Cancer

Re-Cap
Proliferation, differentiation, & survival of individual
cells in multicellular organisms are carefully regulated
to meet needs of the organism as a whole.
Many proteins that play key roles in cell signaling,
regulation of cell cycle, & control of programmed cell
death were 1st identified because abnormalities in
their activities led to uncontrolled proliferation of
cancer cells.
The fundamental abnormality resulting in the
development of cancer is the continual unregulated
proliferation of cancer cells.
The generalized loss of growth control exhibited by
cancer cells is the net result of accumulated
abnormalities in multiple cell regulatory systems.
 Causes of Cancer

Carcinogens substances that cause

cancer, have been identified both by studies
in experimental animals and by
epidemiological analysis of cancer
frequencies in human populations.

Initiators (start cancer)

Promoters (facilitate cancer)
 The Development of Cancer

One of the fundamental

features of cancer is tumor
clonalitythe development
of tumors from single cells
that begin to proliferate
abnormally.
The clonal origin of tumors
does not imply that the
original progenitor cell that
gives rise to a tumor has
initially acquired all of the
characteristics of a cancer
cell.
The Development of Cancer
 The Development of Cancer

Tumor progression continues as additional

mutations occur within cells of the tumor population.
Studies of colon carcinomas have provided a clear
example of tumor progression during the
development of a common human malignancy.
An adenoma (or polyp) is a small benign neoplasm
arising from the glandular epithelium.
Older people should get checked!
colonoscopy
endoscopy
mammography
Hallmarks
of Cancer
Hallmarks of Cancer
Hanahan & Weinberg (2000)
 Self-sufficiency in growth signals (1)
The growth factor requirements of many tumor cells are
reduced compared to their normal counterparts,
contributing to the unregulated proliferation of tumor
cells both in vitro and in vivo.

Autocrine growth
stimulation is
stimulation of cell
proliferation as a
result of growth factor
production by a
responsive cell.
 Insensitivity to growth-inhibitory signals (2)
Contact inhibition is the process in which normal
fibroblasts migrate across the surface of a culture dish
until they make contact with a neighboring cell.
Density-dependent inhibition is the cessation of the
proliferation of normal cells in culture at a finite cell
density.
 Evasion of Apoptosis (3)
Increase anti-apoptotic proteins (like Bcl-2, IAPs)
Decrease pro-apoptotic proteins (like Bax, caspase,
death receptors).
 Limitless replicative capacity (4)

The cancer stem cell?

Leukemias provide a particularly good
example of the relationship between
defective differentiation and malignancy.
 Sustained angiogenesis (5)

Angiogenesis is the formation of new blood vessels

and is needed to support the growth of a tumor beyond
the size of about a million cells, at which point new
blood vessels are required to supply oxygen and
nutrients to the proliferating tumor cells.
 Tissue invasion and metastasis (6)

Metastasis is a
malignant growth Brain (5-15%)
forming at one site
in the body, the Bone (50-75%)
cells of which
derive from a Lung (30-40%)
malignancy located
elsewhere in the Liver (10-20%)
body.
Intestine (5%)
75% of cancer
deaths due to
Other (10%)
metastasis in 2o
(skin, ovary, adrenals)
sites.
Hallmarks of Cancer: The Next Generation
Hanahan & Weinberg (2011)
 Oncogenes

Oncogene is a gene that causes cancer.

Normal versions of these transforming genes are present in

normal cells and have been designated proto-oncogenes.

Cellular oncogenes represent individual components of

complicated pathways responsible for regulating cell
proliferation, division and differentiation.
 Tumor suppressor genes
Negative regulators of cell growth. Inactivation or functional loss
of both alleles of a gene is required for tumor formation.
Sometimes, they form complexes with oncoproteins of certain
DNA tumor viruses.

The prototype of these genes is retinoblastoma (Rb) gene. The

function of normal Rb protein is regulated by phosphorylation.

Another crucial tumor suppressor gene is p53 gene. p53 acts as

transcription factor and blocks cell cycle progression. p53 causes
cells with DNA damage to undergo apoptosis. p53 gene is
mutated in over half of all human cancers.
 Gain- vs. Loss-of-function

Mutations in a proto-oncogenes are dominant

mutations (gain of function) e.g. c-myc

Mutations in tumor suppressor genes are

recessive mutations (loss of function) e.g. p53
and retinobalstoma (pRb)