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INVAZIA LOCALA SI
METASTAZAREA
Sumar
Metastazarea definiie
Fenotipul malign
Cretere necontrolat
Reducerea
sensibilitii la
apoptoz
Independena fa
de semnalele
inhibitorii
Cancer
Dezvoltarea i
meninerea unei
vascularizaii tumorale
(angiogenez)
Invazia i
metastazarea
Potenial nelimitat de cretere
Adapted from Hanahan, et al. Cell 2000
ESENIALE:
1. Invazia i motilitatea
2. Intravazarea i supravieuirea n circulaie
3. Blocarea (arestul) n circulaie i extravazarea
4. Creterea n organe la distan
Modificri genice
Modificri epigenetice - modificarea expresei genice prin:
metilare
(acetilare sau fosforilare)
Invazia local
interaciuni:
laminina
fibronectina,
proteoglicani
vitronectin, colagen IV,
caderine E, P i N
Pas II Distrucia (liza) membranei bazale
- metaloproteinaze ( MMP, matrixine) syntesis: MMP
- seric proteinase
- stromelizina
- aspartases- Catepsina D
Pas III - Migrarea
- Factori de motilitate -AMF
Aderarea
After losing attachment with neighbors, malignant cells interact with the ECM in order to
degrade, remodel, attach, and invade through this matrix.
Molecule de adeziune:
integrins
laminin receptors
caderine E ( epithelial), P (placentar), and N ( neural)
CD 44
immunoglobulins
Invasion starts with alterations in cell adhesion.
In many cases this entails the loss of E-cadherin, which is the prototype member of the
cadherin family (cell-cell adhesion molecules)
Integrine signaling works together with growth factor receptors by allowing cells to
sense ECM attachment and polarity.
Chemothaxine
Autotaxine
Cytoskeleton modification
Aplicaii clinice:
semntura metastazrii (identificarea unui set de gene de metastazare)
rol prognostic + decizii terapeutice;
ex., MammaPrint test i Oncotype Dx pentru cancerul de sn
terapii intite;
ex., ARQ 197 inhib gena MET de iniiere a metastazrii
18
Celule canceroase
(clone cu diferite mutaii
oncogene +GST)
Celule imune
inflamatorii
Celule canceroase
invazive
19
Tumorile prezint o
varietate de celule ale
sistemului imun care
contribuie la formarea
stromei esutului malign.
Tumorile posed celule
infiltrante aparinnd att
sistemului imun nativ ct i
celui de adaptare precum
MDSC, macrofage, DC,
mastocite, eosinofile,
neutrofile, celule NK i
limfocite. Aceste celule
formeaz o reea reglatorie
complex care stimuleaz
proliferarea tumoral si
creeaz un mediu permisiv
pentru eludarea
21
Cancer mamar
ANGIOGENEZA
PremalignantMalignant
tumor
tumor
Tumor
growth
Vascular
MicroMetastatic
invasion metastases
growth
Angiogenic
switch
Enzime de liz (metaloproteinaze sau MMP) sunt produse local i dizolv esuturile din
faa mugurilor vasculari pe care acetia se acomodeaz. Pe msur ce vasele se
extind, esutul este remodelat n jurul vaselor.
Celulele endoteliale sub form de muguri vasculari sunt remodelate pentru a forma
un tub vascular de snge.
Tubii vasculari individuali se conecteaz la ansele vasculare prin care ncepe s circule
sngele.
n final, vasele de snge nou-formate sunt stabilizate de celulele musculare specializate
( celule musculare netede, pericitele) care ofer un suport structural. Curgerea sanguin prin
vase ncepe!
Angiogeneza tumoral
Hypoxia
Under hypoxic conditions, the hypoxia inducible factor (HIF) transcriptional regulatory
proteins HIF-1 and HIF-2 are no longer hydroxylated by a family of oxygenregulated proline hydroxylases (PHD1-3), which disables the binding of the von
Hippel-Lindau (VHL) tumor suppressor protein.
By adapting to the selective pressure of hypoxia, tumor cells acquire the ability to
inducing angiogenesis
Both expression of HIF-1 levels and tumor hypoxia predict for worse overall survival
and a higher risk for metastasis
PROANGIOGENIC
ANTIANGIOGENIC
______________________________________________________________
VEGF-A, VEGF-B, VEGF-C
Trombospodin (TSP1)
PDGF
Angiogstatin
FGF (FDF2, FGF1)
Arrestin (fragment de colagen IV)
Angiopoietin (ANG1, ANG2)
Canstatin (fragment de colagen IV)
IL 8
Tissue inhibitors of
TNF-
metalloproteinases (TIMP)
IFN-, IFN-
Acid retinoic
Fibronectin
Endostatin
Hypoxia
EGF
PDGF
IGF-1
IL-8
bFGF
VEGF release
COX-2
Nitric oxide
Oncogenes
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
Survival
Proliferation
Migration
ANGIOGENESIS
Permeability
Antibodies inhibiting
VEGF receptors
Anti-VEGF antibodies
(e.g. Avastin)
VEGF
VEGFR-2
Soluble VEGF
receptors
Agenii anti-angiogenici
EARLY EFFECTS
Regression
Decreases
tumour size
Normalisation
Improves
delivery of
chemotherapy
CONTINUED EFFECTS
Inhibition
Suppresses new
vessel growth
Cile de diseminare
Circulaia sangvin
Extravazarea
Cancer cells can mimic leukocytes and bind to endothelial E- and P-selectins.
Dormana
Many cancers such as breast and prostate will not give rise to metastasis until
10 or even 20 years after eradication of the primary tumor.
Somatic evolution of cancer during growth at the primary site results in the
selection of tumorigenic functions (light blue) that are fulfilled by
tumorigenic genes.
Metastasis-specific functions are considered those that act on tumor cells
after intravasation and enable them to home to, penetrate, or colonize
distant organs (orange). Genes that provide such functionality are
Mrimea tumorii.
Markeri histologici:
Metastazarea- concluzii
Prevenia cancerelor
Prevenia primar
Medical education
Legislation
Fiscal measures
Temporal and spatial restrictions
Advertising interdictions
Preventie secundar
Prevenie teriar
SCREENING
Sexual behavior is probably largely a surrogate for the risk of exposure to HPV.
Colposcopy
Pap Smear
Rolul depistrii precoce este bine stabilit n cancerul de col uterin, mortalitatea prin
acest tip de cancer scznd cu circa 70% n ultimii 30 de ani n rile cu programe
de screening eficiente.
Screening-ul cancerului de col uterin const din examinarea de rutin a frotiului
citologic cervico-vaginal Babe-Papanicolau (Pap-test).
Persoanele cu anumii factori de risc (infecie cu HIV, imunosupresie, expunerea in
utero la dietilstilbestrol, tratament prealabil pentru o displazie neoplazie
intraepitelial cervical [CIN] de grad 2/3, sau pentru cancer cervical) trebuie
screenate la intervale mai reduse. Vrsta maxim pentru screening-ul cancerului de
col uterin nu este clar definit.
Aspectele citologice (normal, displazie/CIN, malign) sunt clasificate actual dup
sistemul Bethesda. Dac rezultatele unui test Papanicolau sunt pozitive, se va
recomanda colposcopia, eventual cu utilizare de acid acetic glacial. Leziunile
epiteliului cervical (displaziile) cu grad redus de risc vor fi urmrite periodic, pn la
remisiune/progresie, iar cele cu risc crescut trebuie tratate prin proceduri locoregionale ablative/excizionale.
Cea mai important problem n depistarea precoce a cancerelor de col uterin
rmne aceea legat de atragerea unui numr ct mai mare de femei n aciunea
de screening, mai cu seam din categoria celor cu factori de risc crescut
Breast Cancer
* The indications for genetic testing in breast cancer and in other cancers are in rapid
evolution as the true risks become better defined and as prevention (e.g., tamoxifen)
and early detection (e.g., mammography, MRI) strategies mature.
Cancerul mamar
Mijloace de screening
Mammography
Breast self
examination
(BSE)
MRI
Clinical breast
examination
(CBE)
Ultrasound
Metode de screening
Mammography
Relative breast cancer-specific mortality decreased by 15%
Absolute mortality benefit for annual screening starting at age 40 = 4 per 10,000
at 10.7 years, vs. 5 per 1,000 for women screened annually starting at age 50
Absolute benefit approximately 1% overall, but depends on inherent breast
cancer risk, which rises with age
CBE
BC mortality similar for women aged 50-59 undergoing screening CBEs with or
without mammograms.
BSE
No difference in breast cancer mortality seen after 10 years;
enrolled, however, were younger than 40 years.
http://www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional#Section_175
40% of women
Screening
Ritmul de screening
Normal risk
Increased risk
Cancerul colo-rectal
FOBT-Hemocult
Colonoscopia
Dar
Rectosigmoidoscopia flexibil
Nu necesit sedare
Mai ieftin
Colonoscopia normal
Capsule Endoscopy
Recomandari de screening
Prostate Cancer
MELANOMA
Ultraviolet light exposure
(intermittent)
Genetic
Melanocortin receptor
variants
Atypical or dysplastic nevi
Dysplastic nevus syndrome
Phenotypic
Less cutaneous
pigmentation
Regula ABCDE
A- Asimetrie
B- Border - margini
C- Culoare
D- Diametru
E- Elevation - supradenivelare
Malignant Melanoma
Sensitivity
77-96%
64%
86%
17-58%
42-72%
94%
10-12%
12%
94%
7%
N/A
N/A
86-100%
46-89%
5-40%
81%
N/A
81-98%
N/A
4-27%
N/A
8-13%