Molecular basis of cancer Flashcards
Principles of basis cancers- factors that cause it
Tissue homeostasis
- This is key in cancer
Normal cell proliferation process
What do we mean by cell growth and proliferation
Mitogen - instruct cell to divide
Growth factors.- activation needed of nutrient uptake and utilisation
Signalling pathway example to membrane biosynthesis required for cell growth, and increased protein mTOR
Cell cycle block
- The term: cell cycle block” dneoates a molecular circuity operating in cell nucleus that processes and itnegrates a variety of afferent (incoming) signals originating from outside and isnide the cells and decides whether or not the cell should enter into active cell cycle or retreat into a non proliferating state
- In the event that acitve proliferation is decidded upon, this circuitry proceeds to program the complex sequence of biochemical change sin a cell that enabled it to doubles its contents and to divide into 2 daughter cells.
Checkpoint control system in cell cycle
- The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock
- The cell cycle control system is regulated by both internal and external controls
- The clock has specific checkpoints where the cell cycle stops until a go ahead signal is received
- Signals indicate if key cellular processes have been completed correctly
- 2 types of regulatory proteins are invovled in cell cycle control cyclins and cyclin-dependent kinases (Cdks)
- The activity of a Cdk rises and falls with changes in the concentration of its cyclin partner.
The 4 classes of Cyclins
Pairing of cyclins with cyclin-dependent kinases
Each type of cyclin pairs with a specific cyclin- dependent kinase (CDK) or set of CDKs
- D-type cyclins (D1, D2, and D3) bind CDK4 or CDK6
- E-type (E1 and E2) bind CDK2
- A-type cyclins (A1 and A2) bind CDK2 or CDC2
- B-type cyclins (B1 and B2) bind CDC2
Fluctuation of cyclin levels during the cell cycle
Induction of D-type cyclin expression by extracellular signals: source signal and intermediates and type of Cyclin D
Cell cycle dependent phosphorylation of Rb
- The phosphorylation state of Rb (red circle) is closely coordinated with cell cycle advance.
- As cells pass through the M/G1 transition, virtually all of the existing phosphate groups are stripped off Rb, leaving it in anunphosphorylated configuration.
- As cells progress through G1, a single phosphate group is attached as any one of 14 different phosphorylation sites (by cyclin D-CDK4/6 complexes), yielding hypophosphorylated Rb
- However, when cells pass through the restriction (R) point, cyclin E– CDK2 complexes phosphorylate Rb on at least 12 more sites, placing it in a hyperphosphorylated state.
- Throughout the remainder of the cell cycle, the extent of Rb phosphorylation remains constant until cells enter into M phase.
The functional consequences of phosphorylation on Rb
Non-phosphorylated Rb:
- Binds transcription factors collectively called E2Fs
- Prevents E2F-mediated transcriptional activation of many genes whose products (e.g., DNA polymerase) are required for DNA synthesis
Phosphorylated Rb:
- Cyclin D–CDK4/6 kinase activity phosphorylates Rb starting in mid- G1.
- Complete phosphorylation inactivates Rb and disassociates E2Fs to turn on genes required for transition to S and for DNA synthesis, irreversibly committing the cell to DNA synthesis.
- Deregulation of the cell cycle and genome maintenance pathways can cause cancer.
- Mutations that promote unregulated passage from G to S phase are oncogenic in ~80 percent of human cancers.
Rb loss-of-function mutations contribute to cancer:
- Childhood retinoblastoma, a relatively rare type of cancer
- More common cancers that arise later in life (e.g., carcinomas of lung, breast, and bladder)
CDK inhibiitors
- p27Kip1 blocks cyclin A–CDK2 function by obstructing the ATP-binding site in the catalytic cleft of the CDK.
- Inhibitors of the INK4 class, such as p16INK4A, bind to CDK6 and CDK4. These CDK inhibitors distort the cyclin- binding site of CDK6, reducing its affinity for D-type cyclins. At the same time, they distort the ATP-binding site and thereby compromise catalytic activity.
INK4b-ARF-INK4a locus encodes 3 TSG
P53 “guardian of the genome)
- The p53 (TP53) gene is located on chromosome 17p13.1, and it is the most common target for genetic alteration in human tumours
- p53 acts as a “molecular policeman” that prevents the propagation of genetically damaged cells
- G1/S and G2/M checkpoints
- p53 inhibits neoplastic transformation by three
- interlocking mechanisms:
- activation of temporary cell cycle arrest (quiescence)
- induction of permanent cell cycle arrest(senescence)
- triggering of programmed cell death(apoptosis)
- Homozygous loss of p53 occurs in virtually every type of cancer, including carcinomas of the lung, colon, and breast — the three leading causes of cancer death
Tumour viruses
- The World Health Organization estimates that 15.4% of all cancers are attributable to infections and 9.9% are linked to viruses
- Cancers that are attributable to infections have a greater incidence than any individual type of cancer worldwide
- Eleven pathogens have been classified as carcinogenic agents in humans by the International Agency for Research on
- Cancer (IARC)
- After Helicobacter pylori (associated with 770,000 cases worldwide), the four most prominent infection-related causes of cancer are estimated to be viral:
- human papillomavirus HPV (associated with 640,000 cases)
- hepatitis B virus (HBV) (420,000 cases)
- hepatitis C virus (HCV) (170,000 cases)
- oEpstein-Barr virus EBV (120,000 cases
- It has been shown that viruses can contribute to the biology of multistep oncogenesis and are implicated in many of the hallmarks of cancer
- Notably, the discovery of links between infection and cancer types has provided actionable opportunities, such as the use of HPV vaccines as a preventive measure, to reduce the global impact of cancer
Tumour viruses and how they often seek to inactivate Rb and p53 tumour supressors
- Diverse group of viruses specify oncoproteins that are designed to inactivate Rb and usually p53.
- These viruses have evolved to optimize only one outcome – their efficient multiplication in tissues of
- infected hosts.
- Most viruses parasitize the host-cell DNA replication machinery in order to replicate their own genomes; this machinery is available only in the late G1 and S phases of the cell cycle. Consequently, these viruses need initially to inactivate Rb as well as p107 and p130, thereby causing infected, initially quiescent cells to advance into S phase.
- Cells infected by these various viruses respond to Rb inactivation by activating their p53 alarm systems.
- Direct response to the excessive activity of E2Fs that results from the functional inactivation of Rb.
- Human papillomaviruses (HPVs) function differently.
- Infect replicating cells in the cervical epithelium and block the normally occurring exit from the active cell cycle that takes place as these cells differentiate.
DNA Tumour viruses - Human papillomavirus
- Baltimore group I (dsDNA) from the Papillomaviridae family
- Oncogenic potential of HPV can be related to the products of two viral genes, E6 and E7
- The E6 protein binds to and mediates the degradation of p53 and BAX (pro-apoptotic member of the BCL2 family) and it activates telomerase
- The E7 protein binds to the Rb protein and displaces the E2F transcription factors that are normally sequestered by Rb, promoting progression through the cell cycle
- Low-risk strains of HPV (1,2,4,7) cause squamous papilloma (benign warts) while high-risk strains of HPV (16,18) are implicated in cervical cancer in humans
- E6 and E7 from high-risk strains of HPV have higher affinity for their targets than do E6 and E7 from low-risk strains of HPV
Human T-cell Leukemia virus Type 1 - DNA tumour virus
- HTLV-1 causes a form of T-cell leukemia/lymphoma that is endemic in Japan and the Caribbean.
- Baltimore group VI (ssRNA-RT) retrovirus from the Retroviridae family
- The viral DNA gets integrated into the host chromosome and the Tax protein inactivates p53. Also inactivates p16/INK4a, and activates cyclin D, thus dysregulating the cell cycle.
- Ultimately, a monoclonal T cell leukemia/lymphoma results when one proliferating T cell suffers additional mutations.
Tumour viruses often perturb Rb, p53 and or apoptotic function
A critical step in tumourigenesis - viral integration
Classes of Gene implicated in Onset of cancer
How can cancer result from the expression of mutant forms of seven types of proteins
The landscape of mutations - Mutations arising in only about 1% of genes are cancer critical
Gain vs loss of function mutation
A 2 (or multi) step hypothesis in the landscape of mutations:
Retinoblastoma (RB) gene and Knudsons canonical “2 hit” hypothesis oncogenesis
The RETINOBLASTOMA (RB) gene
RB, the first, and prototypic, tumour suppressor gene discovered.
**Knudson’s canonical “two-hit” hypothesis of oncogenesis** Two mutations (hits), involving both alleles of RB at chromosome locus 13q14, are required to produce retinoblastoma.
Possible ways of eliminating normal Rb genes
Epigenetic changes that can lead to cancer
Not all TSG mutations are recessive in classical sense
Types of activating mutations
Multi-step hypothesis in carcinogenesis
Carcinogenesis is a multistep process resulting from the accumulation of multiple mutations:
- these mutations accumulate independently in different clonal cells, generating subclones with varying abilities to grow, invade, metastasize, and resist (or respond to) therapy.
- over a period of time tumours not only increase in size but become more aggressive and acquire greater malignant potential (tumour progression)
Evolutionary cloncal selection process and predictions
Evolutionary (“survival of the fittest”) clonal selection process.
- First mutation – gives one cell a slight growth advantage
- Second mutation – in a progeny cell causes its descendants to grow more uncontrollably and form a small
Predictions:
- Cells in a given tumour should have at least some genetic alterations in common – usually found
- Cancer incidence should increase with age – can take decades for the required multiple mutations to occur
Third mutation – in a cell within the tumour allows it to overcome constraints imposed by the tumour microenvironment and outgrow the others to form a mass of cells, each of which has all three genetic changes
Fourth mutation – in one cell allows its progeny to escape into the bloodstream and establish daughter colonies at other sites (hallmark of metastatic cancer)
Multi step hypothesis and APC tumour supression gene
- APC tumour-suppressor gene mutation in a single epithelial cell – causes the cell to divide to form a localized polyp of benign tumour cells
- Expression of a constitutively active Ras oncoprotein and loss of the tumour-suppressor gene TP53 generate a malignant cell
- Cell progeny invade the basement membrane that surrounds the tissue, but do not penetrate the basement membrane of capillaries
- Some tumour cells invade blood vessels, which will distribute them to other sites in the body
- Additional mutations permit the tumour cells to exit from the blood vessels and proliferate at distant sites
Stages on progression in the development of cancer of epithelium of uterine cervix
Pathologists use standardized terminology to classify the types of disorders they see, so as to guide the choice of treatment:
- In a stratified squamous epithelium, dividing cells are confined to the basal layer.
- In low-grade intraepithelial neoplasia, dividing cells can be found throughout the lower third of the epithelium; the superficial cells are still flattened and show signs of differentiation, but this is incomplete.
- In high-grade intraepithelial neoplasia, cells in all the epithelial layers are proliferating and exhibit defective differentiation.
- True malignancy begins when the cells move through or destroy the basal lamina that underlies the basal layer of epithelium and invade the underlying connective tissue
Benign, Mlaignant examples
Limitless replicative potential in tumour cells
Limitless replicative potential:Tumour cells have unrestricted proliferative capacity, avoiding cellular senescence and mitotic catastrophe.
- Two barries prevent cultures cells from replicating indenfinitely in culture - senescence and crisis
- Senescence invovles cells exsiting long-term in a non growing but viable state
- Crisis involves apoptotic death in cells.
- Most normal human cell shave a capacity of 60-70 doublings
- After this, the cells lose their ability to divide and become senescent
- This phenomenon has been ascribed to progressive shortening of telomeres at ends of chromsomes
- In cells that have disabled chekpoints, DNA repair pathways are inappropriately activated by shortneded telomeres, leading to massive chrosomal instability, mitotic crises and cell death
- Chromosomal instability leads to breakage-fusion-bridge (BFB) cycles and aneuploidy and acquisition of mutant alleles
- Cells that can escape crisis by activating hTERT telomerases, thus staving off mitotic catastrophe and ahcieving immortality
- hTERT is a specialised to elongate telomeric DNA by extending it in to hexanucleotide increments
Invastion-metasisis cascade
The sequence of events in the invasion of epithelial basement membranes by tumour cell
Intravasation
Extravasation
Ability to invade and metastasize
Metastatic organotropism
Epithelial-mesenchymal transition (EMT)
EMT is a process in which epithelial cells disaggregate and exhibit dramatic shape changes.
Ø EMT is essentially a process where cells acquire a “de-differentiated” phenotype
Ø Transitioning epithelial cells lose polarity and intercellular contacts and gain mesenchymal properties:
- increased migratory capacity
- increased contractility
- increased production of extracellular matrix proteins
