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Cancer
Cancer Is an umbrella term covering a range of
conditions characterized by unscheduled and
uncontrolled cellular proliferation.
Molecular Biology of Cancer
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Molecular Biology of Cancer
Topics to be covered in the course
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The hallmarks of cancer (Introduction to the biology of cancer)
Cell Proliferation, Differentiation and cell death
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Molecular carcinogenesis
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Cellular transformation
Oncogenes
Tumor-Suppressor Genes
Recurring Chromosome Rearrangements and Cancer-Associated Gene Mutations in
Human Cancer
Molecular mechanisms involved in carcinogenesis
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Control of cellular proliferation (cell cycle)
Control of Apoptosis
External control of cell cycle (Signal Transduction)
Alterations of Signaling to Cell Division and Survival in Cancer.
Mechanisms of Regulation of Cancer-Related Genes
Invasion and Metastases
Tumor Angiogenesis
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Molecular Biology of Cancer
References
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Holland-Frei Cancer Medicine 6th edition (April
2003):
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Molecular Mechanisms of Cancer (2007)
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By Donald W., Md Kufe, Raphael E., Md Pollock, Ralph
R., Md Weichselbaum, Robert C., Jr., Md Bast, Ted S.,
MD Gansler By BC Decker
By Georg F. Weber
Introduction to the Cellular and Molecular Biology of
Cancer (2005)
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By Margaret A. Knowles and Peter J. Selby
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Molecular Biology of Cancer
Exams and homework
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Midterm exam (30 degrees)
Final Exam (30 degrees)
Assay (10 degrees)
Homework (10 degrees)
The hallmarks of cancer
Molecular Biology of Cancer
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Molecular Biology of Cancer
Overview
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With few exceptions, cancers are derived from
single somatic cells and their progeny.
The emerging neoplastic cells accumulate a series
of genetic or epigenetic changes that lead to
changes in gene activity, and thus to altered
phenotypes.
Ultimately, a cell population evolves that can
disregard the normal controls of proliferation and
territory and become a cancer.
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Molecular Biology of Cancer
Six hallmark features of the cancer
cell phenotype
1.
2.
3.
4.
5.
6.
disregard of signals to stop proliferating
disregard of signals to differentiate
capacity for sustained proliferation
evasion of apoptosis
Invasion
angiogenesis
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Molecular Biology of Cancer
Tumors arise from normal tissues
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Tumor is not a foreign
mass invading the body
from outside world
continuity between normal and
cancerous tissue in the small intestine
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Molecular Biology of Cancer
Four major types of new tissue growth
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Molecular Biology of Cancer
Comparison of normal and neoplastic
growth in the epithelium of the skin
In normal skin, each
cell division gives
rise to one cell that
retains the capacity
to divide and one that
differentiates.
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The uncontrolled cells of a cancer can grow as:
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Molecular Biology of Cancer
A solid mass, which is called a tumor.
Unconnected and free-floating, as in a cancer of blood
cells, e.g., leukemia
The term neoplasm, meaning “new growth”, is
used to refer to many kinds of cancer to signify an
abnormal growth.
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Molecular Biology of Cancer
Tumors are of two basic types
Benign:
1.
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A tumor mass contained, e.g. by a capsule of connective
tissue
not able to spread
Malignant:
2.
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Tumor cells that escape from their site of origin and
move off to grow elsewhere
The distant sites of growth are called “metastases.”
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Molecular Biology of Cancer
A Malignant Tumor vs a Benign
Tumor
1.
Malignant tumors invade and destroy adjacent
normal tissues. Benign tumors grow by expansion,
are usually encapsulated, and do not invade
surrounding tissue.
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Benign tumors may, however, push aside normal tissue
and become life-threatening if they press on nerves or
blood vessels.
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Molecular Biology of Cancer
A Malignant Tumor vs a Benign
Tumor
2.
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.
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Primary tumor – tumor growing at the anatomical site
where tumor progression began and proceeded to yield
this mass
Metastatic tumor – tumor forming at one site in the body,
the cells of which are derive from a tumor located
elsewhere in the body
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Molecular Biology of Cancer
A Malignant Tumor vs a Benign
Tumor
3.
Malignant tumor cells tend to be anaplastic (less
differentiated) than normal cells of origin. Benign
tumors usually resemble normal tissue more
closely than malignant tumors do.
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4.
Anaplasia: reversion to a less differentiated structure
Malignant tumors usually, but not always, grow
more rapidly than benign tumors.
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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.
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Molecular Biology of Cancer
A Malignant Tumor vs a Benign
Tumor
5.
Malignant neoplasms continue to grow even in
the face of starvation of the host
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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.
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Molecular Biology of Cancer
Comparison of benign and malignant
growths
_____________________________________________
Feature
Benign
Malignant
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Metastasis no
yes
Invasion
yes
no
Edges encapsulatedirregular
Growth rate low
high
Nuclei & nucleoli
normal
usually
variable, irregular
Life-threatening
uncommon usual
_____________________________________________
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Molecular Biology of Cancer
Epithelium-derive neoplasms
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The most common types of human cancers
The neoplasms which are derived from
epithelium are called “carcinomas”.
These tumors are responsible for more than
80% of the cancer-related deaths.
Most of the carcinomas fall into two major
categories:
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Squamous cell carcinomas: arising from stratified
squamous epithelium
Adenocarcinomas: arising from glandular epithelium.
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Molecular Biology of Cancer
Nonepithelial cancers
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Sarcomas:
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Derive from a variety of mesenchymal cell types:
fibroblasts (connective tissues), adipocytes (fat),
osteoblasts (bone), myocytes (muscle)
constituting ~1% of the tumors in the oncology
clinic.
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Molecular Biology of Cancer
Nonepithelial cancers
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Cancers arise from various cell types of
blood-forming tissues:
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lymphoma – solid tumors of lymphocytes, most
frequently found in lymph nodes
leukemia – tumors of “white cells” of the blood,
usually moving freely through the circulation
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Molecular Biology of Cancer
Nonepithelial cancers
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Tumors arising from cells of the central
and peripheral nervous system:
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Glioblastoma tumors of astrocytes
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“oma” usually indicates a tumor.
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Molecular Biology of Cancer
carcinoma, sarcoma, lymphoma, myeloma,
neuroblastoma, etc.
Rarely, the “oma” describes a nonneoplastic
conditions.
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granuloma, is a mass of granulation tissue resulting
from chronic inflammation or abscess.
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Molecular Biology of Cancer
Classification of Human Tumors by
Tissue Type
Tissue of Origin
Benign
Malignant
Epithelium
Surface epithelium
Glandular epithelium
Papilloma
Adenoma
Carcinoma
Adenocarcinoma
Connective tissue
Fibrous tissue
Bone
Fibroma
Osteoma
Fibrosarcoma
Osteosarcoma
Endothelial tissue
Blood vessels
Lymph vessels
Hemangioma
Lymphangioma
Hemangiosarcoma
Lymphangiosarcoma
Neural tissue & its derivatives
Glial tissue
Meninges
Nerve sheath
Melanocytes
Retina
Glioma
Meningioma
Neurofibroma
Pigmented nevus
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Glioblastoma multiforme
Meningeal sarcoma
Neurofibrosarcoma
Malignant melanoma
Retinoblastoma
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Molecular Biology of Cancer
Cell Proliferation and Differentiation
The biology of cell division, differentiation, and
apoptosis is exceedingly similar in both normal
and cancer cells.
The cancer cell differs from its normal
counterpart in that it is aberrantly regulated.
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Cancer cells like normal cells generally contain the
full complement of biomolecules necessary for:
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survival, proliferation, differentiation, cell death, and
expression of many cell type-specific functions.
Failure to regulate these functions properly,
however, results in an altered phenotype and
cancer.
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Molecular Biology of Cancer
Four cellular functions tend to be
inappropriately regulated in a neoplasm
1.
2.
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4.
The normal constraints on cellular proliferation are
ineffective.
The differentiation program can be distorted:
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The tumor cells may be blocked at a particular stage of
differentiation.
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They may differentiate into an inappropriate or abnormal
cell type.
Chromosomal and genetic organization may be
destabilized:
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variant cells arise with high frequency.
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Some variants may have increased motility or enzyme
production that permits invasion and metastases.
The tightly regulated cell death program (apoptosis) may be
dysregulated.
PROLIFERATION
Molecular Biology of Cancer
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Molecular Biology of Cancer
One hallmark of cancer is that most
are genetically clonal,
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Cancers usually arise by
expansion of a single cell.
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Evidence from X-inactivation
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Red and blue colors indicate cells with
one or the other X chromosome
inactivated.
Note that all the cancerous cells that
form the “tumor mass” in the middle
of the tissue show only one kind of Xinactivation, suggesting that they all
grew as a clone from a single cell.
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Molecular Biology of Cancer
Cancer evolves through continual genetic
evolution of mutant cells by a process of natural
selection.
In cancers in which preneoplastic lesions
can be identified, the preneoplastic cells are
likely to be genetically distinct from the
overtly neoplastic cells.
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Genetically abnormal cells are generated as a
result of environmental insult or normal errors in
replication.
Some small fraction of these cells escapes
normal controls on cell proliferation and
increases their number.
As this pool of mutant cells proliferates,
additional mutant variants are continuously
generated. If the result of these additional
mutations provides a selective growth
advantage, then the mutant variant will increase
its relative number.
Through multiple rounds of proliferation,
mutation, and selection a neoplastic variant
evolves to cause cancer.
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Molecular Biology of Cancer
Two parameters will critically affect the rate
of this clonal evolution
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The mutation rate, and the rate of proliferation.
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The rate of neoplastic transformation will increase
with mutations that increase the rates of proliferation
or mutation rate.
Such mutations are more likely to be detected in
cancer cells than other types of mutations.
If such a mutation is inherited, the incidence of cancer
within such a family is expected to be significantly
higher than normal.
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Molecular Biology of Cancer
The accumulation of multiple mutations in a
single somatic cell is very improbable
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The probability of mutation is low (one in about 100
million/base pair/cell division)
To get mutations that alter genes that control
cellular behavior is VERY unlikely
To get mutations in many different genes that
control cell behavior is VERY VERY unlikely!
The road to cancer therefore seems to involve the
introduction of abnormal instability into the genome
of the cell that is becoming cancerous
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Molecular Biology of Cancer
A “successful” cancer is one that acquires just the right
degree of genetic instability, allowing it to mutate at rates
that give it selective advantages but not so fast that it dies