub 2011 Nov 22.
& c) b( R) O* G0 T; m/ yCancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer.  ?) V3 I3 r/ t
Vincent M.5 `3 `0 T5 F* g; h! q2 R8 i/ F
SourceDepartment of Oncology, University of Western Ontario, London, Canada. mark.vincent@lhsc.on.ca
8 r; |" F$ E4 \- i3 E
3 w, k0 U! X2 d: D+ D& ?Abstract( j/ }) H6 ~. n( f# ^
Cancer viewed as a programmed, evolutionarily conserved life-form, rather than just a random series of disease-causing mutations, answers the rarely asked question of what the cancer cell is for, provides meaning for its otherwise mysterious suite of attributes, and encourages a different type of thinking about treatment. The broad but consistent spectrum of traits, well-recognized in all aggressive cancers, group naturally into three categories: taxonomy ("phylogenation"), atavism ("re-primitivization") and robustness ("adaptive resilience"). The parsimonious explanation is not convergent evolution, but the release of an highly conserved survival program, honed by the exigencies of the Pre-Cambrian, to which the cancer cell seems better adapted; and which is recreated within, and at great cost to, its host. Central to this program is the Warburg Effect, whose malign influence permeates well beyond aerobic glycolysis to include biomass interconversion and genomic heuristics. Warburg-type metabolism and genomic instability are targets whose therapeutic disablement is a major priority.: u. `* }- Z! ?

" y8 o! C; N# y- F5 O" yCopyright © 2012 WILEY Periodicals, Inc.
5 c7 ]5 D5 Z% N% ^2 @) }7 X; R( A, o- Z* b) l( A
Comment in6 [- }, d9 b. x  J9 h- r0 ?
Bioessays. 2012 Jan;34(1):2.
7 L0 i7 u2 m1 q1 {4 E" a% ZPMID: 22105565 [PubMed - indexed for MEDLINE] 9 [9 @9 g9 ^: z# ?8 M* L  k0 J
4 X  A$ l$ B* G
$ ]6 K* ^% \+ F
3 f; L+ p: ^# g
9 W/ G$ }& g  N& I
【扩展阅读】5 U1 u5 p5 ?8 g) o' P7 V+ i! V' Z
癌是健康而富有活力的细胞 http://www.stemcell8.cn/thread-55695-1-1.html
- x  _. K# h1 M; FNature：胚胎干细胞的“神奇状态”（附原文） http://www.stemcell8.cn/thread-57176-1-1.html. ^4 D& c) b5 e6 N" S5 v) U
日本在世界上首次人工制成癌干细胞 http://www.stemcell8.cn/thread-56885-1-1.html
* o/ v  R  \- K" i; j' ^0 UCollodictyon：生命进化树上的奇葩 http://www.stemcell8.cn/thread-55489-1-1.html8 J: K+ ]# h6 U; L
人类最早祖先或为海绵生物体 http://www.stemcell8.cn/thread-53357-1-1.html
# m! f2 _. c; M人类远古祖先——涡虫 http://www.stemcell8.cn/thread-53298-1-1.html* C4 l. l  s+ F' Y
MBE：所有遗传疾病的基因有同一“祖先”http://www.stemcell8.cn/thread-38156-1-1.html
; w5 z# |* a% `6 g* b0 Y标题理解错误：研究显示疟疾和海藻来自同一祖先 http://www.stemcell8.cn/thread-22348-1-1.html
  }& V* D) G1 Y( l! v" t. X奥地利科学家在祖先多细胞动物中发现“原始的”致癌基因 http://www.stemcell8.cn/thread-38310-1-1.html3 [# d( b: F2 Z% b% x, T) J2 J
疟原虫感染可能用于肺癌的免疫治疗（附原文） http://www.stemcell8.cn/thread-49846-1-1.html, I" q1 s3 D2 ]6 y, x: ]! a
疟原虫会因“争食”而互相抑制 http://www.stemcell8.cn/thread-39888-1-1.html0 a: {& R1 s8 D* b+ r
癌可能是我们最古老的进化祖先 http://www.stemcell8.cn/thread-38172-1-1.html; p. s) F4 j5 V/ m% t. f
Duesberg博士提出新的癌症成因观点——癌症是新进化寄生物种 http://www.stemcell8.cn/thread-44456-1-1.html
7 Y5 I3 B+ ?6 @  o8 z  r+ M
8 R1 ?' K9 t8 ?; {2 E9 F! X! T7 Q9 F$ e; Q

9 z3 F: Y' p$ t4 ?6 G0 L( w7 v- j1 Q5 O) V- ^! u: w6 _
Adv Cancer Res. 2011;112:283-350.2 t9 W2 h, G. G3 |( R  B
Cancer: beyond speciation.9 a: j! o) p' D, ~6 C" c
Vincent MD.) C/ H" J4 v" a
SourceDepartment of Medical Oncology, London Regional Cancer Centre, London Health Sciences Centre, Ontario, Canada.
4 W/ k3 y% z! f- j
  ], U5 A) N3 e& d1 ^Abstract
0 X& i% v9 U3 p+ G2 L3 f( T8 rA good account of the nature of cancer should provide not only a description of its consistent features, but also how they arise, how they are maintained, why conventional chemotherapy succeeds, and fails, and where to look for better targets. Cancer was once regarded as enigmatic and inexplicable; more recently, the "mutation theory," based on random alterations in a relatively small set of proto-oncogenes and tumor suppressor genes, has enjoyed widespread acceptance. The "mutation theory," however, is noticeable for its failure to explain the basis of differential chemosensitivity, for providing a paucity of targets, especially druggable ones, and for justifying the development of targeted therapies with, in general, disappointingly abbreviated clinical benefit. Furthermore, this theory has mistakenly predicted a widespread commonality of consistent genetic abnormalities across the range of cancers, whereas the opposite, that is, roiling macrogenomic instability, is generally the rule. In contrast, concerning what actually is consistent, that is, the suite of metabolic derangements common to virtually all, especially aggressive, cancers, the "Mutation Theory" has nothing to say. Other hypotheses merit serious consideration "aneuploidy theories" posit whole-genome instability and imbalance as causally responsible for the propagation of the tumor. Another approach, that is, "derepression atavism," suggests cancer results from the release of an ancient survival program, characterized by the emergence of remarkably primitive features such as unicellularity, fermentation, and immortality; existential goals are served by heuristic genomic instability coupled with host-to-tumor biomass interconversion, mediated by the Warburg effect, a major component of the program. Carcinogenesis is here seen as a process of de-speciation; however, genomic nonrestabilization raises issues as to where on the tree of life cancers belong, as a genuinely alternative modus vivendi. Philosophical considerations aside, genomic instability offers the prospect of subtle new therapies based on loss of information rather than gain; and the consistent, specific, and broad-spectrum perfidy of the Warburg effect highlights a supplemental target of the highest priority.
) H( t; g$ q7 \& W5 r
; n; J/ f  c" [Copyright © 2011 Elsevier Inc. All rights reserved.# Q" p6 Q5 l1 B

$ E, w# C% W! R1 ?  E5 hPMID: 21925308 [PubMed - indexed for MEDLINE]
' J6 L% o. o8 `( @) G+ ?! t
# c* ~  E6 t- q5 \% R! t
0 _0 J' Q3 H. n% T' B. F) A/ e' e1 N& s% S$ J! A

sunsong7

9 U, Z# v* L, c* ]! {( l! f1 w/ d' [6 o5 o! L
Is Cancer a Survival Program in Disguise?February 16, 2012  http://www.naturalroad.com/nutrition/conditions/cancer/is-cancer-a-survival-program-in-disguise/0 u" f9 z) d& L  |
Since Richard Nixon proclaimed a war on cancer in 1971 by means of the signing of the National Cancer Act, in excess of a hundred billion dollars has been paid out by the US government on researching and drug creation in an effort to eliminate the disease, with trillions more spent by the cancer patients themselves, with all but discouraging success. Despite four decades of waging full-scale conventional (surgery and chemotherapy) and nuclear (radiotherapy) war against cancer, around to one in every four Americans currently will be diagnosed with the disease within their lifetimes. Might this huge catastrophe echo how greatly misinterpreted the condition is, and misdirected are our efforts to avoid and cure it?+ X4 F0 g4 Y/ T" W, N9 I9 K, M
" M% R* W0 s7 |* x
Ever since those words, the 'war on cancer' were uttered, the “Mutational Theory” has offered the predominant description for the cause of the majority of cancers, where by, as the narrative goes, accrued mutations to the DNA inside the nucleus of our cells lead some to “go berserk, ” their “insane” actions an outcome of numerous damaging events to the intelligent code within the cell (DNA) that keep them behaving in a ‘civilized’ manner in comparison to the rest of the body. From this perspective, these rogue cells replicate themselves inordinately, spreading out in a characteristically malignant fashion (cancer = Greek for “crab”), in contrast to the attributes of an infectious process inside the host, sooner or later obstructing vital processes, resulting in morbidity and death. One paper summarizes this view as follows:+ X! N9 U# j& l: q" {

! O& ~) t- [4 z9 T" lCancer is derived from a single somatic cell that has accumulated multiple DNA mutations.8 @( _4 M* f  p9 ~" @2 Q1 j
The default state of cell proliferation in metazoan (animal life) is quiescence: V9 L' \# ?* N$ ]2 C4 x3 b* f
Cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle.* w9 s! f+ E+ b5 w2 O6 P

, f' A: S  J! k- k* XThe difficulty with this perspective is that over 100 cancer-promoting genes (oncogenes) have previously been found nested deep within our genome – barely a byproduct of chance mutation within individual cells. Growth would likely be the default state of all cells, and much of the behavior of healthy, well-differentiated cells is a regulatory overlay on top of a program, or genetic software execution which 'switches on' during carcinogenesis.. Z4 N& L0 t1 ~3 s+ n

$ N, v5 k% m( Q: \7 U" ACancer cells are amazingly coordinated for cells that are thought to be the outcome of strictly random mutations. These cells are capable of utilizing the host to build their own blood supply (angiogenesis), and are able to protect themselves by silencing cancer-suppression genes, secreting corrosive enzymes to move freely all through the body, they can alter their metabolism to exist in low oxygen and acidic environments, and have the capacity to remove their own surface-receptor proteins in order to avoid detection by white blood cells. These sophisticated behaviors, which entail the cooperation between cells is the very definition of Metazoan behavior (multicellularity, i. e. animal life), call into question the view that mutation within ‘rogue cells’ is the primary cause of cancer. What if cancer was the revelation of a built-in survival program within the cell, activated as a last ditch effort to survive an increasingly hostile bodily environment, saturated with carcinogenic and immunotoxic agents?) G6 M8 K% O# \. l; u% w
' {  F9 V3 Q9 t5 l
To simplify, cancer seems to not be some predestined gene-time bomb setting itself off within us, instead, is the logical result of decades worth of cell shock/damage/adaptation to environmental poisoning, nutrient deprivation and psycho-spiritual and/or emotional stress. These cells have learned to survive the constant abuse, and have flipped into survival mode, which is self-centered, hyper-proliferative and aggressive (metastatic).0 a  v% y9 _1 f

: u! ]. k. |/ b5 \2 D, uInstead of a “disease, ” it makes more sense to view cancer as a indication of the environment of the cell has become inhospitable to normal cell function, and in order to survive, the cell undergoes profound genetic changes commonly referred to a cancerous phenotype. This “ecological” view puts the center of focus back on the preventable and treatable causes of the “disease, ” rather on some vague and out dated notion of “defective genes” outside of our capacity to control directly.
; n- a# b) g- F. l# |+ f/ T4 ~# f5 G# L( g8 }1 u- e4 v
Fresh results published in the journal Physical Biology help support this updated view of looking at cancer:
4 X+ g' s) N1 W8 K& J1 v$ d) l& h5 f  z" O
The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient 'toolkit' of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution.. _5 _0 ?- I4 F
0 w; h7 r, f  Y9 m+ }
The reference point here to “Darwinian” evolution is one more way of talking about the Mutation Theory of cancer. If cancer is a byproduct of a sequence of random mutations that “naturally select” for a strong cancerous phenotype, there would be no “cancer toolkit” already embedded deep within the cell’s code.
7 T3 a& k2 P1 V0 L: Q9 {$ E/ F; C4 K& t4 C
This research may shed light on why chemotherapy and radiotherapy have such dismal track records. Tumors often contain a mixture of both highly malignant and benign cell populations. The treatment may destroy the benign cells, releasing the "chemoresistant" and "radioresistant" populations to wreak havoc on the body of the patient. Often treatment failure is attributed to the "treatment resistant" nature of the cancer, when it is a direct result of the inherent toxicity and lack of effectiveness of the therapy being used. In the same way that antibiotics like methicilin have spawned "super germs" like MRSA (Methicillin-Resistant Staphylococcus Aureus), conventional cancer treatment is often responsible for generating greater resistance and subsequent malignancy within certain tumor populations. If the transformation of a healthy cell into a cancerous one is caused by acute and chronic exposures to xenobiotic chemicals, as well as nutrient deficiencies, the use of many conventional anti-cancer drugs actually ads fuel on the fire, forcing those cells to regress further back into their ancestral genetic tool-kits for the means to survive the onslaught.
7 t. ^2 V5 ?$ x3 c- E3 K( p, I# K3 |( e+ I9 G
The time has come to shift the conceptual framework away from the notion that cancer is something undesirable that happens to the body, to something the body does in order to pull through by way of an progressively more toxic and nutrient-deprived environment. Only then we begin to unravel the enigma guiding the huge failure of the conventional medical system and why the ‘war against cancer’ will only be effective when we accept our enemy with greater consideration and comprehension, instead of blasting it into oblivion.
7 M9 a2 q6 \$ c7 P. E1 N
9 h' I3 `* N- D; z7 } The National Cancer Act, http://legislative.cancer.gov/history/phsa/19715 I( h8 g0 Z; ^1 F9 m

# p! t4 A3 Z4 u+ c) \8 Z0 P[ii] Cancer: A de-repression of a default survival program common to all cells?: A life-history perspective on the nature of cancer. Bioessays. 2012 Jan; 34(1): 72-82. Epub 2011 Nov 22. PMID: 22105565.9 f1 F- q! @0 N3 d, X/ Y, Q
1 ?8 A0 d! |0 n8 w6 i: F
$ b! K# E5 h% c& Z
癌是健康而富有活力的细胞 http://www.stemcell8.cn/thread-55695-1-1.html
# v! @5 o8 X: x1 b/ Z# N# i- t

sunsong7

Cancer by Default

Alan Packer

The Society of Cells: Cancer and Control of Cell Proliferation. C. Sonnenschein and A. M. Soto. 154 pp. Bios/Springer-Verlag, 1999.  6 n/ \( g/ {1 m( k3 A
With the War on Cancer approaching the length of the Thirty Years War and billions of taxpayer dollars having been spent since it began, it is not unreasonable to ask why the overall morbidity and mortality associated with cancer has not declined appreciably in the United States. Most scientists and observers of the cancer research efforts of the past quarter century seem to have concluded that this investment of time and money has been amply rewarded with spectacular advances in the basic understanding of the molecular origins of carcinogenesis.
+ V6 S9 S+ \! }On the evidence of The Society of Cells, it is safe to say that C. Sonnenschein and A. M. Soto are rather unimpressed with this entire research program and its premises. Sonnenschein and Soto, physician-scientists at Tufts University School of Medicine, argue that the prevailing paradigm of cancer research is based on three fundamentally flawed views of the basic biology of cancer.
" _4 c0 J3 P" J+ w7 ETheir first proposal is that the default state of cells is proliferation rather than quiescence and that the key to understanding how cellular proliferation is controlled is to identify inhibitors of this default state.
' p- w* U7 l8 Q1 }% OThe second, which is echoed in many quarters, is that too much of today's cancer research is in the reductionist tradition and ignores the properties of tissues that emerge once we lift our sights from a gene-centered view of how cells and organisms operate.
  t1 M2 m% u/ r* Q3 z! n- LFinally, Sonnenschein and Soto suggest that, contrary to the prevailing view, genetic mutations are, at best, indirectly involved in carcinogenesis. Rather, the disruption of tissue organization is the causal factor in transforming a normal cell into a cancerous one.
6 b: L9 L/ S4 LThat cells proliferate rather than enter a quiescent state given the proper nutritive environment is based on both evolutionary common sense and sound technical arguments. After all, the authors note, bacterial and plant cells behave in just such a manner when placed in culture, and there is no compelling reason to believe that this longstanding strategy for living has been overturned in animal cells. & k+ I+ _4 i% i! `
On this point, Sonnenschein and Soto do an excellent job of elucidating the ways in which the opposite assumption (quiescence as the default state) has defined much of the work on cellular proliferation and carcinogenesis over the past few decades, on very little evidence. 8 g/ T* m( o( s; B' |& M
Other areas of their argument, however, seem more problematic. Although some of the criticisms of a gene-centered approach to cancer are sound and interesting, there is now an immense literature—largely generated in the past 15 years—linking mutations in specific genes to overall cancer susceptibility or to the development of specific cancers. In support of their view that this is not the case, Sonnenschein and Soto review the literature in a selective manner, emphasizing animal studies that raise doubts about the molecular genetic origins of cancer while ignoring those that support it. 3 h+ X8 J& _" b% {( m* R
Does more attention need to be paid to the ways in which perturbations of cell-cell signaling and tissue organization contribute to the development of cancer? Certainly. But there is every reason to believe these events can be traced back to DNA damage and genetic mutations. Filling in these pathways is the task at hand not only for cancer researchers but for biologists in general.
% L3 S" r# o7 ^: VIn the epilogue to their book, Sonnenschein and Soto quote the eminent biologist John Tyler Bonner: "What is utterly baffling to me is why one cannot be a reductionist and a holist at the same time." The Society of Cells is certainly a provocative critique of the current program of cancer research—one that attempts to move the field away from an ultrareductionist view. At times, however, it ignores Bonner's sensible question and moves too far in the other direction.—Alan I. Packer, Genetics and Development, Columbia University College of Physicians and Surgeons - {& F% f! \; V
http://www.americanscientist.org/bookshelf/pub/cancer-by-default
* f. k2 i8 Q9 Y+ {

sunsong7

) g: s: w2 T; K% ?3 C" p+ Y  @8 W+ b; B0 m4 D8 ]
Bioessays. 2012 January; 34(1): 36–37. ) D$ l; x1 T7 l, D
doi:  10.1002/bies.201100138% {- A/ D7 k/ ?
PMCID: PMC3266487% c+ ~  j% Y& b9 s+ S

1 {1 h& J) d  U! V% yThe default state of the cell: Quiescence or proliferation?( v, O- E- J& d1 |/ ?; S

' S  X: p+ V, S. z9 L; V[url=http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=PubMed&term=%20Parr%2BE[auth]]Edward Parr[/url]# }6 r( R& B8 F  q1 W$ M# i5 C

4 ?& h+ z+ o6 d; ^; ZUBC Envision Group, Southport, CT, USA" o: @1 G/ r6 n
Corresponding author: Edward Parr E-mail: ed.parr@ubc-envisiongroup.com 5 T" G( I6 I( `0 b  p7 Z

3 z( M7 L3 I- _- }Author information ► Copyright and License information ►+ p, {% s1 ]: A6 e" j% w
* m5 ]3 k; x. Y, D0 B+ F
Copyright © 2012 WILEY Periodicals, Inc.
$ d2 |! j' Y  uRe-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
- T6 W0 }8 [- r, N0 U  W. {. n. G4 M/ ]0 w0 k! {
+ k( u8 K* m+ a/ n

1 o/ [. n% s$ ~( f2 W7 C
: L" e! p) Y' j0 B. a* ], T

There exists abundant evidence that mutations that change the function or expression of growth-regulatory genes can lead to progression to a cancerous phenotype, and the progressive accumulation of such changes as the underpinning of tumorigenesis forms the basis for the somatic mutation theory (SMT) of cancer [1]. At a molecular level, that model of tumorigenesis suggests that progression to a cancerous phenotype can be driven by gain-of-function in growth-promoting oncogenes and/or loss-of-function in growth inhibitory tumor suppressor genes within somatic cells (a third class of “stability” genes are also a contributor to tumorigenesis [2] but are not considered in this paper). A frequently used analogy for that model compares these classes of genes to the gas pedal and brakes of an automobile [2]. However, there is evidence that this model may not be sufficient in itself to explain the development of cancer [3]. For example, the influence of the milieu of tumor development may strongly influence its development, and so an alternative model in which the tissue microenvironment is a critical factor in tumorigenesis has provided the basis for the tissue organization field theory (TOFT) [4]. Although not all differences between these theories are irreconcilable, a key difference between these models is that quiescence is postulated to be the default state of “normal cells” in SMT, whereas proliferation is assumed as the default state of cells in TOFT [4].

It follows from the requirement for growth promotion in the SMT that the default state of the cell is static. Indeed, it is well established that primary cultured cells from metazoan organisms fail to proliferate in the absence of appropriate growth factors. Johnston et al. have further suggested that cellular progression to a cancerous phenotype may represent a reversion of metazoan cells to a more primitive evolutionary phenotype whose “freedom to proliferate” occurs at the expense of the host's long-term survival [5]. This suggestion is supported by similarities between the behavior of cancer cells and the likely behavior of unicellular ancestors of metazoan organisms, as in both cases their growth is not subject to external regulation by other cells. Again, this phrasing also implies a freedom not to proliferate. However, as pointed out by Soto and Sonnenschein [4], that freedom does not seem to be enjoyed even by modern unicellular eukaryotes. If the default state of growth is truly different between unicellular and multicellular organisms, then it follows that a profound change in the default state of cells occurred during evolution of metazoan organisms and that the change is reversed in carcinogenesis. However, there may be another, simpler explanation that requires considering the growth-promoting signaling pathways from an evolutionary perspective.

The earliest cells would necessarily have been required to be independently growing entities limited externally only by the supply of resources and internally by their capacity to proliferate. As also argued by Johnston et al. [5], millennia of selective pressures in unicellular ancestors of modern eukaryotes would have favored those that were able to divide most rapidly. In that way, evolution may have led to the development of early cells as organisms designed primarily or entirely to proliferate at the maximum possible rate. During the evolution of metazoans, it seems highly unlikely that complex, ligand-dependent signaling pathways emerged de novo as a requirement for growth. Rather, the most straightforward explanation for their appearance may be that they evolved from growth-related processes that already occurred in a ligand-independent manner in their unicellular ancestors. There may be any number of ways that could have been accomplished. One such example may be presented by the membrane-associated Ras protein and its associated signaling pathways, which play a vital role in cell cycle progression of both unicellular organisms and cells of metazoans. At least in some unicellular organisms such as yeast, regulation of Ras does not involve receptors for extracellular ligands, but rather involves intrinsic signals relating to stress and metabolism [6]. However, in cells of most or all metazoan organisms, Ras acts as a downstream effector for growth factor receptor signaling [7]. Thus, in metazoan cells, growth factor signaling pathways may have arisen by co-opting processes that occurred constitutively in their unicellular ancestors. In that sense, ligand binding may not actually stimulate growth but instead permit it by completing an interrupted circuit, in the same way that turning on a light switch permits the flow of electricity to light a bulb. It is possible to envision other scenarios that might also have led to the appropriation and repurposing of intracellular processes to become part of other ligand-responsive signaling pathways in metazoans. In the assessment of any such potential scenarios, it may be particularly instructive to analyze the structure and functions of signaling pathway components identified in unicellular organisms that are closely related to metazoans [8].

If this proposal is correct, then the function of ligand-stimulated signaling pathways could be viewed not as a system wherein growth factors can be added to promote growth but rather as a system in which growth factors can be withheld to control growth. Thus, the quiescence of cultured metazoan cells in the absence of growth factors would not reflect a passive lack of growth stimulation but rather an active process of growth inhibition. Furthermore, such a model would imply that oncogenes, which are considered stimulators of growth, actually function to permit growth by overcoming limitations imposed during the transition to multicellularity.

Although this concept does not argue against an important role for genetic changes within cells during progression to cancer, as proposed in the SMT, it does support the idea of proliferation as a default state of cells, as proposed in TOFT [1, 3, 4]. It further suggests that gene products that appear to “promote” growth actually act to reveal the cell's innate tendency to grow. Thus, this proposal calls into question the gas pedal and brake analogy for cell growth. If it is valid, then perhaps a better comparison would be a soapbox racer rolling down a hillside pathway. In this analogy, the pull of gravity would represent the innate tendency to grow. Transient and reversible growth-inhibitory processes (e.g. absence of ligand) could be incorporated into this model as brakes that could be applied by the driver. Mechanisms to permanently halt growth are readily incorporated into such an analogy by invoking runaway lanes on one side of the pathway into which the racer can be steered and brought to rest off the main pathway (terminal differentiation), and by invoking a steep cliff face parallel to the pathway on the other side over which the racer could be steered (apoptosis). This analogy would also suggest that at least some limited cell cycle progression would be required for cell death, a proposal that is consistent with observations of cell-cycle progression in many apoptotic cells [9]. Although superficially this is a more complicated analogy than the gas pedal and brake, this model is still approachable and more readily accounts for the various potential fates of the cell. In addition, this concept may better account for the evolutionary emergence of growth-factor dependence in cells of metazoans.

1 s3 s% P8 }) U8 `( H5 \- |$ ?Go to:) c1 D  s% r  [* b: Q& }% f
Acknowledgments

I thank Drs Andrew Moore and Howard Wong for feedback to help shape the focus and flow, and Dr Randal Johnston for helpful suggestions.

1 I. n  U& z9 {& q8 k0 y/ c) `! b2 F; ]6 |6 P
Go to:
1 l9 o  v7 K6 H, H! bDisclaimer

The views and opinions expressed in this paper are those of the author and do not necessarily reflect those of UBC Envision Group or any of its other employees.

6 h8 q" Q- z' e; G1 z+ W) [- K; q
Go to:, ]# O$ Y) O' i+ c
References1. Vaux DL. In defense of the somatic mutation theory of cancer. BioEssays. 2011;33:341–3. [PubMed]- l, X- ^+ E1 W" H
2. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–99. [PubMed]
2 R1 ?  @# ^- E/ P  O8 d3. Thomas D, Moore A. Counterpoints in cancer: The somatic mutation theory under attack. BioEssays. 2011;33:313–4. [PubMed]8 D7 K& E, w/ t4 ]3 F$ b- v
4. Soto AM, Sonnenschein C. The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. BioEssays. 2011;33:332–40. [PubMed]$ G4 R) N& _& c5 r2 z, J
5. Johnston RN, Pai SB, Pai RB. The origin of the cancer cell: oncogeny reverses phylogeny. Biochem Cell Biol. 1992;70:831–4. [PubMed]7 ~7 a  ?' P0 s. r4 J' o) @3 V) P
6. Tamanoi F. Ras signaling in yeast. Genes Cancer. 2011;2:210–5. [PMC free article] [PubMed]
( X8 E" a; h8 ~1 i, f8 _" T' S1 n7. Margolis B, Skolnik EY. Activation of Ras by receptor tyrosine kinases. J Am Soc Nephrol. 1994;5:1288–99. [PubMed]
* ^& g. Q* Z' X( U8. King N, Westbrook MJ, Young SL, Kuo A, et al. The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature. 2008;451:783–8. [PMC free article] [PubMed]4 s' o% H/ q- A
9. Fotedar R, Diederich L, Fotedar A. Apoptosis and the cell cycle. Prog Cell Cycle Res. 1996;2:147–63. [PubMed]; B# c! S9 G; E1 ]* `* \
8 @1 ^/ T3 c% ^' z) ]1 P) C! ]

' E4 L3 m- H3 s# q: L$ c! hhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266487/
: [4 |, E' n$ D; b* a$ a
1 B6 h. m/ m1 r- {+ }
; o2 A7 t; j9 r. U干细胞是细胞的默认状态吗？ http://www.stemcell8.cn/thread-54785-1-1.html( E. }  V& w' w

sunsong7

+ X7 I# M! B& H2 r" @" {2 ]
" A. g' B4 `2 d* P4 u% j* E

谁是癌症真正的“肇事者” 1 ^* C& v' e; n/ p% C- }, y2 a- i日期：2012-05-23 作者：何积惠 来源：文汇报

1 E: ~+ [9 W- t; [% `" c* J; o! ?# @& N. `; N* J 通常认为，“癌症是一种基于细胞异常增殖的疾病”，然而，这一理论越来越无法解释在胚胎发育期间观察到的很多现象。两位长期致力于癌症机理研究的学者最新的研究发现是，无论正常发育抑或致癌作用，都是在生物组织的层面上发生的。从细胞中心观到组织中心观的这个视角变化，将有助于揭示—— 谁是癌症真正的“肇事者” 　　□何积惠 编译 # @3 F- X. p% ?6 [2 v2 E) E7 C 　　学术界一般认为，癌症是起因于DNA突变和恶性细胞。然而，如果增殖是细胞的默认状态，如果有一种截然不同的致癌机制理论正在悄然兴起，你会作何感想呢？让我们来听一听执教于美国塔夫茨大学医学院解剖和细胞生物学系的卡罗尔斯·索南夏因和安娜·索托的研究心得吧。 　　 如何回答这个问题——正常细胞到底受了什么“刺激”才异常增殖的？ 　　对知识的追求永远是一场事先未经踏勘的历险，它多半是在已知与未知间的朦胧状态下完成的。因此，在对重大理念的探索中没有稳操胜券的方法。 　　我们探索致癌作用新理论的曲折之路，始于40年前卡罗尔斯·索南夏因被要求回答一个“直截了当”的问题之际：卵巢雌酮是如何“刺激”它们在子宫、阴道、乳腺、垂体腺和其他器官中的靶细胞增殖的。对他来说，显而易见的第一步是建立对雌酮敏感的细胞系——这是第一次将设想付诸实验。 　　正是这一里程碑式的收获，激励着安娜·索托加入了实验室，因为这个细胞系可望成为探究雌酮如何调节基因表达的有效工具，这在当时是一个颇受关注的课题。然而，细胞系自相矛盾的行为令我们感到困惑：以动物为例，这些细胞只有在用雌酮为动物治病时才会增殖，而一旦放在细胞培养器皿中进行试验，它们不管有没有雌酮都会增殖。 　　按照上世纪60年代盛行的理论，取自多细胞有机物的细胞，如果被置于细胞培养器皿中就会处于一种静止状态，即使营养物达到最佳浓度也不会促使其增殖。它们只有在受到信号——生长因子——诱导时才会增殖。 　　然而微生物学家还知道，细菌、变形虫和酵母等单细胞有机物是不需要信号的，只要遇到营养物就会迅速增殖。因此，这些有机物的默认状态就是增殖，由此形成了一个从进化角度来看合乎情理的观念。归根到底，有机物除此之外还会以什么方式来增殖呢？ 　　无论单细胞抑或多细胞，其真核细胞的周期组分在本质上是相似的。那么，是否可以根据这一事实对这些细胞的默认状态作出教科书式的诠释呢？我们在详尽检索文献后找到的数据或理论，都没有对它们的默认状态随着多细胞有机物的披露而发生的根本变化作出解释。这就促使我们去搜索能解释雌酮在体内和体外的结果相互冲突的动因。 　　我们在血清中找到了抑制被雌酮当作靶标的细胞的增殖动因。看来，雌酮只是中和血清的抑制效果而已。由于细胞培养器皿中并不存在血清，因而雌酮是不起什么作用的。 　　 事实果真如此吗——当时我们像其他人那样认为，癌症是一个细胞增殖的问题。 　　在我们的研究成果发表后若干年，有人得出结论称：胚胎干细胞的默认状态就是增殖，淋巴细胞的生殖静止是经过了诱导而并非固有的。简而言之，多细胞有机物逐渐形成了调整细胞增殖的方式：它们时刻作好增殖的准备，却因受到其他细胞及其所在组织的影响而无从实现。 　　我们在阅读进化生物学家列奥·布斯影响卓著的《个性的进化》（1987年）一书后提出，游走性是单细胞和多细胞有机物的默认状态。动物的细胞是会活动的，从它们的出生部位不断涌向死亡部位，而有些类型的细胞活动性要自由得多，例如血液中的细胞。 　　在积累了20余年的研究经验后，我们走上了令人愉快的历险之路，那就是撰写一本有关控制细胞增殖和癌症的专著。当时我们像其他人那样认为，癌症是一个细胞增殖的问题，由此推断对细胞增殖控制的深入洞悉将会揭开致癌作用机制的奥秘。 　　然而，19世纪末曾有过另外一种观点，它把癌症解释成一种基于组织的疾病，跟胚胎发育背离正道的状况很相似。直到1914年德国生物学家特奥多尔·博韦利才提出：癌症是一种基于细胞的疾病。 　　这种以细胞为中心、如今有体细胞突变理论（SMT）之称的看法，随着分子生物学革命大行其道而愈益占据主导地位，形成了生物学上一切现象必须从分子水平上去解释这个以基因为中心的观念。 　　通过这一历史回顾，我们不得不对各种无法用基于细胞的观点来解释的实验作了重新阐述，其中有些实验证明：癌细胞被置于器官（即提取细胞的源头）的健康组织（例如将肝癌细胞植入正常的肝，或是将胚胎癌细胞植入胚泡）时即可恢复正常。还有一个例子显示：正常细胞被植入错误的部位——例如将胚胎细胞植入睾丸——时是如何变得异常的。 　　 一个未说完的故事——新的理论需要实验来直接验证，但其技术难度在目前尚无法逾越。 　　我们阐述这些实验的目的，是为了确认器官的正常结构是靠组织互动来维持的——与决定胚胎基本形态或形态发生的结构相类似。为了反映从细胞中心观到组织中心观的这个视角变化，我们给自己的著述（1999年）冠以《细胞社会》之名。书中提出和阐述了致癌作用的所谓组织结构场理论，还设计了旨在对它加以测试的实验。 　　在这些实验中，有一项是让小鼠乳腺的供养组织或基质单独暴露于致癌物质。一旦两个组织重新结合，就足以诱导未暴露的正常上皮细胞发生癌变。 　　相反，将提取自小鼠乳腺癌基质的上皮细胞植入正常的腺基质，结果便形成了正常的上皮组织。这些实验揭示了癌症的可逆转性，表明组织互动研究除了有助于理解癌症外，还能进一步探明它的逆转性。 　　与体细胞突变理论相比，我们的理论更能吻合下述事实：在胚胎发育期间观察到的绝大部分现象，很少是通过一味着眼于细胞水平的研究来给出解释的。无论正常发育抑或致癌作用，都是在生物组织的层面上发生的。 　　另一方面，细胞中心论则越来越无法适应层出不穷、相互冲突的数据及其关键性前提。至于直接验证致癌作用的主要理论，进而最终夯实癌症的所谓“生成”细胞实际上是真正的“肇事者”这一理念，其技术难度在目前尚无法逾越。所以，我们留下的是一个未说完的故事。重大发现的影响力是无法预言的，也取决于众多无法估量的因素，但通过对悖论的认定，依然能精准地预测科学技术的突破口。 9 E! p8 x7 y1 S/ ? + D& r( \! R4 F& ~; Z3 b8 S& y- c5 `- o* [; R: n% ~1 o( d $ |+ R" p: t8 X2 @9 w

http://whb.news365.com.cn/kjwz/201205/t20120523_430416.html

sunsong7

0 [url=]0[/url]
& \: p9 C7 U  {3 w
$ a$ R4 M1 k+ T0 ]0 d6 @$ f& S0 i7 |3 K8 |7 ?2 d, P) y- a
Genetics：组织结构延缓癌症发生" m4 z% L9 W& y+ v- j
作者：mumu 来源：生物谷 2011-12-20 9:59:31
9 a9 Q- o( t  ]4 ^* k, Q( Q  G& P! V/ T* Y! |
# g2 n% ]0 s' c  r! V( r9 d
( g; y9 M  i1 c% }4 t( q6 R
9 j# g2 X2 Z$ w! f6 G
; i; ~6 P' Q) D4 ~# H" {
        癌症成长通常跟随着一个漫长的发展时期。随着时间推移，基因突变经常累积于细胞内，首先引起癌前期的条件，最后导致肿瘤生长。用数学模型，Göttingen、宾夕法尼亚大学和旧金山加利福尼亚大学马普动力学与自组织研究所的科学家们已经揭示，空间组织结构，就如在结肠中发现的，减慢了遗传突变的累积，从而延缓癌症的发生。他们的模型有助于活组织检查的评估，增强特定癌症进展的预测。
$ _' x4 c! N$ M. l许多癌症在体内不为人知地经过数年发展才爆发。偏离点由遗传突变提供，其中遗传突变包括点突变、拷贝数异常、杂合子丢失和其他的结构重组，这些遗传突变在细胞内逐渐累积，导致形成癌前期损伤。如果突变在单个细胞内达到一定量，细胞开始不受抑制地增殖。对于一些癌症，累积过程可花费20年时间。但是，不是每一个带有癌前组织的人都在事实上发生癌症，异常细胞的形成通常没有医学后果。到现在为止，仍不清楚为什么肿瘤在一些情况下发生，而在其他情况下不发生。
, N5 N( g/ J4 {. d0 u5 W) u0 O& C( G      由Göttingen马普动力学与自组织研究所Erik Martens 和Oskar Hallatschek牵头的研究小组应用数学模型，研究了遗传突变如何扩散，突变累积过程速度和累积过程对癌前期条件的影响。他们揭示，致瘤或致癌突变的命运部分依赖于它们出现的地方与来自其他的、类似突变的竞争有多大。在没有任何空间结构的环境中，例如血液中，遗传突变传播和累积相对快。在有清晰空间结构的组织中，就象直肠，细胞累积肿瘤形成所需的突变数量需要较长时间。
0 O3 B6 P5 L8 @5 f3 T; [8 R& O研究以2个普朗克科学家开发的进化理论模型为依据。许多遗传突变对于已突变细胞是有害的，因此不使它昌盛。另一方面，一些遗传改变给它们的宿主带来优于其他细胞的竞争优势。例如，这包括突变增加细胞分化率。Erik Martens解释到："直接优势使具有这种突变类型的细胞能在组织中增殖和累积；但在一些情况下，也就是有益于细胞的对病人有害，因为它最终导致癌症。"
; U8 k0 I& W2 t) F$ n       这项研究所用的模型是以如小肠壁样的组织为依据，这样的组织有许多小孔或隐窝，每个隐窝有独立的可累积和携带不同突变的细胞群。如果突变出现少，它们可不受阻碍地通过癌前组织扩散。但是，如果在通过组织扩散的最早突变前出现其他的突变，各种突变克隆汇集，与另一个竞争生存。在这种情况下，有许多失败者和少许胜利者，只有某些突变能成功地建立自己。
* P! g2 T% k; V' s/ f原则上，有益突变在空间结构细胞中增殖不能象在完全混杂或无结构细胞那样快速。结果是，空间结构组织中的突变竞争通常很强烈，突变累积率低于无结构组织。根据这个研究，这就是为什么结构组织达到突变的重要数量花的时间更长，从而延缓了癌症发生。; |5 R7 [5 V, ^% x9 d$ Y
       " 纵使许多类型癌症在机体组织中以清晰空间结构出现，大部分癌演进早期模型忽略了这个方面，而以混合细胞群为根据"。Erik Martens解释说，"但是，为了更好地预测癌前条件如何进展，结合结构方面信息是很重要的。例如，在给定的时期，空间结构组织相对于无结构细胞累积更少的突变。因此，触发一定癌症的所需的突变数量就超过估计。"研究人员希望他们的发现有助于改善活组织检查的解释，促进更多真实的癌演进预测。（生物谷bioon.com)
' f) L1 O; y# ?+ w. n( [* ^  H: t0 @+ a: P; n
8 J) X' B+ e3 }9 d& z) l) q; t
doi:10.1534/genetics.111.130112
3 i$ A0 D1 y: s" a( KInterfering Waves of Adaptation Promote Spatial Mixing
! {9 Y. C5 O! Q" a1 G+ _! E# ]8 W0 h+ R7 @$ [# w
Erik A. Martens,Oskar Hallatschek: |9 P: T3 G$ p
Abstract A fundamental problem of asexual adaptation is that beneficial substitutions are not efficiently accumulated in large populations: Beneficial mutations often go extinct because they compete with one another in going to fixation. It has been argued that such clonal interference may have led to the evolution of sex and recombination in well-mixed populations. Here, we study clonal interference, and mechanisms of its mitigation, in an evolutionary model of spatially structured populations with uniform selection pressure. Clonal interference is much more prevalent with spatial structure than without, due to the slow wave-like spread of beneficial mutations through space. We find that the adaptation speed of asexuals saturates when the linear habitat size exceeds a characteristic interference length, which becomes shorter with smaller migration and larger mutation rate. The limiting speed is proportional to μ1/2 and μ1/3 in linear and planar habitats, respectively, where the mutational supply μ is the product of mutation rate and local population density. This scaling and the existence of a speed limit should be amenable to experimental tests as they fall far below predicted adaptation speeds for well-mixed populations (that scale as the logarithm of population size). Finally, we show that not only recombination, but also long-range migration is a highly efficient mechanism of relaxing clonal competition in structured populations. Our conservative estimates of the interference length predict prevalent clonal interference in microbial colonies and biofilms, so clonal competition should be a strong driver of both genetic and spatial mixing in those contexts.
8 r8 J& h6 X) z+ w# T8 D3 T6 ?* F
$ U) l# e% n3 z5 f( C4 ahttp://www.bioon.com/biology/cancer/513961.shtml
. ]" T6 ~4 R: G* [$ R, I+ n; j9 D$ L
$ ^7 I7 n" N! G" `. ^3 J! ]7 J

: r& R; _  l/ J3 c4 s4 ^7 q# l3 L0 j4 G+ w