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Ernesto Burgio
ISDE Italy
Scientific Committee
DOHAD
X rays
Metals
Viruses
CEM
Xenobiotics
EDCs
Environment���� Dynamic (Epi)-Genome
���� Neolamarckian Paradigm2
3
1
1
2
3
4
4
4
Fetal origins of adult diseases and cancer
….NON si tratta di una tematica di esclusiva pertinenza endocrinologica…e/opediatrica
Organismo umano: clone cellulare derivato da un’unica cellula totipotente (zigote) e
costituito da miliardi di cellule con unico DNA
e differente (epi)genoma
Parole chiaveEDCs
DOHAD
Fetal Programming
Fluid (Epi-Genome)
Finestre di Esposizione
Cellule totipotenti…multipotenti…
Differenziazione
cellulare
Plasticità
potenzialità
MASSIMA
Gli interferenti endocrini sono sostanze mimetiche o comunque in grado di interferire sul cell signaling intercellulare e intracellulare a vario livello: comunicazione intercellulare (discorso analogo potrebbe esser fatto per gli antibiotici tra gli organismi monocellulari), sui recettori membranari e nucleari, sulle pathways di trasduzione dei segnali dalla membrana al nucleo, sui meccanismi di trascrizione, traduzione etc. Gli effetti più significativi sono connessi alla possibile loro azione su cellule/tessuti di organismi in via di sviluppo, con particolare rilievo per specifiche fasi di sviluppo di organi e tessuti (finestre di esposizione). Il problema fondamentale (in ambito biomedico) connesso alla diffusione in ambiente (catene alimentari !) di molecole xenobiotiche, metalli pesanti ecc.. in grado di agire da interferenti endocrini (perturbatori informatici) può essere riassunto in una sigla: DOHAD
12
3
4
Fetal Programming
Differentiation
Organismo adulto = Clone di 100mila miliardi di cellule derivanti da uno zigote: tutte uguali sul piano genetico differenti sul piano epi-genetico e morfofunzionale
In developmental biology, cellular differentiation is the process by which a less
specialized cell becomes a more specialized
cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism
changes from a single zygote to a complex system of tissues and cell types. Differentiation is a common process in adults as well: adult stem cells divide and create fully-differentiated daughter cells during
tissue repair and during normal cell turnover. Cell differentiation causes its size, shape, polarity, metabolic activity, and
responsiveness to signals to change
dramatically.
These changes are largely due to highly-controlled modifications in gene expression. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.
Cellular differentiation during development can be understood as the result of a gene regulatory network. A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive
input and create output elsewhere in the
network . The systems biology approach to developmental biology emphasizes the importance of investigating how developmental
mechanisms interact to produce predictable patterns (morphogenesis).
A
B
Cellular Differentiation: an Epigentic process
A
TCDD
Viruses
HERVs
CEM
3
2
1
SYNERGISM ?!
“FLUID EPI-GENOME”
4
Dovremmo rappresentare l’”ambiente “ come un flusso
continuo di informazioni semplici - i fotoni: singoli pacchetti di E = M = Informazione - o complesse (molecole organiche …virus… etc..) in grado di interagire con le cellule (recettori
membranari � proteine di trasduzione � (epi)-genoma…
Everyday levels matterEveryday levels matter
At truly low levels At truly low levels ……
it interferes with it interferes with
gene activationgene activation
At high levels… arsenic kills people
At moderately low levels…it causes a range of diseases
KaltreiderKaltreider et alet al. 2002. 2002
The Epigenetic Players
DNAMethylation
Histonemodification
ChromatinRemodelingmachinery
+
ON OFF
Euchromatin
Heterochromatin
Epigenetics is defined as mitotically and meiotically heritable changes in gene expression that do not involve a change in
the DNA sequence…. DNA methylation and histone modifications are known to have profound effects on controlling gene
expression.. MicroRNAs (miRNAs) are small RNA molecules, _22 nucleotides long that can negatively control their target
gene expression posttranscriptionally
Fraga et al., PNAS. 2005.
1
4
32
MicroRNAs
Chuang JC, Jones PA Epigenetics and MicroRNAs Pediatr Res 2007; 61: 24R–29R
Histone Tails
are subject to a variety of covalent
modifications
Histone Code”hypothesis: modifications
of the Histone tails
act as marks read
by other proteins
to control the expression
or replication of chromosomal regions
E.g. generally, Histone Acetylation
is associated with
transcriptionally
active genes
Deacetylation
is associated with inactive genes
(= gene silencing)
Mismatch Repair EnzymesTrascription Factors
Hormones
Correct organizationof chromatin
Gene- and tissue-specific epigenetic patterns
Silencing repetitive elements
Genomicimprinting
X chromosomeinactivation
Controlling active and inactive states of embryonic and somatic cells
1
2
ab
c
d
e
f
3 microRNAs
Once thought to play only a structural role, it now
appears that chromatin plays a key regulatory role by
marshalling access to the DNA template…
…chromatin itself is the direct target of many toxicants *
… toxicant-induced perturbations in chromatin structure
may precipitate adverse effects (* Heavy metals, EDCs..)forcing genome to change
Nuclear ReceptorDNA Response Element
Histone
Lysine
Acetylation
Histone Deacetylases.
Histone Acetyltransferases;
Histone Methyltransferases
ATP-dependent Nucleosome
Remodeling Complex
Many toxicants cause rapid alterations in gene expression by activating
protein kinase signaling
cascades.
The resulting rapid,
defensive alterations in
gene activity require the
transmission of a signal
directly to the histones
present in the chromatin
of stress response genes:
within minutes
of exposurethe phosphorylation of
serine 10 of histone H3
and the acetylation
of lysines 9 and/or 14
take place
H3-K9 H3-S10
P
These modifications are believed to be
essential for the full transcriptional response to
stress-inducing chemicals
http://www.ewg.org/reports/generations/
CHEMICAL FALL OUT
UParticlesHeavy MetalsEDCs (Dioxines like molecules), PCBs,
Bisphenol A, Phtalates1 2 3
The gift our mothersnever wanted to give us
XXI century: a dramatic transformation of the
environment and uterine microenvironment
The main problem that the myriad sources of pollution across the planet is likely to causeto our health and to future generations is indeed the load of toxic molecules many of which
are incidental products of incomplete combustion.. accumulated in our bodies: EPA
(Environmental Protection Agency); US Centers for Disease Control and Prevention; Environmental
Working Group (EWG) (an environmental organization specialized in environmental research)are systematically biomonitoring the body burden of toxic chemical compounds, elements,
or their metabolites (Chemical Body Burden), in biological substances since many years
À présent de nombreuses études, en différentes pays, cherchent d'évaluer la charge chimique du corps (chemical body burden) .. surtout chez les femmes, les enfants, les embryons/foetus, fournissant des résultats dramatiques. Parmi les plus connus sont les études réalisées par des chercheurs de l'Environmental Working
Group, qui ont documenté la présence de centaines de substances toxiques, mutagènes et cancérigènes dans le sang, l'urine, le lait maternel, le sang de cordon: inquiétude a suscité une étude qui documenté la présence de substances (géno) toxiques et mutagènes dans tous les cordons ombilicaux testées, démontrant l'omniprésence et la précocité de l'exposition fœtale
Epigenetic perturbations early in life
Epigenetics and human disease
Viruses
Chemicals
X Rays, UP..
First Hit (s) Second Hit (s)…
Genetic Damages
Fetal Programming (Epigenetic)
E’ possibile ipotizzare/dimostrare che le modifiche dell'assetto epigenetico si trasformino progressivamente in modifiche
genetiche e/o cariotipiche … e che, nella misura in cui coinvolgono i gameti possano trasmettersi di generazione in
generazione ecc..
Insulino-resistance
Diabetes
Cardiovascular Diseases
the XX Century Epidemic Revolution
Barker Hypothesis (1989)
(1989)
ab
c
We may even hypothesize that a lot of diseases characterizing what we may call the XX Century Epidemic
Revolution
[the epidemic change we are witnessing all over the world, and especially in the most developed countries, concerning a switch from a prevalence of acute exogenous
(infectious and parasitic) to a prevalence of chronic endogenous (immuno-mediate, neurodegenerative, neuro-endocrine, cardiovascular and neoplastic) diseases, - atopy/asthma and autoimmune disorders (diabetes I, celiac disease etc); obesity, metabolic syndrome, diabetes II; atherosclerosis (stroke, infarct etc); Alzheimer Disease, Parkinson Disease; Cancer] is a late result, in adults, of a developmental process gone awry, deeply rooted in the first stages of
embryo-fetal development
• Perchè la celiachia (glutine + DQ2-DQ8 + Permeabilità
Intestinale + Gut Ecosystem/TLRs) ha un incremento
di circa il 10% annuo in Italia..?
• Perché asthma/allergie di I tipo GC sono passate da una prevalenza dell'1% a 25-30% in meno di un secolo (allergens + genes + flogosis/remodeling) ecc..
• Che legame c'è tra l’incremento epidemico di obesità.. sindrome metabolica.. diabete II.. aterosclerosi e
patol.cardiovascolari (genes+epigenetics/phlogosis + TLRs)
• ENVIRONMENT HEALTH
• Genome and Epi-genome
• The Epidemic Revolution of XXth Century
• 3 PARADIGMSBarker HypothesisHygiene HypothesisSystemic-chronic (low grade) Inflammation
• Back to the NEO-LAMARCKIAN PARADIGM ENVIRONMENT � Epigenetic Changes
���� Fetal Programming
Fluid (Epi)genome
1
2
3
HSPs
Activation
HSPs/petidesDanger Theory
(Auto)Immunity
Autoinflammation
ROS
The Epidemic Revolution
Of the XX century
Environment
mRNAs
fluid (epi)genome
developmental
plasticity
Pharmaceuticals,
pesticides,
air pollutants,
industrial chemicals,
heavy metals,
hormones,
nutrition,
and behavior
can change
gene expression
through a broad array of
gene regulatory
mechanisms..
highlighting the potential
role for altered
DNA methylation
in fetal origins
of adult disease
and inheritance
of acquired
genetic changes
Les origines embryo-fœtales du cancer : cancérogénèse
transplacentaire et transgénérationnelle
Ernesto Burgio
ISDE Italy
Scientific Committee
DOHAD
X rays
Metals
Viruses
CEM
Xenobiotics
EDCs
Environment���� Dynamic (Epi)-Genome
���� Neolamarckian Paradigm
2
3
1
1
2
3
4
4
4
Incidenza di tumori (anno/100.000) Incidenza di tumori (anno/100.000)
Poumon 80
60
40
20
4
2
1,5
Sein
Colon
EstomacLymphôme
10
LeucLeucéémie mie
lymphatilymphati
quequeLeucLeucéémie mie lymphatiquelymphatique
Encéphale
Lymphômes
Neuroblastoma-Retinoblastoma1
<1 Tessuti molli, rene (Wilms), gonadi
5
ReinCerveau
In genere si afferma che i
tumori infantili sono una
patologia rara. Bisogna però
intendersi. E’ opportuno
ricordare come, in termini
assoluti, di cancro si ammali
un bambino su 5-600 e che
oltre 13 mila bambini si
ammalano ogni anno di
cancro nei soli USA; come
nonostante i significativi
miglioramenti prognostici
degli ultimi decenni il cancro
rappresenti la prima
causa di morte per malattia
In età pediatrica ; come
anche in questa fascia
d’età, da 40 anni a questa
parte, si assista in tutto il
mondo a un incremento
significativo e continuo
della patologia tumorale
Bleyer A, O’Leary M, Barr R, Ries LA,
editors. Cancer epidemiology in older
adolescents and young adults 15-29
ears of age, including SEER incidence
and survival: 1975-2000. NIH Pub. No.
06-5767. Bethesda (MD): National
Cancer Institute; 2006. Jemal A, Siegel
R, Ward E, et al. Cancer statistics,
2008. CA Cancer J Clin 2008;58:71 – 6.
Alberto Tommasini,
Laboratorio Immunologia
Pediatrica, IRCCS
Burlo Garofolo
Le CA est le facteur principal de décès
par maladie dans l'enfance et l’on assiste à une augmentation
importante et constante des tumeurs
dans le monde pour ce groupe d'age
…. une accumulation des lésions oxydantes au niveau du ADN
…. une amélioration de la qualité du diagnostic
L’on oublie trop souvent que l’augmentation du nombre
de cancers touche toutes les tranches d’âge…... et, surtout, qu’il y a une augmentation très importante des cancers chez les enfants.
INCIDENZA DI INCIDENZA DI NEOPLASIE in INFANZIA E ADOLESCENZANEOPLASIE in INFANZIA E ADOLESCENZA IN IN EUROPA (anni 1970EUROPA (anni 1970--1999)1999)
mother
latency
Un primo report del progetto, pubblicato su Lancet nel 2004, evidenziò un incremento
annuo dell’1-1,5 % per tutte le neoplasie (con aumenti più marcati per linfomi, sarcomi dei tessuti molli, tumori delle cellule germinali e del sistema nervoso).
.. come risulta chiaramente dal recente progetto ACCIS (Automated Childhood Cancer Information System) - un ampio monitoraggio condotto da una
squadra di epidemiologi IARC su 63 registri oncologici di 19 paesi europei, per un totale di oltre 130 mila tumori di tutti i tipi (113 mila pediatrici e 18 mila di età adolescenziale)
Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, CoeberghJW, Lacour B, Parkin M. Geographical patterns and time trends
of cancer incidence and survival among children and
adolescents in Europe since the 1970s (the ACCISproject): an
epidemiological study. Lancet. 2004 Dec 11-17;364(9451):2097-105
http://www-dep.iarc.fr/accis.htm
Miglioramenti diagnostici !?
Ucraina, Bielorussia ?!
I dati del progetto ACCIS pubblicati su Lancet furono ben presto confermati dalla successiva rassegna (la più completa a tutt’oggi) dei dati emersi dallo studio, che costituisce ormai il più ampio database europeo sul cancro, pubblicata due anni dopo, in un numero monografico, dall’European Journal of Cancer: 18 articoli in tutto, che contengono l’analisi dettagliata dei dati sui tassi di incidenza e sui trends di prevalenza
e sopravvivenza…
E’ sufficiente sottolineare come in 20 anni (tra il 1978 e il 1997) si sia assistito, in Europa, ad un incremento
medio generale di neoplasie ad insorgenza in età
pediatrica dell’1,1% annuo
(ma del 2% annuo circa nel
primo anno
di vità e dell’1,3% in età
adolescenziale).
Increased risk was obtained for both
cellular and cordless phones, highest in the
group with >10 years latency period.
… se possibile ancora peggiori sono le notizie per i bambini italiani. I recenti dati del Rapporto AIRTUM
(Associazione Italiana Registri
Tumori) 2008 sui tumori infantili , dimostrano infatti come i dati di
incidenza e gli andamenti
temporali siano in Italia peggiori
che negli altri paesi europei e negli
USA (il che, sia detto per inciso, priva di qualsiasi valore l’ipotetico fattore “miglioramento diagnostico”).
Rapporto AIRTUM 2008 - Tumori infantili.
Incidenza, sopravvivenza,
andamenti temporali Epidemiologia & Prevenzione 2008; 32(3) Suppl 2: 1-112
• L’incremento più consistente riguarda i bimbi sotto l’anno di età (+ 3,2%), seguiti da quelli tra 10 e 14 anni (+2,4%), mentre è simile negli altri due gruppi (+1,6% nella fascia di età1-4 anni, +1,8% tra i 5 e i 9 anni).
• I tre tumori più frequenti nei bambini sono tutti in aumento:• leucemie + 1,6% annuo; linfomi + 4,6% annuo; tumori del sistema
nervoso centrale + 2,0% annuo• Un fenomeno simile è stato osservato in diversi Paesi,
• ma… in Italia il cambiamento percentuale annuo risulta più alto che in Europa:per l’insieme di tutti i tumori (+2% vs 1,1%)per le leucemie (+1,6% vs 0,6%)per i tumori del sistema nervoso centrale (+2% vs 1,7%) per i linfomi (+4,6% vs 0,9%).
• (Negli Stati Uniti il tasso per tutti i tumori non è aumentato in modo significativo (+0,6%), l’incremento delle leucemie è dello 0,4% e i tumori del SNC sono stabili (-0,1%))
On ne peut pas expliquer tout cela par l’accumulation des lésions oxydantes comme chez les sujets plus âgés. De plus, cette augmentation touche tout particulièrement les enfants dans leur première
année de vie (le taux de l'incidence a augmenté de >2% dans le première année; de 1,3% pendant l'adolescence)
Prenatal origin of certain childhood leukaemias
Le processus de cancérogénèse est généralement très long…
Donc, le véritable problème est l’exposition des parents (gamètes) aux facteurs de risque.
Le processus de cancérogénèse a débuté bien avant la naissance de l’enfant *.
On peut aussi dire que la phase d’initiation *
tumorale (1° Hit de Knudson) survient lors
du développement ontogénétique du fœtus
1
Trasmissione transgenerazionale 2
Alterazione memoria epigenetica-gameti
3
Il n’y a que deux possibilités:1) l’exposition du fœtus à des agents physiques (X-rays), chimiques ou biologiques (virus)
(transmis par transmission trans-placentaire ) qui puissent endamager directement le foetus 2) la transmission trans-generationelle d’une ou plusieurs lesions genètiques ou epi-génetiques
Cheryl Lyn Walker UT MD Anderson Cancer Center
Ce sont des quantités minimales de molécules (epi)génotoxiques, induisant des transformations continuelles de la chromatine, qui constituent le véritable problème. C’est un processus très lent pouvant démarrer lors des premières
étapes du développement fœtal. Et, même dans les gamètes. Si les tissus du fœtus sont mal programmés au début et s’il y a un stress épigénétique
progressif, les mutations génétiques et chromosomiques vont davantage se produire
Herewe are
Cancro Malattia genetica ? Sì o piuttosto: dapprima epi-
genetica e infine genetica come praticamente tutte le
malattie croniche (flogistico-degenerative)…
Si le cancer est le produit de plusieurs
mutations stocastiques (SMT)…
.. pourqoui faudrait’il se produire cette
augmentation progressive
d’accidents génetiques ?!
Tout ça paraît raisonable… Mais le veritable problème est:
pourquoi cette augmentation continuelle et progressive ?!
Alterations in three types of genes are responsible for tumorigenesis: oncogenes, tumor-suppressor genes and stability genes
Unlike diseases such as cystic fibrosis or muscular dystrophy, wherein mutations in one gene can cause disease, no single gene defect'causes' cancer. Mammalian cells have multiple safeguards to protect them
against the potentially lethal effects of cancer gene mutations, and only when several genes are defective does an invasive cancer develop
The revolution in cancer research can be summed up
in a single sentence: cancer is, in essence, a genetic disease
STEP 1 La delezione o la mutazione del gene APC in 5q21 è sufficiente perché il colon venga tappezzato di polipi adenomatosi; Il DNA
diventa ipometilato ⇒⇒⇒⇒nuove mutazioni
STEP 2 Le mutazioni di K-RAS (K-RAS1 in 6p12-11 e K-RAS2
in 12p12) sono spesso coinvolte nella progressione degli adenomi da precoci a intermedi.
STEP 3 Il presunto gene soppressore dei tumori coinvolto è DCC (“Deleted in Colon Cancer” → perdita di eterozigosi in 18q21.3).
STEP 4 mutazioni gene oncosoppressore
p53 (localizzato in 17p12-13).
STEP 5 MutazionI del gene NM23-H1 (17q22)
rendono il CA altamente invasivo/metastatico..
Darwinian Evolution Through Random Mutation
BC Genetics
BRCA1
BRCA2
CHEK2
HMMR
TP53
Somaticmutations
that can lead to breast cancer have been experimentally linked to estrogen exposure
… HMMR gene, encoding a centrosome subunit, interacts with the
well-known breast cancer gene BRCA1 ...
In contrast to the somatic mutation theory, the TOFT postulates that: (i) carcinogenesis represents a problem of tissue organization,
(ii) proliferation is the default state of all cells, and (iii) carcinogenesis is a reversible phenomenon
DOHAD
Le cancer est bien plutôt un processus d’évolution raté, qui à ses originesdans les premiéres phases du dévelopment fœtal (fetal programming)
Tumors are complex tissues in which mutant cancer cells
have conscripted and subverted normal cell types
to serve as active collaborators in their neoplastic agenda
… un processus d’évolution imparfaite qui produit un petit organe doué d’une vascularisation propre, d’un stroma (un tissu de soutien), d’un veritable système immunitaire constitué de macrophages activés(liens entre inflammation et cancer).
1) TAMs secrete a variety of proteases to breakdown the basement membrane
2) macrophages cooperate with tumor cells to induce
a vascular supply
3) Macrophagesin hypoxic areassecrete factors
that suppress
the antitumor
functions of immune effectors
4)���� metastasis: a subpopulation of TAMs associated with tumor vesselssecretes factors like EGF to guide tumor cells in the stroma toward blood vessels
Our findingssuggest thatmicrovascular
endothelial cells in
B-cell lymphomas
are in parttumor-related
…. les mêmes mutations génétiques et
chromosomiques, d’ailleurs toujours
assez complexes (aneuploïdie,
translocations, mutations des oncogènes et des gènes suppresseurs) se trouvent dans plusieurs tissus intéressés
Istituto Superiore di Sanità 3 11 08 - Giornata in ricordo di Lorenzo Tomatis
CANCRO:Il paradigma epigenetico
Ernesto Burgio
Comitato ScientificoISDE Italia
Cancerogenesi ambientaleIl contributo della scienza medica alla
risoluzione dei problemi di inquinamento ambientale
1
2
3
2
Ce qui se passe, au début, ce n’est que des modifications épigénétiques produites par un stress prolongé du tissu et du génôme :
une hypométhylation de séquence d’ADN et une hypeméthylation spécifique des promoteurs des gènes suppresseurs...
We have now analyzed a series of promoter
hypermethylation changes in 12 genes.. each rigorously characterized for association with abnormal gene silencing in cancer…
Our results provide an unusual view
of the pervasiveness of DNA alterations, in
this case an epigenetic change, in human
cancer and a powerful set of markers to
outline the disruption of critical pathways in
tumorigenesis
Conclusions
Our data demonstrate, using a candidate gene approach, that promoter hypermethylation
of 12 genes involving important cellular pathways
in tumorigenesis is a feature of each of 15 major
human tumor types studied. Moreover, although many tumors share this change for a given gene, unique profiles do exist
for the tumor types.
In the present study, we demonstrate how one single type of DNA alteration,
aberrant methylation of gene
promoters, can point to pathways
disrupted in every type of cancer and can provide markers
for sensitive detection of virtually
all tumor types.
ONE OR MORE OF THE GENES STUDIED IS HYPERMETHYLATED IN EVERY TUMOR TYPE. HOWEVER, THE PROFILE
OF PROMOTER HYPERMETHYLATION FOR THE GENES DIFFERS FOR EACH CANCER TYPE, PROVIDING A TUMOR-
TYPE AND GENE-SPECIFIC PROFILE. SOME GENES, SUCH AS THE CELL CYCLE INHIBITOR P16INK4A, ARE
HYPERMETHYLATED ACROSS MANY TUMOR TYPES INCLUDING COLORECTAL, LUNG, AND BREAST CARCINOMAS
Other changes, such as for the DNA repair gene MGMT and DAPK, also have a wide
distribution
These mechanisms may be activated in cells by
continuing proliferative
and survival signaling
in a sustained stress
environment (SSE)…
longterm exposure
to this signaling epigenetically
reprograms the genome
of some cells..
.. finalement, ce processus n’est pas fondamentalement de nature
stochastique… mais réactif-adaptatif
Mutations match epigenetic tags
Selection of Mutants follows !
Many epigenetic tags are Induced in stem cells duringfetal programming
tags = marcature
.. cells with the properties of stem cells are integral to
the development and perpetuation of several forms of human cancer
Stem cells have three distinctive properties: selfrenewal (i.e., at cell division, one or both daughter cells retain the same biologic properties as the parent cell), the capability to develop into
multiple lineages, and the potential to proliferate
extensively..
Aberrantly increased
self-renewal, in combination with the intrinsic growth
potential of stem cells, may account for much of what is considered a malignant phenotype..
Julius Cohnheim.. in 1867 proposed that tumors derived not from normal adult tissues, but from “embryonal cell rests”,
Model for carcinogenesis resulting from persistence of a state of injury repair.
1
2autonomous Wnt or Hh signalling
Further genetic or epigenetic change in such a persistently activated stem cell might produce a cancer
stem cell.. aggressively propagating a CA
3
3
http://science.nasa.gov/headlines/y2006/images/telomeres/caps_med.jpg
Telomere_caps.gif� (600 × 471 pixels, file size: 61 KB, MIME type: image/gif)
Nota EVO DEVO:
l’attivazione tanto dei C-ONC.. quanto della telomerasi rappresenta il ritorno a un assetto proprio del periodo embrio-fetale.. allorché telomerasi e “proto-oncogeni (geni importanti nelle pathways di proliferazione e differenziazione cellulare) sono particolarmente attivi.
Potter demonstrated the presence of embryonal biochemical markers in mouse and human hepatomasleading him to conclude that hepatoma cells are arrested in their development and this differentiation
block may contribute to tumor formation: “oncogeny is blocked ontogeny”
The hypothesis developed in this article is that chronic
stressors can induce adaptive
rearrangements
of the genome which might result in new proteins helping
survival in a harmful
environment or trigger the
development of a completely
‘‘new’’ organ – the cancer –which also survives – even though its survival is at the
expenses of its host.
Stressors, which cannot be compensated for with the usual cell possibilities might arouse evolutionary mechanisms
intended to create new protein variants. One of these is the activation of transposable elements which leads to a reformatting of the genome.
1
2
1
3
Transposable elements can be seen as a natural genetic engineering system
capable of acting not just on one location at a time but on the genome as a whole ..This dynamic view of the genome has been illustrated most impressively by Shapiro who stated that the genome is composed of modular units arranged
in a “Lego-like” manner that can be altered under certain circumstances
THE CAUSE OF CHROMOSOMAL
ABNORMALITIES REMAINS POORLY UNDERSTOOD.
STUDIES OF VARIOUS TYPES OF LEUKEMIA
HAVE SHOWN THAT CERTAIN
ENVIRONMENTAL AND
OCCUPATIONAL
EXPOSURES AND THERAPY WITH
CYTOTOXIC DRUGS CAN INDUCE
CHROMOSOMAL ABERRATIONS. FOR EXAMPLE, CASES OF MYELODYSPLASTIC
SYNDROME OR AML
THAT ARISE AFTER TREATMENT WITH ALKYLATING AGENTS ARE FREQUENTLY
ASSOCIATED WITHUNBALANCED ABNORMALITIES,
PRIMARILY DELETION OR LOSS OF
CHROMOSOME 5 OR 7 (OR BOTH),
…WHEREAS THERAPY WITH TOPOISOMERASE II INHIBITORS IS
TYPICALLY ASSOCIATED WITH BALANCED
ABNORMALITIES, MOST COMMONLY TRANSLOCATIONS
INVOLVING THE MLL GENE ON
CHROMOSOME
BAND 11Q23.1
Are TRANSLOCATIONS chromosomal aberrations or reactive/positive rearrangements ??
THE FIRST EVIDENCE THAT CANCER ARISES FROM SOMATIC GENETIC
ALTERATIONS CAME FROM STUDIES OF BURKITT'S LYMPHOMA, IN WHICH
ONE OF THREE DIFFERENT
TRANSLOCATIONS JUXTAPOSES AN ONCOGENE, MYC, ON CHROMOSOME
8q24
TO ONE OF THE LOCI FOR
IMMUNOGLOBULIN GENES. CHROMOSOMES 14q, 22q, AND 2q
— THE TRANSLOCATION PARTNERS —
EACH CARRIES ENHANCER
ELEMENTS IN THE
IMMUNOGLOBULIN LOCI,
THEREBY ACTIVATING THE
JUXTAPOSED C-MYC
ONCOGENE
Croce CM. Oncogenes and Cancer. N Engl J Med 2008;358:502-11.
++
+
Are the antibody gene loci
quite“dangerous places” for
proto-oncogenes to take up residence ?
IN THE CANCEROUS B CELLS, THE PORTION OF CHROMOSOME 18 CONTAINING THE BCL-2 LOCUS HAS UNDERGONE A RECIPROCAL TRANSLOCATION WITH THE PORTION OF CHROMOSOME 14 CONTAINING THE ANTIBODY HEAVY CHAIN
LOCUS. THIS T(14;18) TRANSLOCATION PLACES THE BCL-2 GENE CLOSE TO THE HEAVY CHAIN GENE ENHANCER.
H Chain-enhancer is very active in B cells...
Figure 1. Agricultural exposure drives a dramatic increase of t(14;18)+ clones in blood
Agopian et al. Journal of Experimental Medicine 2009:206:1473-
1483
© 2009 Agopian et.al.
Evolution of t(14;18) frequency in PBMCsfrom control and exposed populations
For each individual, independent BCL2/JH
clones are pictured in distinct shades
Clonality analysis
Figure 2. t(14;18)+ cells in HI are actively transcribing BCL2 from the translocated allele
Agopian et al. Journal of Experimental Medicine 2009:206:1473-
1483
© 2009 Agopian et.al.
... il gene bcl 2 è espresso nella zona follicolare .. ha un ruolo fisiologico
importante: blocca
l’apoptosi nei cloni linfocitari destinati a diventare cellule di
memoria. ma può essere
attivato anche in cellule della corticale mediante diversi meccanismi: il principale è la traslocazione t14:18.. che può porre il gene sotto il controllo del promoter
delle Ig o del TCR
in altri casi di linfoma follicolare il gene espresso in modo
eccessivo (���� anti-apoptosi) è il Bcl 6..
Exposure to NHL-associated carcinogens,such as dioxin or pesticides, may cause
expansion of t(14;18)-positive clones.
Translocations typical of myeloid leukaemia, probably due to maternal exposure to some toxic compound, were shown to be present at birth in children who developed the disease years later (while not sufficient per se to cause the disease, they might
increase the risk for leukaemia by inducing genomic instability) Tomatis L. Identification of carcinogenic agents and primary
prevention of cancer. Ann N Y Acad Sci. 2006 Sep;1076:1-14
Translocation involving band
11q23 in AML may occur as a result of a deletion or trans-
locations
with a number of otherchromosomes and is usuallyassociatedwith M4 or M5 and a poor prognosis
Nakamura T, Mori T, Tada S, et al. ALL-1 is a histone methyltransferase that
assembles a supercomplex of proteins involved in transcriptional regulation
Cell 2002;10:1119-1128.
IN ALL AND AML, THE ALL1
(ALSO NAMED MLL) GENE CAN FUSE WITH 1 OF MORE
THAN 50 GENES. ALL1 IS
PART OF A MULTIPROTEIN
COMPLEX. MOST OF THE PROTEINS IN THE COMPLEX ARE COMPONENTS OF TRANSCRIPTION
COMPLEXES; OTHERS ARE INVOLVED IN HISTONE
METHYLATION AND RNA
PROCESSING. THE ENTIRE COMPLEX REMODELS,
ACETYLATES, DEACETYLATES,
AND METHYLATES
NUCLEOSOMES ANDHISTONES. THE FUSION OF
ALL1 WITH 1 OF these 50
PROTEINS RESULTS IN THE FORMATION OF THE
CHIMERIC PROTEINS THAT UNDERLIE ALL AND AML.
ALL1 (MLL) FUSION PROTEINS
DEREGULATE HOMEOBOX
GENES (WHICH ENCODE TRANSCRIPTIONS FACTORS)..AND MICRORNA
GENES SUCH AS MIR191.
AF9 Location 9p22
MLL * Location 11q23
*
Several lines of evidence point to a mishap in non-homologous end joining of double strand breaks as the most likely reason for 11q23 translocations.
The first and most striking property of MLL fusion proteins is their incredible diversity. Mbeen found in 73 different translocations and 54 partner genes have been cloned (http://atlasgeneticsoncology.org/Genes/MLL.html).
1
2
3
Diethylstilbestrol
God does not play dice È la celebre affermazione che suggella l'acceso dibattito tra Einstein e i sostenitori di una certa interpretazione della fisica quantistica…
God is subtle but not malicious
I believe in Spinoza's God who reveals himself in the orderly harmony of what exists
“A clever man solves a problem, a wise man avoids it”
‘‘We can’t solve problems by using the same kind of thinking we used when we created them’’