Lecture 25. Transformation and Oncogenesis
Flint et al, Chapter 18
BSCI437
Cancer: a genetic disease
 Results from growth of successive populations of cells in which mutations have
accumulated
 Affect 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 be a side effect of viral infection or host response to virus.
Some cancer terms (Box 18.1)
 Benign: a growth that does not infiltrate into surrounding tissues.
 Malignant: Any disease of a progressive, fatal nature
 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.
 Neoplasm: an abnormal new growth
 Tumor: swelling; caused by abnormal cell growth not from inflammation; can be
benign or malignant.
 Oncogenic: causing a tumor
 Metastases: Secondary tumors derived from cells of primary tumor that
disseminated to other parts of the body.
Types of cancers
 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: overproduction of erythrocytes
 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
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High saturation densities
Loss of contact inhibition
Anchorage independent (can grown in soft agar)
Altered morphology (rounded and refractile)
Tumorogenic: can cause tumors when transplanted into animals
Control of cell proliferation
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
o Rb phosphorylation: allows passage of G1 restriction point, entry into Sphase
o Rb dephosphorylation: signals end of M phase.
Oncogenic Viruses (Fig. 18.6)
Cause cancer by inducing changes that affect cell proliferation
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.
Approx 20% of all human cancers causes by one of 5 viruses”
1. Epstein-Barr virus
2. Hepatitis B
3. Hepatitis C,
4. HTLV I
5. Hum. Papillomaviruses
History
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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.
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
Hepatocellular carcinoma
Retroviridae
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.
o e.g. c-myc (Fig. 18.11)
 Transformation can also occur if insertion disrupts tumor suppressor genes.
Viral transforming genes
 2 general strategies
o Permanent activation of cellular signal transduction cascades
o Disruption of cell cycle regulation
v-oncogenes (see Fig. 18.7, Table 18.6)
 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
o e.g. overexpression of myc is sufficient to induce transformation
o 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
Constitutively active viral receptors (Fig. 18.3, Table 18.8)
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. 18.3)
Viral adapter proteins (Fig. 18.14, Table 18.9)
Binds to cellular tyrosine kinases
Permanently activates them
Turns on cellular signal transduction pathways.
e.g. mT protein of Polyomavirus
Transformation via cell cycle control pathways
Inhibition of Rb function by viral proteins (Fig. 18.17)
 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
Production of virus specific cyclins
 e.g. Human herpesvirus 8 v-cyclin
 Binds to and activates Cdk6  Rb phosphorylation
 Promotes G1  S transition
 See Fig. 18.16A.
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
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