Lecture 25. Transformation and

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Lecture 25. Transformation and
Oncogenesis. Flint et al, Chapter 18
• Cancer: a genetic disease
• Results from growth of successive populations of
cells in which mutations have accumulated
• Alteration of steps in regulatory pathways that
control cell communication and proliferation
• Uncontrolled growth  Cellular disorganization 
Cancer
• Approx. 20% of all human cancers are of viral origin.
• Viruses are major causes of liver and cervical
cancers
• Malignancy can result as a consequence of a side
effect of viral infection or of host response to virus.
Some cancer terms (Box 18.1)
• Neoplasm: an abnormal new growth
• Benign: a growth that does not infiltrate into surrounding
tissues.
• Malignant: Any disease of a progressive, fatal nature
• Tumor: swelling; caused by abnormal cell growth not from
inflammation; can be benign or malignant.
• Cancer: A malignant tumor; growth not encapsulated;
infiltrates into surrounding tissues; spread by lymphatic
vessels to other parts of body; death caused by destruction of
other organs, by extreme debility and anemia or by
hemorrhage.
• Carcinogenesis: Complex multistage process by which
cancer develops.
• Oncogenic: causing a tumor
• Metastases: Secondary tumors derived from cells of primary
tumor that disseminated to other parts of the body.
Types of cancers
Cancers get their names based on the tissue of origin
• Adenoma: A cancer of hormone secreting cells. Many
cancers of reproductive tracts.
• Carcinoma: cancer of epithelioid tissue
• Fibroblast: tissue derived from connective tissue
• Fibropapilloma: Solid tumor of cells derived from
connective tissue
• Hepatocellular carcinoma: a cancer of liver epithelial
cells
• Endothelioma: any tumor, particularly a benign one,
arising from the endothelial lining of blood vessels
• Leukemia: A cancer of white blood cells
• Lymphoma: a cancer of lymphoid tissue
• Retinoblastoma: Cancer of retinal cells
• Sarcoma: A cancer of fibroblasts
Transformed cells (Table 18.1)
Much of what we know about cancer is derived from
studies of Transformed Cells
These have abnormal growth parameters and behaviors:
• Immortality: can grow indefinitely
• Reduced requirement for serum growth factors
• Loss of capacity for growth arrest upon nutrient
deprivation
• High saturation densities
• Loss of contact inhibition
• Anchorage independent (can grow in soft agar)
• Altered morphology (rounded and refractile)
• Tumorogenic: can cause tumors when transplanted into
animals
Sensing the environment: (Fig. 18.3)
• Cells must sense
what is going on
around them
• Cell surface receptors
interact with ligands
• Signal transduction
cascades
• Second messengers
• Activation and
repression of genes
The cell cycle (Fig. 18.4)
• Cell growth regulated
by an internal timer:
cell cycle
• Divided into 4 phases
• G1: cell growth,
restriction point
• S: DNA synthesis
• G2: preparation for
cell division
• M: Mitosis
Cell cycle control (Fig. 18.5)
•Cell cycle is controlled by the cyclin-Cdk machinery
•Different cyclins and cyclin dependent kinases
expressed at different stages of the cell cycle.
Rb protein: phosphorylation
status of Rb used to control
cell cycle
– Rb phosphorylation: allows
passage of G1 restriction
point, entry into S-phase
– Rb dephosphorylation:
signals end of M phase.
Oncogenic Viruses
• Cause cancer by inducing changes that affect
cell proliferation
• Approx 20% of all human cancers causes by
one of 5 viruses”
–
–
–
–
–
1.
2.
3.
4.
5.
Epstein-Barr virus
Hepatitis B
Hepatitis C,
HTLV I
Hum. Papillomaviruses
Oncogenic Viruses: a Genetic
Paradigm for Cancer (Fig. 18.6)
• Study of viral
transformation of cells
laid the foundations
for our current
understanding of
cancer.
• Enabled identification
of Oncogenes and
Tumor Suppressor
genes
• Foundation for the
genetic paradigm of
cancer
History
• 1908: Ellerman and Bang show that avain
leukemia could be transmitted through filtered
extracts or serum from infected birds.
• 1911: Rous showed that solid tumors could be
produced in chickens by using cell-free extracts
from a transplantable tumor (Rouse Sarcoma
Virus: the first discovered retrovirus)
• 1933: Shope isolates papillomavirus from warts
• 1978: Bishop and Varmus define oncogene
Oncogenic viruses and cancer
(Table 18.2)
Family
Associated Cancer(s)
RNA viruses
Flaviriridae
Hepatitis C virus
Retroviridae
Hepatocellular carcinoma
Haemopoetic cancers, sarcomas, carcinomas
DNA viruses
Adenoviridae
Various solid tumors
Hepadnaviridae
Hepatocellular carcinoma
Herpesviridae
Lymphomas, carcinomas, sarcomas
Papillomaviridae
Papillomas and carcinomas
Polyomaviridae
Various solid tumors
Poxviridae
Myxomas and fibromas
Insertional mutagenesis
• Integration of retroviral progenomes
mutates the genome of a cell.
• Proviral promoters can activate
transcription of nearby genes.
• Transformation can occur if the nearby
gene is an oncogene.
– e.g. c-myc
• Transformation can also occur if insertion
disrupts tumor suppressor genes.
Viral transforming genes
• 2 general strategies
–Permanent activation of cellular
signal transduction cascades
–Disruption of cell cycle regulation
Viral transforming genes
v-oncogenes (see Table 18.6, Figs. 18.7. 18.8)
• Characteristic of transforming viruses
• Cellular origin (Bishop and Varmus, Nobel Prize
1989)
• Picked up by retroviruses
• Typically fusions of viral + cellular genes
• Viral sequences alter expression, regulation and
localization of gene products
– e.g. overexpression of
myc is sufficient to induce
transformation
– e.g. v-erbB is a truncated
form of the epithelial growth
factor receptor. Expression
stimulates growth of cells by
mimicking the “on” state of the
receptor.
Viral proteins that alter cellular signaling
pathways (Fig. 18.13, Table 18.8)
• Constitutively active
viral receptors Of
viral origin, do not
resemble cellular
proteins.
• Proteins specifically
recruit and activate
signal transduction
pathways
• e.g. LMP-1 in Epstein
Barr virus
(Fig. 18.13)
Viral adapter proteins that alter
cellular signaling pathways
• See Fig 18.14, and Table
18.9
• Bind to cellular tyrosine
kinases
• Permanently activates
them
• Turns on cellular signal
transduction pathways.
• e.g. mT protein of
Polyomavirus activates
c-Src tyrosine kinase
Fig. 18.14
C-SRC
Cell cycle Regulation by the Rb protein
Fig. 18.16
Transformation via cell cycle
control pathways
• Inhibition of Rb function by viral proteins Many
viruses actively inhibit Rb function
• Result: bypass of restriction point control
• Passage from G1  S phase
• e.g. SV40 LT, adenovirus E1A, HPV E7 proteins
•(Fig. 18.17)
Transformation via cell cycle
control pathways
• Production of virus specific cyclins
• e.g. Human herpesvirus 8 v-cyclin
• Binds to and activates Cdk6  Rb
phosphorylation
• Promotes G1  S transition
Inhibition of p53 functions (Fig. 18.20, 21)
• p53 is a tumor suppressor gene
• Determines response of cells to DNA damage
and hypoxia
• p53 promotes either
– Cell cycle arrest (until problem is fixed)
– Apoptosis (unfixable problem)
• Virus infection is a stress that turns on p53
• Proteins from many viruses
mislocalize or block p53
• e.g. Adenoviruses,
papillomaviruses,
polyomaviruses
p53 regulation (Fig. 18.20)
Inhibition of p53 functions (Fig. 18.21)
Oncogenesis by hepatitis
viruses (Fig. 18.22)
• Hepatitis B (Hepadnavirus), Hepatitis C
(Flavivirus)
• Persistent infections
• Sustained low level lever damage due to
immune system attack
• Lots of cell proliferation/regeneration
• Lots of cellular DNA replication + Lots of
oxidative stress
• = Increased chance of mutation
Oncogenesis by hepatitis
viruses (Fig. 18.22)
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