STUDY GUIDE FOR EXAM 3, BIO 302 Fall 2019

STUDY GUIDE FOR EXAM 3, BIO 302 Fall 2019

• Do cancer cells do anything (have behaviors) that normal cells cannot ever do?• Do cancer cells have molecular features that normal cells never have?• What are the key differences between cancer cells and normal cells?What causes cancer?• What’s a mutation?

• Permanent change in the nucleotide sequence of DNA of a gene that can be

passed on to daughter cells with cell division.

• Can change form and/or function, change structures of proteins, change functions

of cell pathways and behaviors, and can change the amount of RNA or protein made.

• Name some ways of causing a mutation:

• Duplication (gene amplification), deletion, single nucleotide substitution,

translocation, inversion of a nucleotide sequence, insertion of a new sequence (viral) Mutation types • What are driver genes?

• Oncogenes and tumor suppressor genes
• either control proliferation (oncogenes) or genes that “fix” mutations and control

ability to divide

• Oncogenes

▪ PUSH CELL DIVISION IN SOME WAY, the first hallmark between ALL cancers are UNCONTROLLED CELL PROLIFERATION ▪ mutated form of proto-oncogene, which control signals to cells to divide, they “push” growth ▪ Don’t need signal from a growth factor “gain of function” ▪ genes that drive cell division are always “on” or gain function ▪ Only takes a mutation in 1 of 2 alleles for the adherent function to occur, dominant mutation

• Tumor suppressor genes

▪ SUPPRESSING TUMORS. Suppressing cells with mutations that go on to divide ▪ control repair of DNA damage (change in DNA sequence) repairs replication damage or if unable to repair the genes that control the cell cycle identify the mutated cells and apoptosis “cell suicide” ▪ Almost always recessive mutations ▪ Inactivated tumor suppressor genes: inhibit cell division are “off” or lose function

• What are passenger genes?

• genes other than driver genes that get expressed on the surface of cells that are

recognized by the immune system ▪ More mutations that have, mutational burden, the better the immune response is likely to be ▪ Beneficial in a therapeutic essence

• produce TSA (tumor specific antigen)

• only significant if it lands in a gene that would affect the behavior of the gene

o Mutations: Some of the DNA changes are in genes that don’t change the

behavior of the cell

• The more passenger gene mutations you have, the more likely your immune

system is active to these and the more you respond to therapy

• A passenger mutation has no effect on the fitness of a clone (recessive)

• What is the epigenome?

• DNA methylation and gene silencing – a Rx target?
• Histone modification and gene silencing – a Rx target?
• Epigenetic silencing of tumor suppressor genes is reversible.

Name the Hallmarks of Cancer – what’s their basis?• Sustained proliferative signaling – what are oncogenes? Cell surface through nucleus and cell cycle (positive regulators like cyclins)

• Increasing growth factor production/utilization
• Producing it’s own growth factors
• Increasing the number receptors on cell surface
• Utilizing mutated receptors
• Activating downstream proteins in the growth pathway
• Stimulating normal cells to produce more growth factors

• Evading growth suppression – what are tumor suppressor genes?

o Caretakers: damage detection and repair enzymes

• Gatekeepers: DNA damage cell cycle checkpoint control: repair or die

▪ Why is tp53 tumor suppressor gene so important?▪ It REGULATES THE CELL CYCLE and is the primary gatekeeper – it is called “the master tumor suppressor gene” and is the most commonly mutated tumor suppressor gene in cancer ▪ p53 is also known as “the guardian of the genome” because ▪ it is responsible for detecting DNA damage in the genome and eliminating cells with damaged genomes ▪ p53 also promotes normal aerobic metabolism so ▪ its loss pushes the cancer cell to anaerobic metabolism

• Invasion and metastasis: Describe the steps required for

metastasis.

• EMT to MET

• Disengaged from fellow epithelial cells on both sides and basement and changes its

ability to move and attachment complex

• Epithelium to mesenchymal transition EMT not to cover wound but to

metastasize

o 1st line of metastasis in lymphatics : in the lymph nodes connected in series

• Then into the venous system and can go anywhere

▪ What is EMT? What happens during this process and what abilities does it confer on the cancer cell?▪ Epithelium to mesenchymal transition ▪ process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cell ▪ What is MET? What happens during this process and what abilities does it confer on the cancer cell?▪ capable of free movement within tissue

• MET- going back to an epithelial cell (planted)
• EMT- removes self from other cells

• Is metastasis an efficient process (i.e., do most cancer cells have all the capabilities needed for successful metastasis?▪ No, most cells are not successful in metastasis

• Resisting cell death: apoptosis

• Normal way to eliminate defective or senescent cells and maintain cell balance in

body

• The cancer cell increases cell death (apoptosis) inhibitors (like Bcl2) and

decreases cell death activators (like Bax); mutated cells escape cell death!▪ P53 here again • Replicative immortality

• Telomeres
• No damage consequence (p53 again)

• Angiogenesis

• inducing growth of new blood vessels for a private blood supply

▪ VEGF, FGF, PDGF etc. – growth factors from tumor and cells in environment • Avoiding immune destruction

o Multiple mechanisms: immune suppressive cytokines; checkpoint inhibitor over-

expression • Deregulating cellular energetics

• Cancer cells use glycolysis (anaerobic metabolism) and lactate production in the

presence of oxygen instead of aerobic glycolysis – called the Warburg effect (normal cells use anaerobic glycolysis only when oxygen is absent)

• Less ATP produced but many other beneficial effects for the cancer cell result
• Glycolysis leads to increased lipid and nucleotide production to support cell

proliferation

o Lactate: stimulates growth factor production by tumor-associated macrophages

and other cells leading to angiogenesis

• Lactate stimulates mitosis, invasiveness in cancer cells
• Some tumor cells can even utilize lactate as fuel

• Enabling characteristics:

• Genomic instability and mutation

o Tumor-promoting inflammation: what is the tumor microenvironment??

Cytokines, chemokines proteases that allow the tumor to manipulate its environment to support its growth and survival

• Describe cancer as a complex adaptive system (CAS): what are the key features of cancer as a CAS that pose challenges to therapy?

• Typical features of a complex adaptive system
• Number of component elements is sufficiently large that conventional

descriptions are not only impractical, but cease to assist in understanding the system

• Interactions among components are rich

▪ EX. element or subsystem in the system is affected by and affects several other elements or sub-systems

• The interactions are non-liner

▪ small changes in inputs, physical interactions or stimuli can cause large effects or very significant changes in outputs

• Disproportionate response is referred to as chaos

▪ chaos is a property of the system

• System is open and may be difficult or impossible to define system boundaries
• Operate under far from equilibrium conditions and require a constant flow of

energy to maintain the system

• Evolve and are “adaptive”

o NOT predictable: characterized by irregular unpredictable behaviors

• Describe cancer as an evolutionary system and the necessary and sufficient

requirements for evolution that cancers possess:

• variation in the population; variation is heritable; variation affects reproduction

and survival

• What is meant by “cheating” on multicellular cooperation?

▪