Chapter 20: Cancer

• properties of tumor cells

• causes of cancer
• oncogenes
• tumor suppressors
• tumor viruses
• tumor promoters

(4th ed: p. 712-720) 5th ed: p. 718-729

 Benign and malignant tumors

A benign tumor remains inside the basal lamina that marks

the boundary of the normal structure (e.g. duct of a gland).

A malignant tumor (such as an adenocarcinoma, or

carcinoma of a gland) destroys the integrity of the structure.
 Properties of cancer cells

Cancer cells and transformed cells in culture share the

following properties:

• uncontrolled growth: defective cell cycle controls are

• invasive: cells can grow outside their environment of origin
• loss of adhesive properties
• immortal: cells can proliferate indefinitely
 Loss of contact inhibition

Normal cells form a monolayer and stop dividing when no

more room is available (contact inhibition).
Tumor cells do not stop dividing and can form multilayers.
 Colon cancer begins as a polyp

Loss of APC (Adenomatous Polyposis Coli)

tumor suppressor gene
 Development of a carcinoma
Carcinomas are cancers of epithelial cells, and account for
90% of all cancers.
• A genetic change in one cell that stimulates cell division
will result in the formation of a patch of cells with
increased cell division rate (regression will likely occur).
• Formation of an adenoma (benign tumor): cells can grow
on top of each other but the colony stays in the same place
(growth may stop and regression may still occur).
• Formation of a carcinoma (malignant tumor): cells invade
the underlying connective tissue (cells can now grow
outside their environment of origin).
• Metastasis (systemic invasion): malignant cells reach the
bloodstream or lymphatic system, spread throughout the
organism, and form secondary colonies at other sites.
 Progression of a cancer of the
epithelium of the uterine cervix

Neoplasia: abnormal and disorganized growth of new tissue

 Cells of the epithelium of the uterine cervix
The Papanicolaou (Pap smear) - cells are collected by
scraping the surface of the uterine cervix:

A. Normal: the cells are large and well differentiated, with

small nuclei.

B. Precancerous lesion: differentiation and proliferation are

abnormal (the cells are in various stages of differentiation)
but the lesion is not yet invasive.

C. Invasive carcinoma: the cells all appear undifferentiated

and with large nuclei.
Cells of the epithelium of the uterine cervix
 Pancreatic cancer

Pancreatic cancer is
the deadliest form
of human cancer.

Low survival = 9%

• initial stages are mostly asymptomatic, and malignant

cells rapidly invade the normal pancreatic tissue
• complete removal is difficult because the detection of
early localized tumors is rare
• most patients die within 3-6 months after diagnosis
• cancer cells have dark purple-staining nuclei (dye stains
the highly condensed DNA of dividing cells)
 Tumor development
Several mutations in the same cell are needed for the
transformation of a normal cell into a tumor cell.

• mutations that cause cancer result in:

1) the loss of tumor suppressor genes, or
2) the activation of oncogenes

• the first mutation increases the rate of cell division

(or simply returns the cell from G0 to the cell cycle)
• successive mutations further increase the rate of cell
division, resulting in clonal selection and amplification
of tumorigenic cells
 Inactivation of a tumor suppressor
The inactivation of a tumor suppressor, such as p53, alters
the control of cell division or apoptosis.

• in normal tissues, apoptosis (programmed cell death)

balances cell division to maintain homeostasis

• during the development of cancer, either an increase in cell

division or an inhibition of apoptosis lead to the
increased cell numbers leading to tumorigenesis
Inactivation of a tumor suppressor
 Causes of cancer
1) Carcinogens: any substance that can cause tumors.
- mutagens react with DNA and alter the sequence of tumor
suppressors and proto-oncogenes
2) Genetic causes: mutations that activate proto-oncogenes or
inactivate tumor suppressor genes.
3) Viruses: viral infections can lead to tumors by introducing
cancer-causing genes or by altering the normal expression
of cellular genes.
4) Tumor promoters: non-mutagenic substances that stimulate
cell proliferation.
 1) Carcinogens

Mutagens are often flat molecules that can fit within DNA
helix and interfere with DNA replication

Other Carcinogens can stimulate proliferation by altering

signal transduction pathways that control cell division
 2) Genetic causes of cancers
Proto-oncogene
• normal component of signal transduction pathway
involved in the control of cell division, such as receptor,
protein kinase, phosphatase, transcription factor
• mutational change can convert it to oncogene (cancer-
promoting)

Oncogenes
• dominant gain-of-function mutation: encodes a
constitutively active (always ON) gene product
• oncogenicity can also occur if a proto-oncogene is
expressed at higher than normal levels
 Oncogenic pathways

Ras oncogene

The product of a Ras oncogene is a mutant form of Ras that

cannot hydrolyze GTP and is independent of RTK activation.
 Proto-oncogenes

• receptors are oncogenic if they become ligand-

independent

• GTP-binding proteins are oncogenic if remain in the GTP-

bound form, or if their activity becomes independent
of the activating protein

• MAP kinases are oncogenic if their activity is

independent
of phosphorylation, or if they can not be
deactivated

• transcription factors are oncogenic if they are

The Ras-MAP pathway

GEF
 Other genetic causes of oncogenicity

Oncogenicity can also result from:

• gene amplification: multiple copies of the same gene
• chromosome rearrangement: transfer of a gene to a new
location where it will be expressed at levels above normal,
resulting in increased product activity
• a rearrangement can also yield a hyperactive fusion
 A single mutation can cause oncogenicity

A gain of function mutation converts a proto-oncogene

into an oncogene
• this is a dominant allele, a single copy is sufficient to
cause a phenotype
 Two mutations are needed to eliminate
tumor suppressor activity

A loss of function mutation inactivates tumor suppressor gene

• this is a recessive allele, so both copies of the tumor

suppressor gene must be mutated to cause a phenotype
 Control of entry into mitosis by Rb protein

The retinoblastoma Rb tumor suppressor protein binds and

inactivates the cell cycle transcription factor E2F.

• normal control: mitogens activate G1/S-Cdk to

inactivate Rb protein, and therefore allow expression of
genes required for cell proliferation

• loss of control: if there is a loss-of-function Rb

mutation, then E2F remains active, normal control of
the cell cycle is lost, and tumors form
 Normal regulation of
Rb tumor suppressor

E2F
 The genetic cause of retinoblastoma

Retinoblastomas are caused by

inactivation of the Rb tumor
suppressor gene.

• in normal, healthy individuals,

occasional mutations may
inactivate one Rb gene

• no eye tumor: one functional

Rb gene is sufficient to provide
tumor suppressor activity to
properly regulate cell cycle.
 3) Tumor viruses
Slowly-transforming viruses
• their tumorigenicity does not rely on viral genes
• random insertion of the viral genome into the host cell’s
genome may allow the strong viral promoter to
transcribe a nearby cellular proto-oncogene at higher
than normal levels
Result: oncogenicity

Acute-transforming viruses
• these viral genomes contain overactive viral-oncogenes
(cellular genes captured by virus from a previous host)
• the infected cell is transformed when v-onc is expressed
Result: oncogenicity
 Tumorigenicity of the human papilloma virus

The human papilloma virus (HPV) causes warts (benign

tumors) and may lead to cervical carcinomas.

• the viral oncoproteins E6 and E7 sequester the host

proteins p53 and Rb (both tumor suppressors)
respectively, causing a bypass of the G1 checkpoint
and promoting cell proliferation
Tumorigenicity of the human papilloma virus
 4) Tumor promoters
Tumor promoters are non-mutagenic substances that can
stimulate abnormal cell proliferation in cells that have
already been exposed to tumor initiators.

tumor initiator = mutagen that causes latent genetic

damage
- increases the incidence of cancer when the
cells are exposed again to the mutagen or to non-
mutagenic insults, such as tumor promoters

tumor promoters:
- phorbol esters - plant-derived compounds that
hyperactivate protein kinase C (PKC) > promote cell
proliferation
Tumor promoters