What is Cancer and How It Occurs?

DR.dr. Ikhwan Rinaldi Sp.PD (K) HOM

Overview
One in three people is
likely to suffer from
cancer during their
lifetime.

The worldwide incidence

was wstimated to be about
12,7 million cases in 2008
(Jemal et al. 2011)

In order to understand the

carcinogenesis, we must
know the intricacies of
cell function and the
molecular pathways
underlie it

2 1. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-
16p.
What Is Cancer?

Cancer is a group disease characterized by unregulated cell growth and the invasion
and spread off cells from the site of origin, or primary site, to other site in the body.

Approximately 85% of cancers occur in epithelial cells and are classified as

carcinomas

Cancers derived from mesoderm cells (e.g bone, muscle) are called sarcomas

Cancer of glandular tissue (e.g breast) are called adenocarcinomas.

There are differences in the molecular mechanisms invoved in carcinogenesis within

each cell type and the patterns of spread cells from the primary site.

31. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
The 10 Hallmarks of Cancer

41. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
 The 10 Hallmarks of Cancer

Growth Signal Evasion of growth Avoiding immune Unlimited replicative

Autonomy inhibitory signals destruction potential

• Cancer cells are • Cancer cells do not • Successful cancer • Cancer cells
not dependent on respond to growth cells may be those maintain the
normal growth inhibitory signals that do not length of their
factor signaling • Acquired stimulate an telomeres
• Acquired mutations or gene immune response • Altered regulation
mutations short- silencing interfere or can interfere of telomere
circuit growth with the inhibitory with the immune maintenance
factor pathaways pathaways. response so as to resluts in
eading to avoid immune unlimited
unregulated destruction. replicative
growth. potential

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 The 10 Hallmarks of Cancer

Tumor- promoting Invasion and Genome Instability Evasion of cell Reprogramming

Angiogenesis
inflammation metastasis and mutation deaths energy metabolism
• Virtually all • The movement of • Cancer cells • Faulty DNA repair • Normal cells are • Uncontrolled cell
tumors contain cancer cells to induce Pathways can removed by division demands
inflammatory other parts of the angiogenesis, the contribute to apoptosis, often in increases in fuel
immune cells body is a major growth on new genomic instability response to DNA and biosynthetic
• Inflammatory cells cause cancer death blood vessels, damage precursors that is
can release • Alterations of the needed for tumor • Cancer cells evade obtain by adjusting
oxygens species genome may affect survival and apoptotic signals. energy metabolism
that are mutagenic the activity and/or expansion.
levels of enyzmes • Altering the
involved in balance between
invasion or angiogenic
moleculer involved inducers and
in cell-cell or inhibitors can
cellular- activate the
extracelullar angiogenic switch
adhesion

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 Benign vs. Malignant
A benign tumor1 Malignant tumour

• is not evidence of cancer • Do not remain encapsulated

• Do not spread throughout the body , • Show features of invasion
they dont metastasize. • Metastasize
• Some can be life threathening
because of their location.

Cancer cells can be distinguished from normal cells in cell culture conditions.

Normally, cells grow as a single layer, or monolayer in a petri dish due to a property called contact
inhibition

Transformed cellss (cells that have become cancer cells) acquire the following phenotypes;

• Fail to exhibit contact inhibition

• Can grow in conditions of low serum
• Adopt a round morphologyrather than flat and extended one
• Able to grow without attching to a substrate
71. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Cancer is a Disease of the Genome at the Celullar Level

Most agents that

cause cancer Similarly to all
( carcinogens) are genetic disease,
agents that cause
alterations to the cancer results
DNA sequence or from alterations
mutations in DNA.
(mutagens).1

DNA of tumour cells

The accumulation of
contains many mutations in cells over
alteratons ranging time represents a
from subtle point multistep process that
mutations to large underlies
chromosomal carcinogenesis
abberations, such as increased risk of cancer
with age andbecome more
deletions and prevalent over the
chromosomal century1
translocations.

81. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Cancer Patogenesis

Growth,
Apoptosis, and Oncogens and
Differentiation Tumor Supressor
Regulate Cell Genes
Numbers

91. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Growth, Apoptosis, and Differentiation Regulate Cell
Numbers

The important process that contribute to overall net cell number in an

individual are :

Cell proliferation or cell growth Apoptosis Regulate cells numbers

• Cells undergo division, growth, • the elimination of cells by • During the process of
and death. programmed cell death also differentiation cells can enter an
• These cell events are tightly affects the net cell number inactive phase of cell growth and
regulated by cell cycle regulator thus differentiation can affect
proteins. cells numbers.
• Cell cycle regulator proteins are
coded by genes called proto-
oncogenes.
• Proto-oncogenes are the normal
genes which regulate the cell
division. They are encoded for
all these positive cell cycle
regulator proteins essential for
normal cell division.

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1. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Growth, Apoptosis, and Differentiation Regulate Cell
Numbers

Normal Abnormal

• If four of one cells shown in the • If apoptosis is blocked in one

(a) divide, and four are
progrramed to die by apoptosis
and one differentiates (neither
dies nor divides) the cell
numbers will remain the same.
cell and that cell divides instead,
the total number of cells will
increase to 11

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Proto-Oncogens Conversion
Cell cycle regulator proteins perform many
functions such as stimulation of cell division,
prevention of cell differentiation or regulation
of programmed cell death (apoptosis), etc.

The DNA sequence of the proto-oncogenes

can change due to mutations.

When proto-oncogenes are mutated, the

mutated or defective genes are called
oncogenes

The mutated proto-oncogenes produce

different proteins which cause uncontrolled
cell divisions.

Conversion of proto-oncogenes into oncogenes The uncontrolled cell divisions cause the
formation of cancers or tumors.

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Proto-Oncogens  Oncogens
Proto-oncogenes become oncogenes due
to several genetic modifications or
mechanisms such as mutations, gene
amplifications, chromosomal
translocations.
1. Production of overactive gene products
by point mutations, insertions or
deletions.
2. Increased transcription by point
mutations, insertions or deletions
3. Production of additional copies of proto-
oncogenes by gene amplification
4. Movement of proto-oncogenes into
different chromosomal site and cause for
increased expression
5. Fusion of proto-oncogenes with other
genes which can cause oncogenic
activity
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Oncogenes and Tumours Suppresor Genes

Oncogenes
Two major types of mutated
genes that contribute to
carcinogenesis Tumor Supressor
Genes.

Oncogene Tumor Supressor Genes

• Develop from protooncogenes. • Regulate and inhibit inappropriate cellular growth

• Protooncogenes mutate when exposed to carcinogenic
agents such as radiation, chemicals or viruses, or as a
result of inherited factors.
• Activation of oncogenes results in dysregulation of
normal cell growth, which produces excessive cellular
proliferation
and proliferation. Mutation of these genes results in
loss of control over normal cell growth.
• Code for proteins that play role in inhibiting both
growth and tumor formation.
• Loss growth inhibition occurs when mutations cause a
loss of function of these genes.

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1. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Oncogenes

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Tumor Supressor Genes

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1. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Tumor Supressor Genes

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Influential Factors in Human Carcinogenesis

Environment

Additional Reproductive
influences : life

Influential
Factors in
Human
Carcinogenesis

Alcohol Diet

Smoking

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Cancer Prevention & Screening

Diet, BMI, Physical

Tobacco Control
Excercise

Behavioural
Specific Initiative in
Interventions in Cancer Nutrition SELECT
Cancer Prevention
Prevention

Nutritional Prevention
Chemoprevention
of Cancer
Modeling of new
Design for Early
Detection and Cancer
Prevention Clinical
Trials

Specific Initiative in Prostate, Lung,

Cancer Screening and Colorectall and
Early Detection Ovarian Cancer
Screening Trial (PLCO)

Mammographic
Screening for early
Low dose Helical/Spiral Detection of Breast
CT Screening for early Cancer
Detection of Lung
Cancer

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2. Dunn BK, Grenwald P . Cancer Prevention 1 : Introduction. Seminars in Oncology, Vol 37, No 3, June 2010,
pp 190-201 194-8p.
 Staging

The most widely used staging system among clinicians is the TNM system maintained
by the American Joint Committee on Cancer (AJCC) and the International Union for
Cancer Control (UICC). 5
• Codes the extent of the primary tumor (T),
• Regional lymph nodes (N), and
• Distant metastases (M) and
• Provides a “stage grouping” based on T, N, and M.
• AJCC and IUCC update the TNM cancer staging system periodically. 

Principles of Cancer Staging6

• Determining the extent of disease and the organs involved is essential to the proper management
• Staging should describe both the tumor and the host, including the following factors:
• Organ of tumor origin
• Histologic type and grade of tumor
• Extent of primary tumor (size; invasion of adjacent tissues; involvement of nerves, blood vessels, or
lymphatic system)
• Sites of metastases
• Functional status of the patient

21 4. Manual of Clinical Oncology

5. Edge, S.B. & Compton, C.C. Ann Surg Oncol (2010) 17: 1471. https://doi.org/10.1245/s10434-010-0985-4
Estimated Number of US Cancer Survivors
by Site

226. Cancer Treatment and Survivorship Statistics. A Cancer J Clin 2014;64:252-27 1.American Cancer Society.
 Age Distribution of Survivors for Selected
Cancer Types, January 1, 2014.

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Principles of Cancer Therapy
By interfering with Any therapy
autocrine/paracrine
signaling within with the stated
ttumours goal to treat and
disrupting cancer
By blocking
heterotypic
possibly cure
cell autonomous signaling between cancer must
process tumour or blood show
vesseles.
differential
Inducing toxicity toward
cancer tumor cells
cells to relative to
undergo normal cells

Apoptosis Necrosis senescence differentiate

243. Ji Luo,IN L. Solimini, Stephen JEI, Cell 136. 2009. Elsevier. 823p.
Principles of Conventional Cancer Therapies
The earliest therapeutic strategy used againts cancer : Surgical
•  remove as much of the cancer as possible.
•  relatively easy in some types, imposibble in other types.
The objective of cancer therapies are
• Cytostatic effect : to prevent proliferation
• Cytotoxic effect : to kill the cancer cells

Chemotherapy
• uses chemicals that target DNA, RNA, and protein to disrupt the cell cycle in
rapidly dividing cancer cells and thus has broad specificity.
• The ultimate goal of cytotoxic chemotherapy is to cause severe DNA damage and
to trigger apoptosis in the rapidly dividing cancer cells.

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1. Lauren P. Molecular Biology of Cancer : Mechanisms, Targets, Therapy. 3rd Edition. Oxford; 2012. 1-16p.
Principles of Cancer Therapy

Supressing
Oncogen Activity

Restoring Tumor
Suppresion
Function
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Additional Hallmarks

Targeting these hallmarks

and their associated
vulnerabilities in a wide
variety of cancers has
shown promise for
therapeutic intervention

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Cancer Therapies Targeting Various
Hallmarks of Cancer
Therapeutics are selected based on the diversity of their chemical structures, the hallmarks they attack,
and their cellular targets.

These agents are either investigational drugs or approved for selective oncology indications.

Abbreviations:

• OA, oncogene addiction;

• NOA, non-oncogene addiction;
• TSGH, tumor suppressor gene hypersensitivity

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Attacking the Hallmarks of Cancer ;
Cancer Therapies Targeting Various Hallmarks of Cancer

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Conclusion

Cancer is a common disease that results Carcinogenesis is a multistep process

in the spreading of mutated cells that requires the accumulation of
throughout the body several mutatins

Cancer is a genomic disease at the Change in lifestyle factors can affect

celullar level cancer risk

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 THANKYOU

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