Douglas Hanahan, Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue...

Douglas Hanahan , Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue 5 2011 646 - 674

2000

Douglas Hanahan , Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue 5 2011 646 - 674

2011

La cellula tumorale acquisisce queste caratteristiche

mediante

• mutazioni

• alterazioni epigenetiche

in un processo mutagenico multi-step

Mutazioni

Mutazioni puntiformi

Brevi inserzioni/delezioni

CNA (copy number abnormalities): gain, loss, amplificazioni

Aberrazioni cromosomiche bilanciate: traslocazioni, inversioni

Mutazioni di oncogeni:gain-of-function, amplificazione, e/o

iperespressione

Mutazioni di oncosoppressori: loss-of-function, delezione, e/o

silenziamento epigenetico

Walther A. et al., Nature Review Cancer 2009

Two forms of genetic instability are described in CRC:•Microsatellite Instability (MIN): characterized by a deficiency of the mismatch repair system that leads to slippage in microsatellites

Chromosomal Instability (CIN): comprise 85% cases and it is characterized by aneuploidy.

Teoria della selezione clonale

Eterogeneità clonale

Più cloni (derivati da una unica cellula di origine del tumore, ma caratterizzati da eterogeneità genetica) possono coesistere contemporaneamente nella massa tumorale

TUMOR

MUCOSA

Colorectal Cancer

Intratumor heterogeneity by double-sampling data

Mean of correlation coefficient in 18 double sampling pairs

Within pairs 0.75

Between pairs 0.19

0.8

Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, USA.

The Cancer Genome Atlas (TCGA) project was started in 2006 with the goal of collecting and profiling over 10,000 tumor samples from at least 20 tumor types. Half of these studies have been completed so far. The globally coordinated International Cancer Genome Consortium (ICGC), of which TCGA is a member, will add thousands more samples and additional tumor types

The cancer genome hyperbola

The distribution of SFEs in tumors indicates that the number of copy number alterations in a sample (x axis) is approximately anticorrelated with the number of somatic mutations in a sample (y axis).

We separated cases (84%) with a mutation rate of < 8.24 per 106 and those with mutation rates of >12 per 106 (median number of total mutations 728), which we designated as hypermutated

Mutazioni “driver” che portano a variazioni funzionali importanti per il fenotipo tumorale

Mutazioni “passenger” : neutrali, dovute all’instabilità del genoma delle celluletumorali

Overall, we identified 32 somatic recurrently mutated genes in the hypermutated and nonhypermutated cancers. After removal of non-expressed genes, there were 15 and 17 in the hypermutated and non-hypermutated cancers, respectively

Leucemia Mieloide Cronica (LMC)

Dimostrabile nel 95% dei pazienti affetti da LMC

Il cromosoma Philadelphia: l’anomalia citogenetica responsabile della malattia

1 2 3 4 5

6 7 8 10 119 12

13 14 15 16 17 18

19 20 21 22 x Y

Janet Davison Rowley (born April 5, 1925) the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers.

Formazione del cromosoma Philadelphia (Ph)La traslocazione t (9;22)

Proteina di fusione con attività

tirosina-chinasica leucemogenica

22

bcr

abl

9

Ph

Bcr-Abl

9+Cromosoma

Cromosoma

Cromosoma

Cromosoma

ABL ABL

Tyr Tyr

BCR BCR

Autophosphorylation by dimerization

P

Phosphorylation of substrates

The constitutive TK activity of BCR-ABL isthe primary factor causing the expansion

of the Ph-positive clone

NUCLEUS

Cell Cycle

BCR/ABL

Paxillin

F-actin

2. Changes in adhesion to stromal layer

General overview

3- Inhibition of

apoptosis

PIK3 -AKT

RAS

JAK-STAT

1. Activation of proliferation

MYC

Glivec (imatinib) Inibitore selettivo della tirosina-chinasi Bcr-AblMeccanismo d’azione

Goldman JM, Milo JV, NEJM 2001, 344:1084-1086

ProteinaBcr-Abl

Substrato

Substrato

Effettore

ATP

P

Y

Y

PP

P

ProteinaBcr-Abl

Substrato

Substrato

Effettore

GLIVEC

Y

Y

Y = TirosinaP = Fosfato

LEUCEMIA PROMIELOCITICA ACUTA

Role of transcription factors involved in promyelocytic acute leukemia

Apoptosis Terminal myeloid differentiation

Oncogenesis

(via p53 and/or Rb)