Ch. 20: Cancer

Describe the metabolism of cancer cells

- Consume glucose avidly - Only a small fraction is used for oxidative phosphorylation even when O2 available - Lots of lactate produced - Remaining carbon atoms are used for raw synthesis materials

How can viruses indirectly promote tumor formation?

- Hepatitis B & C: chronic inflammation stimulates extensive cell division promoting evolution of tumor cells - AIDS: HIV destroys the human immune system that prevents secondary infections that have direct carcinogenic action (e.g. Kaposis sarcoma) - H. pylori: chronic infection of the stomach

Describe the tumor microenvironment

- Tumor relies on communication between tumour cells and tumor stroma - Stroma is composed of normal connective tissue - Cancer cells secrete signal proteins to alter the behaviour of stromal cells to their advantage - Cancerous stromal cells secrete proteins to stimulate cancer cells growth and remodel the matrix - Only the cancer cells are genetically abnormal!

Describe the Ames test.

-add suspected mutagen with rat liver extract in a test tube and add to a media lacking histidine -incubate the plate and check for colonies of revertant bacteria in comparision on a control plate that only contains the rat liver extract

How do cancer cells activate the PI-3 kinase/Akt/mTOR intracellular signalling pathway?

1. Abnormal activation of a growth factor receptor 2. Loss of PTEN phosphatase (normally suppresses the pathway, a tumour suppressor gene) 3. High levels of insulin in the circulation - type 2 diabetes

Give an example of a proto-oncogene being converted into an oncogene

1. Activation of the EGF (epidermal growth factor) receptor by a deletion that removes a part of the extracellular domain, causing it to be active even in the absence of EGF. 2. Overproduced Myc protein due to a gene amplification/a stabilising point mutation/change in a regulatory element that acts on the gene

Define the main steps of metastasis

1. Cancer cells invade local tissues and vessels 2. Move through the blood or lymphatic circulation 3. Leave circulation 4. Establish new colonies at distant sites

What external agents are linked to carcinogenesis?

1. Chemical carcinogens - simple local changes in the nucleotide sequence 2. Radiation e.g. x-rays and UV light 3. Genetic defects in DNA repair mechanisms

What are the mechanisms for inactivating tumour suppressor genes?

1. First copy lost by a chromosomal deletion/inactivated by a point mutation. 2. Second copy lost by errors in chromosome segregation or the normal gene is replaced by a mutant version through mitotic recombination or gene conversion 3. Epigenetic changes - packaged into heterochromatin, C nucleotides in CG sequences methylated. These can occur in any order along with genetic changes.

What does rational combination drug therapy include?

1. Identification of pecularities of cancer cells that make them more vulnerable 2. Drugs that target each one of these peculiarities 3. Match the combination of drugs to a specific set of peculiarities in the individual patient

How do cancers evolve resistance to anticancer drugs?

1. Initial cancer treatment fails to destroy a subpopulation of tumour cells that carry a protective mutation or an epigenetic change 2. Overproduction of a transport ATPase that prevents the intracellular accumulation of cancer drugs - multidrug resistance

How can cancers be treated with immunological therapy?

1. Injecting the patient with antibodies that target the cancer cells 2. Overcoming the immunosuppressive environment in a tumor through the use of specific antibodies that prevent the tumor cells from engaging with inhibitory receptors on T cells so that an immune response against cancer is activated; e.g. a monoclonal antibody targeting an inhibitory receptor called CTLA4

What are the 3 necessary conditions for metastasis?

1. Local invasiveness - relaxation of the mechanisms that hold epithelial cells together. EMT - switching of the E-cadherin gene (a tumour suppressor). 2. Traveling via blood or lymph node to a distant site - helped by angiogenesis due to secretion of angiogenic factors. Resulting vessels are abnormally leaky. 3. Surviving and multiplying at the new site

How do cancer cells give riser to lymph node metastases?

1. Lymphatic vessels are large and flimsy 2. Cancer cells can enter the circulation in small clumps 3. Cancer clumps become trapped in lymph nodes, forming a metastasis.

How do cancer cells avoid replicative cell senescence?

1. Maintain activity of telomerase as they proliferate - telomeres do not shorted 2. Evolve an alternate mechanisms based on homologous recombination to elongate their chromosome ends

Why are carcinomas the most common cancer in humans?

1. Most of cell proliferation occurs in epithelia 2. Most likely exposed to physical and chemical damage

What are the distinct types of DNA sequence changes found in oncogenes compared to tumour suppressor?

1. Oncogenes - same nucleotide change is repeatedly found among the missense mutations in a gene 2. Tumor suppressor - abort protein synthesis by creating stop codons

How does papillomavirus give rise to cancer?

1. Papilloma virus interferes with the cell-cycle arrest to allow the replication of its own genome in the cervical epithelium. 2. If this happens in the basal layer (e.g. integration of a plasmid into the host genome), it can lead to cancer instead of a harmless wart. The unregulated production of viral proteins also interferes with the basal cell division. Example: E6 ja E7 genes in the virus produce viral proteins that bind to tumor suppressor proteins (Rb and p53)

What mutations typically accumulate in colorectal cancers?

1. Proto-oncogene K-ras involved in receptor tyrosine kinase signalling 2. Tumor suppressor Apc involved in Wnt signalling. Both copies need to be inactivated for effect.

What are the two broad classes of cancer critical genes?

1. Proto-oncogenes - gain of function mutation drives cell toward cancer. Mutation has a dominant, growth-promoting effect of the cell. 2. Tumour suppressor genes - loss of function mutation contributes to cancer. Mutation is generally recessive so two are needed.

What heritable properties define cancer cells?

1. Reproduction in the defiance of the normal restraints on cell growth and division 2. Invade and colonise territories normally reserved for other cells

What kind of accidents can convert a proto-ocogene into an oncogene?

1. Small change in DNA sequence - point mutation/deletion 2. Gene amplification 3. A chromosomal rearrangement

List all the key attributes of cancer cells

1. They grow (biosynthesize) when they should not, aided by a metabolism shifted from oxidative phosphorylation toward aerobic glycolysis. 2. They go through the cell-division cycle when they should not. 3. They escape from their home tissues (that is, they are invasive) and survive and proliferate in foreign sites (that is, they metastasize). 4. They have abnormal stress responses, enabling them to survive and continue dividing in conditions of stress that would arrest or kill normal cells, and they are less prone than normal cells to commit suicide by apoptosis. 5. They are genetically and epigenetically unstable. 6. They escape replicative cell senescence, either by producing telomerase or by acquiring another way of stabilizing their telomeres.

Define oncogene dependance

A cancer cell having undergo an oncogenic mutation usually undergoes further mutations and changes that are reliant on the hyperactivity of the initial mutation. Blocking the activity of the oncogenic protein could therefore kill the cancer cell with little damage to its neighbours.

What is the function of p53?

A cellular stress sensor whose concentration raises in response to conditions that put the cell in danger of death or serious injury e.g. DNA damage, telomere loss, hypoxia, unregulated and uncoordinated regulatory signals (e.g. overexpression of Myc) and oxidative stress. Modes of action: - Cell-cycle arrest - Senescence - Apoptosis through promoting the transcription of p21 which prevents the cell from progressing onto the S phase and replicating its DNA.

What is a typical cancer inducing mutation in p53?

A single mutation in its DNA binding domain (tetramer) that has a dominant negative effect causing a loss of function in p53 (oncogene).

Define imatinib

A synthetic drug that inhibits the activity of the chimeric Bcr-Abl tyrosine kinase. Cancer cells can acquire resistance due to secondary mutations.

Define Rb gene

A tumor suppressor gene that encodes the Rb protein which is a universal regulator of the cell cycle by acting as a brake. Mutant in retinoblastoma.

Define Ras oncogene

Abnormal Ras proteins (monomeric GTPases) that contain point mutations making them hyperactive so that they don't shut off by hydrolysing GTP to GDP. Has a dominant effect on the cell. Proto-oncogenic.

Define cancer critical genes

All the genes whose alternation contributes to the causation or evolution of cancer by driving tumorigenesis

Define the Apc protein

An inhibitory protein in the Wnt signalling pathway that binds B-catenin protein to induce its degradation in the absence of Wnt to prevent it from acting as a transcription regulator in the nucleus to drive cell proliferation and maintaining the stem cell state.

How do cancers progress?

As a series of subclones - cancer cells constantly mutate, multiply, compete and evolve as they expand to new sites and respond to treatments (natural selection).

Define chondroma

Benign tumour of cartilage

Define adenoma

Beningn epithelial tumour with a glandular organisation

How do cancer cells avoid apoptosis?

By accumulating mutations that disable the normal safety mechanisms that would occur in the cell stress a cancer cell produces. Cancer cells typically die by necrosis e..g in a large tumour where resources are scarce.

How do many naturally inert chemical carcinogens become active in the human body?

By conversion to a more reactive molecule by metabolic processes in the liver catalysed by cytochrome P-450 oxidases that can interact with DNA. E.g. aflatoxin B1 in mold.

Define sarcoma

Cancer arising from connective tissue or muscle cells

Define metastasis

Cancer cells spread and multiply at new sites in the body, often deadly because the cancer becomes impossible to eradicate.

What is evidence for cancer being caused by progressive accumulation of mutations in a single lineage of cells?

Cancer incidence rising with age proportionally

Define lymphomas

Cancer of lymphocytes

Define leukemia

Cancer of white blood cells and their precursors

Define malignant tumor

Cancerous tumour due to cells acquiring the ability to invade surrounding tissue to form metastases

Define carcinoma

Cancers arising from epithelial cells

Define replicative cell senescence

Cell-division counting mechanisms depending on the progressive shortening of telomeres that eventually changes the chromosome structure to trigger a permanent cell cycle arrest. This is because many proliferating cells are deficient in telomerase that prevents telomeres from shortening.

Define genetically unstable

Cells that accumulate genetic changes at an abnormally rapid rate. Extent of this instability differs. Can develop from inability to repair DNA so changes in DNA sequence, e.g. translocations, develop or from defects in chromosome segregation during mitosis E.g. cancer cells contain an unusually large amount of heterochromatin (silences genes).

Define philadelphia chromosome and chimeric Abl-Bcr protein

Chromosome translocation present in chronic myelogenous leukaemia (CML) resulting from breakage and rejoining at Abl and Bcr genes, creating a hybrid Abl-Bcr gene that codes for a chimeric Abl-Bcr protein. This makes Abl (tyrosine kinase) hyperactive, stimulating proliferation of hemopoietic precursor cells in a CML patient. The protein is a target for therapeutic attack.

Describe the PI-3 kinase/Akt/mTOR intracellular signalling pathway. How is it involved in cancer?

Critical for cell growth control by stimulating glucose uptake and utilisation in the cell including conversion of citric acid cycle intermediates into acetyl CoA for lipid and protein synthesis. Abnormally activated in cancer - functions without extracellular signals.

What viruses are associated with human cancers?

DNA tumour viruses - directly interfere with apoptosis and cell cycle controls by breaking through the normal constraints of DNA replication

Define the Warbung effect

Excessive rate of glycolysis in tumour cells explained by the abnormal activation of the PI-3 kinase/Akt/mTOR intracellular signalling pathway.

How do traditional cancer therapies work?

Exploit the genetic instability of cancer - radiation and anticancer drugs damage DNA/interfere with chromosome segregation and kill hypersensitive cancer cells since they have deficiencies in repair mechanisms to survive this damage. Normal cells just arrest the cell cycle.

What are the two types of signals cells require to proliferate?

Extracellular signals to drive cell-cycle progression and cell growth (mitogens and growth factors)

Define adenocarcinoma

Malignant epithelial tumour of glandular origin

Define chondrosarcoma

Malignant tumour of cartilage

How is cancer incidence related to environmental influences?

Most cancers are preventable or avoidable. Environmental factors dictate cancer risk, e.g. smoking, diet, obesity, lack of exercise, viruses, alcohol and UV.

Define driver mutation

Mutation that causes the development of cancer. On the order of 10 for a single case of cancer. Very frequently occurrent.

Define passenger mutation

Mutation that has occurred in the same cell as the driver mutation due to genetic instability but is irrelevant for the development of the disease. Not as frequently occurrent as driver mutations.

What mutations predispose HNPCC (hereditary nonpolyposis colorectal cancer)?

Mutations in genes that code for the central components of the DNA mismatch repair system. Only one of the two copies is defective but if the other one is spontaneously lost/inactivated, spontaneous mutation rate is elevated.

Explain the cancer stem cell hypothesis

Only a subpopulation of cells within the tumor-cancer stem cells-have the ability of unlimited self renewal with a much larger number of dividing transit amplifying cells that have a limited capacity of self-renewal. It is thought cancer cells can switch between states of differentiation that express different molecular markers. The tumor cells are genetically similar but phenotypically diverse.

Define primary tumour

Original site of cancer arising by cell division from a single cell that initially experienced some heritable change.

What is the driving force for development of cancer?

Selective advantage possessed by the mutant cells - e.g. by increasing the rate at which a clone of cell proliferates and enabling it to continue proliferating when normal cells would stop. Cells show a transformed phenotype. Transformed cells continue proliferating... - in suspension - after confluence (cells pile up) - in the absence of positive signals from surroundings for divison

Define tumor progression

Initial mild disorder of cell behaviour evolves gradually into full blown cancer. It involves successive rounds of random inherited change followed by natural selection. Often over time, a variety of subclones will arise in a tumour due to diversification.

Why is multidrug therapy beneficial for cancer?

It is much less likely that there are cells carrying a whole set of rare mutations resistant to all the drugs at once

Define genome maintenance genes

Genes whose alteration results in genomic instability in order to hasten the occurrence of other inherited changes that directly stimulate tumor growth

Define oncogene

The mutant, overactive or overexpressed form of a proto-oncogene. The mutation has a dominant, growth-promoting effect on a cell.

What is the ideal treatment for cancer?

Synthetic-lethal; cell-lethal in combination with some lesion in cancer cells, but harmless to normal cells. Achieved by targeting specific mutations.

Define the Warburg effect

Tendency of tumour cells to de-emphasize oxidative phosphorylation even when oxygen is plentiful and taking up a lot of glucose at the same time to promote cancer cell growth. Allows tumours to be selectively imagined.

Define somatic mutation

Tumour cells have one or more shared detectable abnormalities in their DNA sequence distinguishing them from normal cells surrounding the tumor.

Define invasiveness

Tumour shows a disorganised pattern of growth and ragged borders, extending to surrounding tissue. Requires a disruption of the adhesive mechanisms that normally keep cells tethered. E.g. the epithelial-mesenchymal transition for carcinomas.

How do PARP inhibitors work?

Used to treat cancers that have defects in Brca1 or Bca2 genes which are required to produce a protein that aids in homologous recombination (DNA double-strand break repair), e.g. in breast and ovarian cancer. PARP inhibitors inhibit the another pathway for DNA repair using an enzyme called PARP. This kills Brca deficient cells since they have no alternative mechanism for DNA repair now.