USTHB-FSB- Dpt BCM 2020-21

MASTER EN SCIENCES PHARMACOLOGIQUES -

SPM2-S3

bd

PHARMACOLOGIE ET ONCOLOGIE
CELLULAIRES (POC) DATA1
Cell in green is apoptotic
Cause of Death No. of deaths % of all deaths
USA 2003
1. Heart Diseases 685,089 28.0

2. Cancer 556,902 22.7

3. Cerebrovascular 157,689 6.4

diseases
6. Diabetes mellitus 74,219 3.0
7. Influenza 65,163 2.7
pneumonia
8. Alzheimer disease 63,457 2.6
9. Nephritis 42,453 1.7
10. Septicemia 34,069 1.4
 Epidemiology: Etat des lieux et evolution
• Taux spécifique par tranche d’âge relativement bas
dans les deux sexes jusqu’à …….ans

• occurrence et vitesse d augmentation/ sex

• Âge médian au diagnostic du cancer / an et dans

une periode de temps

• Comparaison avec d autres populations

(geographie, ethnie etc
 Epidemiology: Etat des lieux et evolution
• Taux spécifique par tranche d’âge relativement bas
dans les deux sexes jusqu’à …….ans

• occurrence et vitesse d augmentation/ sex

• Âge médian au diagnostic du cancer / an et dans

une periode de temps

• Comparaison avec dautres populations

(geographie, ethnie etc)
2006 Estimated US Cancer Cases* Men
720,280 Women 679,510
Prostate 33% 31% Breast
Lung & bronchus 13% 12% Lung & bronchus
Colon & rectum 10% 11% Colon & rectum
Urinary bladder 6% 6% Uterine corpus
Melanoma of skin 5% 4% Melanoma of skin
Non-Hodgkin 4% 4% Non-Hodgkin
lymphoma lymphoma
Kidney 3% 3% Thyroid
Oral cavity 3% 3% Ovary
Leukemia 3% 2% Urinary bladder
Pancreas 2% 2% Pancreas
All Other Sites 18% 22% All Other Sites
- If one sibling or twin gets cancer, other usually does
not
- Populations that migrate – profile of cancer becomes
more like people indigenous to new location
Si un frère ou un jumeau contracte le cancer, les autres ne le font pas systematiquement.
- Des populations qui migrent - le profil du cancer qui les touche ressemble plus à celui
des personnes d ou ils sont originaires
Most cancers result from aging
Most cancers result from aging
Factors Contributing to Global Causes of Cancer

Herbicides,
pesticides, asbestos,
cool tars!!!!
 Environmental Risk Factors
Xenobiotics:
Toxic, mutagenic, and carcinogenic chemicals in
food
- Activated by phase I activation enzymes
Defense mechanisms
- Phase II detoxification enzymes
Examples
Compounds produced in the cooked fat,
meat, or proteins
Alkaloids or mold by-products
 Viruses and Cancer

– Hepatitis B and C viruses

– Epstein-Barr virus (EBV) Epstein-Barr virus,
associated with mononucleosis, may contribute
to cancer
– Kaposi’s sarcoma herpes virus (KSHV)
– Human papillomavirus (HPV) Human
papillomavirus (HPV), virus that causes genital
warts, has been linked to cervical cancer
– Human T cell leukemia–lymphoma virus (HTLV)
 Bacterial Cause of Cancer

Helicobacter pylori
–Chronic infections are associated with:
• Peptic ulcer disease major factor in
the development of stomach cancer
• Stomach carcinoma
• Mucosa-associated lymphoid tissue
lymphomas
Types of Ultraviolet Rays

Figure 16.7
Environmental Risk Factors

Electromagnetic fields
Carcinogenic?
 DC

Inflammation and cancer connection

 Inflammation-associated cancers
Cytokine release from inflammatory cells. Nitro-oxidative
stress. Decreased response to DNA damage
 Risks For Cancer
- Lifetime risk the probability that an individual,
over the course of a lifetime, will develop cancer
or die from it
- Relative risk measure of the strength of the
relationship between risk factors and a particular
cancer
- Smoking 30% of all cancer deaths, 87% of lung
cancer deaths
- Obesity 50% higher risk for breast cancer in post
menopausal women, 40% higher risk in colon
cancer for men
 There are over 100 different forms of
cancer
Cancer is one of the most common
diseases in the developed world:
1 in 4 deaths are due to cancer
1 in 17 deaths are due to lung cancer
Lung cancer is the most common cancer in
men
Breast cancer is the most common cancer
in women
 What is Cancer
Neoplasia: new growth
Neoplasm: the actual lump of new tissue
Tumour: swelling
An actual definition of cancer is surprisingly
hard to come up with “a neoplasm of
abnormal tissue, the growth of which
exceeds and uncoordinated with normal
tissue and persists once the stimulus for its
growth is removed
 Definitions

• Hyperplasia : increased number of cells

• Hypertrophy : increased size of cells
• Dysplasia: disorderly proliferation
• Neoplasia : abnormal new growth
• Anaplasia : lack of differentiation
• Tumor : originally meant any
swelling, but now equated with neoplasia
• Metastasis : secondary growth at a
distant site
Four major types of new tissue growth
Four major types of new tissue growth
 Compiler les 3 cliches suivants
Benign: slow growth, non-invasive, no metastasis
Benign tumours do not spread from their site
of origin, but can crowd out (squash) surrounding
cells eg brain tumour, warts.
Malignant: rapid growth, invasive, potential for
metastasis
Malignant tumours can spread from the original
site and cause secondary tumours or metastasis.
They interfere with neighbouring cells, block blood
vessels, the gut, glands, lungs etc.
Why are secondary tumours so bad?
Both types of tumour need a huge amount of
nutrients to sustain the rapid growth and division
of the cells.
 Benign vs. Malignant Tumors (neoplasms)

Benign Malignant
Grow slowly Grow rapidly
Well-defined capsule Not encapsulated
Not invasive Invasive
Well differentiated Poorly differentiated
(Defined border, regular (irregular border, larger
nuclei) nuclei)
Low mitotic index High mitotic index
Do not metastasize Can spread distantly
Mitotic index = rate of growth (metastasis)
Comparison of benign and malignant growths
_____________________________________________
Feature Benign Malignant
_____________________________________________
Metastasis no yes
Invasion no yes
Edges encapsulated irregular
Growth rate low high
Nuclei & nucleoli normal variable, usually
irregular
Life-threatening uncommon usual
_(mise en danger)
Characteristic Benign Malignant

Differentiation Well Anaplastic

differentiated
Growth Rate Slow Rapid

Mode of growth Expansive Infiltrative and

expansive
Metastases None Can spread to
distant sites
Prognosis Usually harmless Can be fatal if
not treated
A Malignant Tumor vs a Benign Tumor
- Malignant tumors invade and destroy
adjacent normal tissues

- Benign tumors grow by expansion, are

usually encapsulated, and do not invade
surrounding tissue.
Benign tumors may, however, push aside
normal tissue and become life-threatening if
they press on nerves or blood vessels.
 A Malignant Tumor vs a Benign Tumor
Malignant tumors metastasize through
lymphatic channels or blood vessels to lymph nodes
and other tissues in the body. Benign tumors remain
localized and do not metastasize
primary tumor:
tumor growing at the anatomical site where tumor
progression began and proceeded to yield this mass
metastatic tumor : (metastases)
tumor forming at one site in the body, the cells
of which derive from a tumor located elsewhere
in the body
 A Malignant Tumor vs a Benign Tumor

Malignant tumor cells tend to be

“anaplastic” or less differentiated than
normal cells of the tissue in which they
arise.
Benign tumors usually resemble normal
tissue more closely than malignant tumors
do.
anaplasia: reversion to a less differentiated
structure
A Malignant Tumor vs a Benign Tumor

Malignant tumors usually, but not always,

grow more rapidly than benign tumors.
Once they reach a clinically detectable
stage, malignant tumors generally show
evidence of significant growth, with
involvement of surrounding tissue, over
weeks or months.
Benign tumors often grow slowly over
several years.
A Malignant Tumor vs a Benign Tumor

Malignant neoplasms continue to grow

even in the face of starvation of the host.
They press on and invade surrounding
tissues, often interrupting vital functions.
The most common effects on the patient
are cachexia (extreme body wasting),
hemorrhage, and infection.
 Benign tumors
–Named according to the tissues
from which they arise, and include
the suffix “-oma”
• Lipoma

• Hemangioma

• Leiomyoma

• Chondroma
 Malignant tumors
Malignant epithelial tumors are referred to as
carcinomas
Adenocarcinoma (from glandular epithelium)
Malignant CT tumors are referred to as
sarcomas
Cancers of lymphatic tissue are lymphomas
Cancers of blood-forming cells are leukemias

• Carcinoma in situ (CIS). Epithelial malignant

tumors that have not broken through BM or
invaded the surrounding stroma
 Types of cancer
• Carcinomas constitute 90% of cancers, arising
from stratified squamous epithelium (squamous
cell carcinomas
Adenocarcinoma (glandular epithelium)
• Sarcomas are rare and consist of tumors of
connective tissues (connective tissue, muscle,
bone etc.)
• Leukemias and lymphomas constitute 8% of
tumors. Sometimes referred to as liquid tumors.
Leukemias arise from blood forming cells and
lymphomas arise from cells of the immune system
(T and B cells).
• Carcinoma in situ (CIS). Epithelial malignant
tumors that have not broken through BM or
invaded the surrounding stroma
 Cancer: Selection for Single-Cell Survival in a
Multi-Cellular Organism
• Cells must make critical decisions
– Stem cell renewal
– Differentiation
– Growth / quiescence
– Death

• Things can go wrong at all of these levels

 Growth Fraction
Growth Fraction Doubling
Experimental tumors Fraction (%) Time (days)

L1210 (mouse) 86 0.5

B16 (mouse) 55 1.9
LL (mouse) 38 2.9
DMBA (rat) 10 7.4

Human tumors

Lymphoma (high grade) 90 29

Squamous cell carcinoma 25 58
Adenocarcinoma 6 83

Normal Human Bone Marrow 35 --

 Measuring Cytotoxicity

- Clonogenic Assay (colony forming assay)

- Sulforhodamine B (SRB Assay)

 Colony Forming Assay

Treatment is applied to a sample of cells.

• The cells are plated in a tissue culture vessel
and allowed to grow.
• The colonies produced are fixed, stained, and
counted
• Cell survival – surviving fraction vs. drug
concentration
 Too many
to count

Before
Treatment

After
Treatment

Franken N., Rodermond H., Stap J, Haveman J, van Bree C. (2006). Clonogenic assay of cells in vitro. Nature Protocols 1: 2315-2319.
 Premalignant Lesions
Premalignant conditions also exist
Metaplasia: replacement of one normal
epithelium with another, but in an unusual
location
Dysplasia: disordered growth and
differentiation of an epithelium
Reversible
Colonic Polyps
Stades du cancer du colon
Histology of Colonic Polyps

Colon Cancer
from Kinzler and Vogelstein, Cell 1996
 Tumors arise from normal tissues
- tumor is not a foreign mass invading the body from outside world

腺癌

發育不
正常的

continuity between normal and cancerous

tissue in the small intestine
Figure 2.1a The Biology of Cancer (© Garland Science 2007)
 Convergent driver events
• Between the complexity and heterogeneity,
• there is some order

• Finite number of major pathways that are

affected
by drivers
 Convergent driver events

Hanahan2011
 R L -

L+
Check points of signaling pathways affected by oncogenes and tumor