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BASIC OVERVIEW OF CANCER

Hallmark of cancer
Multihit of carsinogenesis: Mutation-epigenetic
Tumor niche : Tumor microenvironment----- inflamation
Oncogenesis: Virus-Free radical-oksidative stress
Oncogen-suppresor gene-apoptosis
Aging-Senescence-cell cycle disruption
Cancer stem-cell

Dr H Agung Putra.Msi. Med


Reference:

Useful refs
Harvey Lodish: Molecular Cell Biology
Thomas D.Pollard: Cell Biology

Robert Weinberg: Biology of Cancer

Agung putra: Molekuler Onkogenesis

Agung putra Basic science: Tumorigenesis (in-process)

Useful weblinks:
http://mydsn.org/docs-tools/BIO240/ Chapter-11.ppt
http://www.hugo-international.org/resources/

Isik_Yulug_Molecular_Basis_of_cancer.ppt
Nobel Prize for Medicine
Genetic Basis of cancer

Prof Dr Harold E. Varmus:


Director of the US. NCI ( National Cancer Institute)
Recognition of the widespread applicability
of the Moleculers concept will increasingly
affect the development of new means to
treat human cancer.

Robert A. Weinberg
The biology of tumors can no longer
be understood simply by enumerating
the traits of the cancer cells
Introduction
Diversity of neoplastic diseases (Hanahan and
Weinberg, 2000).
Normal cells evolve progressively to a

neoplastic state
Acquire a succession of Hallmark capabilities

Tumor Pathogenesis: Multistep process

Niche tumor: tumor microenvironment

Contribute for to tumorigenesis.


Complexities of Neoplastic

The hallmarks constitute an organizing


principle for rationalizing the complexities
of neoplastic disease
Tumor as Complex Tissues

Composed of multiple distinct cell types


The recruited normal cells as active participants in
tumorigenesis rather than passive bystanders
Stromal cell
To form Tumor-associated stroma : TAS
Contribute to the development and expression of
certain hallmark capabilities.
Macrophage
To form Tumor-associated macrophage: TAM
The Basic of Cancer
Genome instability
Underlying hallmarks of cancer
Mutation: Multistep process
To acquire the traits of hallmarks of cancer

To become tumorigenic

Ultimately malignant

Genetic diversity
Expedites the acquisition of hallmarks

Inflammation
Foster multiple hallmark functions
The Hallmarks of Cancer

Comprise 6 biological capabilities acquired during


the multistep development of human tumors.
1. Sustaining proliferative signaling,
2. Evading growth suppressors,
3. Resisting cell death,
4. Enabling replicative immortality,
5. Inducing angiogenesis, and
6. Activating invasion and metastasis.
Deregulating Signals
Cancer cells deregulate these signals are to become masters of
their own destinies.
Enabling signals : Growth factors
Binding to cell-surface receptors (Intracellular Tyrosine
kinase)
Emit signals via branched intracellular signaling pathways
Regulate progression of
Cell cycle
Cell growth (increases in cell size)
Signals influence yet other cell-biological properties,
Cell survival and energy metabolism.
Controling of Mitogenic Signaling
Mechanisms controlling the release of the mitogenic signals.
The growth factor signals
Controlling cell number and position within tissues

Be transmitted in a temporally and spatially regulated


fashion from one cell to its neighbors
Paracrine signaling
The mitogenic signaling in cancer cells (Lemmon and
Schlessinger, 2010; Witsch et al., 2010; Hynes and
MacDonald, 2009).
The Capability to Sustain
Proliferative Signaling
1. Produce growth factor ligands--- respond via the expression of
cognate receptors--- Autocrine proliferative stimulation
Stimulate normal cells within the supporting tumor-associated
stroma, which Reciprocate by supplying the cancer cells with
various growth factors (Cheng et al., 2008).
2. Elevating the levels of receptor proteins displayed at the cancer
cell
hyperresponsive to otherwise-limiting amounts of growth factor
ligand
3. Structural alterations in the receptor molecules that facilitate
ligand-independent firing
External stimulation : inhibisi keberlanjutan siklus
dan menyebabkan sel memasuki Go phase
Tumors exhibit another dimension of complexity
They contain a repertoire of recruited, ostensibly
normal cells that contribute to the acquisition of
hallmark traits by creating the tumor
microenvironment.
Hallmark of cancer
Conceptual progress in the last decade has added
two emerging hallmarks of potential generality to
this list reprogramming of energy metabolism and
evading immune destruction.
Struktur Retroviral
Viral oncogenes : v-oncs, Moleculer dissection pd
genomes
Transforming
proses
Proses Insersi

V-oncs hampir identik dengan DNA normal


Translokasi kromosome
HOW SIGNAL TRANSDUCTION MECHANISMS
WORK
AT MOLECULER LEVEL
Growth factor Tyrosine kinase pathway
Ras-MAP Kinase

Subunit Subunit
tyrosien tyrosien Phosphorylation Tyrosine RAS
kinase kinase RAS-
PIP3+DA Grb2
domain domain GTP Ra
receptor receptor G SOS
f
GTP
Dimerize
PIP2
GDP Ra
MAPK
transphosporilation f
ERK1
ERK2 MEK1
MEK2
Cyclin D
Protein G- Protein G- ustsable Active transcription
b @ factor
Cdk 4/6
p21/p27 Sinthesis
pRB Cyclin D
Cdk4/6-CyclinD-p21 phosporilasi
pRB
DNA
E2F/DP1 Replication
Nucleus DNA
DNA Damage
Pathology of lung adenocarcinomas according to
2004 WHO classification

Mixed subtype
Acinar
Papillary
BAC
Non mucinous
Mucinous
Mixed
Solid adenocarcinoma
Colloid
Fetal
Mucinous cystadenocarcinoma
Signet-ring
Clear-cell
Major changes in the new IASLC/ATS/ERS classification

Discontinuation of the term BAC


Discontinuation of the mixed subtype
Comprehensive pathologic subtyping in 5% increments and
classification of adenocarcinomas according to the
predominant subtype
Introduction of AIS and MIA as new entities
Introduction of micropapillary adenocarcinoma as a
predominant subtype
Introduction of lepidic predominant adenocarcinoma and
lepidic growth as new terminologies
Exclusion of signet-ring and clear cell adenocarcinomas
IASLC/ATS/ERS classification
Pre-invasive lesions
Atypical adenomatous hyperplasia
AIS
Non-mucinous
Mucinous
Mixed
MIA
Non-mucinous
Mucinous
Mixed
Invasive adenocarcinomas
Lepidic predominant
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin production
Variants of invasive adenocarcinomas
IMA
Colloid
Definitions
Primary Tumor (T)
TX
Primary tumor cannot be assessed, or tumor proven by the presence of
malignant cells in sputum or bronchial washings but not visualized by
imaging or bronchoscopy
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral
pleura, without bronchoscopic evidence of invasion more proximal than the
lobar bronchus (for example, not in the main bronchus)1
T1a
Tumor 2 cm or less in greatest dimension
T1b
Tumor more than 2 cm but 3 cm or less in greatest dimension
T2
Tumor more than 3 cm but 7 cm or less or tumor with any of the
following features
Classifed T2a if

5 cm or less: involves main bronchus,


2 cm or more distal to the carina;
invades visceral pleura (PL1 or PL2);
associated with atelectasis or obstructive pneumonitis that
extends to the hilar region but does not involve the entire lung
T2a
Tumor more than 3 cm but 5 cm or less in greatest dimension
T2b
Tumor more than 5 cm but 7 cm or less in greatest dimension
T3
Tumor more than 7 cm or one that directly invades any of the
following: parietal pleural (PL3), chest wall (including superior sulcus
tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal
pericardium; or
Tumor in the main bronchus less than 2 cm distal to the carina1 but
without involvement of the carina; or associated atelectasis or
obstructive pneumonitis of the entire lung or separate tumor
nodule(s) in the same lobe
T4
Tumor of any size that invades any of the following: mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, esophagus,
vertebral body, carina, separate tumor nodule(s) in a di erent
ipsilateral lobe
Distant Metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
M1a
Separate tumor nodule(s) in a contralateral lobe, tumor with pleural
nodules or malignant pleural (or pericardial) e usion2
M1b
Distant metastasis (in extrathoracic organs)
The uncommon supercial spreading tumor of any size with its
invasive component limited to the bronchial wall, which may
extend proximally to the main bronchus, is also classiFed as
T1a.
Most pleural (and pericardial) eFusions with lung cancer are
due to tumor.
Multiple cytopathologic examinations of pleural
(pericardial) fluid are negative for tumor, and the fluid is
nonbloody and is not an exudate.
Where these elements and clinical judgment dictate that the
efusion is not related to the tumor, the efusion should be
excluded as a staging element and the patient should be
classifed as M0.
ANATOMI C STAGE/ PROGNOSTI C GROUPS
Occult Carcinoma T X N0 M0
Stage0 T is N0 M0
StageIA T 1a N0 M0
T 1b N0 M0
StageIB T 2a N0 M0
StageIIA T 2b N0 M0
T 1a N1 M0
T 1b N1 M0
T 2a N1 M0
StageIIB T 2b N1 M0
T 3 N0 M0
StageIIIA T 1a N2 M0
T 1b N2 M0
T 2a N2 M0
T 2b N2 M0
T 3 N1 M0
T 3 N2 M0
T4 N0 M0
T4 N1 M0
StageIIIB T 1a N3 M0
T 1b N3 M0
T 2a N3 M0
T 2b N3 M0
T 3 N3 M0
T4 N2 M0
T4 N3 M0
StageIV AnyT AnyN M1a
AnyT AnyN M1b
Lung Cancer Staging
IL
Th
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