Lecture 2: Cancer development Flashcards
What is the difference between benign vs malignant tumours?
- Benign tumour cells grow only locally and cannot spread by invasion or metastasis. Whereas, malignant tumours can invade neighbouring tissues, enter blood vessels and metastasis to different sites
- Local invasion is a feature of both benign and malignant cells, nearly all benign tumours grow as cohesive, expansive masses that have the capacity to infiltrate, invade or meatstasise to distant sites. They remain localised to thier site of origin and as they grow, they usually develop a rim of compressed connective tissue, a fibrous capsule that separates them from the host tissue. In contrast, the growth of malignant cancers is accompanied by progressive infiltration, invasion and destruction of the surrounding tissue, it is very poorly demarcated from the surrounding normal tissue and a well-defined cleavage plane is difficult in surgery. Most malignant tumours are obviously invasive. Invasiveness is the most reliable feature that differentiates malignant from benign tumours.
Compare the microscopic appearance of cancer cells
Cancer cells have a large number of irregularly shaped dividing cells, large variably shaped nuclei, small cytoplasmic volume relative to nuclei, variation in cell size and shape, loss of noral specialised cell featutres, disorganized arrangement of cells, poorly defined tumour boundary
Compare the growth characteristics of benign and malignant tumours
In benign tumours, the tumour edges move outward in a smooth manner (encapsulated), grows by expansion and compresses and displaces surrounding tissues. The tumour cells stay attact hed to the clone or mass of cells and do not break away and start new growths elsewhere in the body. Whereas, malignant tumour edges move outward in an irregular fashion (usually no capsule) and can infiltrate, invade and destroy surrounding tissues. The tumour cells can break away from the cloned mass, live independentrly, move to other area of the body and start new clones or growths
Compare the rate of growth of benign and malignant tumours
Benign tumours have slow growth rates, malignant tumours have rapid growth rates
Compare the degree of vasularity of benign and malignant tumours
Benign tumours have slight vascularity whereas malignant tumours have moderate - marked vascularity
Compare the recurrence after surgical removal of benign tumours and malignant tumours
In benign tumours there is seldome recurs after removal, in malignant tumours there is frequient recurs after removal
Compare the degree of necrosis and ulceration of benign and malignant tumours
In benign tumours the necrosis and ulceration is unusual whereas, in melignant tumours necrosis and ulceration is common
Compare the liklihood of causing systemic effects in benign and malignant tumours
In benign tumours systemiic effects are unusual unless the tumour is a secreting endorcirne neoplasm. In malignant tumours, systemic effects are common and usually life threatening
What are metastisis?
Metastisis are tumours that develop secondary to and discontinuous with the primary tumour
Do benign neoplasms metastisise?
No
What do metastisis do?
Penetrate into blood vessels, lymohatics and body cavities
Can all cancers metastisise?
yes with very few exceptions - neoplasms of the glial cells in the central nervous system, called gliomas, and basal cell carcinomas of the skin
What characteritics of primary neoplasms make a neoplasm more likely to metastasise?
The more aggressive, the more rapidly growing and the larger the primary neoplasm the greater the liklihood it will metastisise
What are the most common sites of cancer matastisis and their symptoms?
- Brain: Headache, seizures, vertigo
- Lymph nodes: Lymphadenopathy
- Respirartory: cough, hemoptysis, dyspnea
- Liver: Hepatomegaly, jaundice
- Skeletal: Pain, fractures
What is the route of spread of metastise from arterys?
artery - brain - lung/ liver
What is the route of spread of metastise from lymph?
Lymph - lymph nodes
What is the route of spread of metastise from vein?
Vein - Vertebral column
What are the cancer treatment strategies?
- Surgery which is the primary treatment and most curative. It is very effective for early, non metastatic cancer. It can be used in combination with radiotherapy and chemotherapy
- Radiotherapy - can replace surgery when surgery in particular sites can cause morbidities
- Chemotherapy - is the only effective treatment that can be used for spread cancers
What is the central paradigm for designing cancer drugs?
To find what the differene between cancer and normal cells is - we want to kill cancer cells but not noral cells because this leads to toxciity. The dufferential is called the therapuetic index/ differentla
What do most conventional chemotherapy drugs target?
Cell division
What does the cell cycle regulate?
Cell growth and division
What are the 4 stages of the cell cycle?
G1, S, G2, M
What is G0 of the cell cycle?
known as Quiescene, the cells no longer divide, quienscene is reversible
What are cyclins?
Proteins which control the progression through the cell cycle, they act by activating CDK enzymes.
What do CDK do?
Signal the cell that it is ready to pass into the next stage of the cell cycle
How do cyclins work?
Cyclins bind to CDKs, activating the CDKs to phosphorylate other molecules that will allow the cell to progress through the cell cycle. The cyclin- DSK complex acts as a protein kinase which triggers downstream processes. Without cyclins CDK is inactive.
What are CDKs controlled by?
Inhibitors Eg P21 protein
What is p21 protein?
also known as cyclin dependant kinase inhibitors 1 or CDK interacting protein 1, it’s a CDK inhibitor that inhibits the complex of CDK 2 and CDK 1 which are in turn controlled by oncogenes and tumour suppressor genes such as p53
What is p53?
protein that regulates the cell cycle and hence functions as a tumour suppressor gene which are important for cells in multicellular organisms to suppress cancer
What are cell cycle checkpoints?
These are points at which the cell checks whether it is ok to proceed with the cycle. It checks on DNA damage and chromosome alignment. If its not okay then cells will arrest at these points. Cells can either repair or apoptose.
Describe cell cycle checkpoints in cancer cells
In cancer cells, if the repair is faulty then the cells progress and divide which leads to genomic instability and mutation.
What is cell arrest controlled by?
p53 and pRB
What is Rb protein?
tumour suppressor, which plays a pivotal role in the negative control of the cell cycle and in tumour progression. It has been shown that Rb protein is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth
What are the hormone related canacers?
- Breast
- Endometrium
- Ovary
- Prostate
- Testis
- Thyroid
- Osteosarcoma
- Cervical
- Vaginal
What is the mechanism of carcinogeneisis in hormone related cancers?
Endogenous and exogenous hormones drive cell proliferation and thus the opportunity for the accumulation of random genetic errors. The emergence of a malignant phenotype depends on a series of somatic mutations.
What are the possible carcinogenic mechanisms of estrogen?
- Estrogen binds to receptors and sends growth signals to the cell
- Estrogen also directly induces cell growth pathways such as MAP kinase pathway
- Estrogen metabolism makes nasty metabolites which can directly cause DNA damage
what are the risk factors for breast cancer?
- Early menarche: internal hormones in the body earlier so will be around for longer so more likely to cause carconigenic effect
- Late menopause: internal hormones are around for longer, more chance of inducing cancer
- Alcohol consumption
- Post menopausal obesity
- HRT: additional hormones in the body so more likely to drive cancer
What are the protective factors for breast cancer?
- Young age at full term pregnancy
- Prolonged lactation
- Exercise reduces carcinogenic effects of oestrogen
How does being overweight cause cancer?
- Fat cells make extra hormones and growth factors
- Hormones and growth factors tell cells in our body to divide more often
- This increases the chance of cancer cells being produced
- Which can continue to divide and cause a tumour
How do you target the oestrogen receptor?
- Reduce/ block the formation of oestrogen by using drugs called aromatase inhibitors such as aromasin
- Block oestrogen interaction with oestrogen receptor by using oestrogen receptor antagonist eg tamoxifen
What is tamoxifen?
Sold under the brand name Nolvadex. It is used to prevent breast cancer in woman and to treat breast cancer in men and woman.
What is hormone receptor positive breast cancer?
Hormone receptor-positive breast cancer is sensitive to hormones like estrogen, which can promote the growth of cancer cells.
What is tamoxifen therapy associated with?
- prolonged disease free survival irrespective of age menopausal status or nodal status
- decreased mortality irrespective of age menopausal status or normal status
- increase survival benefits with increased duration of therapy
- reduced risk of development of new primary breast tumours
- positive effects on bone mineral density and reduces risk for cardiovascular disease
What are the adverse effects of tamoxifen?
- woman who are pre menopausal and are administered tamoxifen, it brings on menopause because eastrogen can’t bind to the various things in the body that require for this to happen before menopause are affected so you get all the effects of menopause plus things like anorexia and atrophy of the lining of the vagina
What is arimidex and how
Arimidex is the brand name for the generic drug anastrazole. It is used usually for the treatment of hormone receptor positive breast cancer in post menopausal woman. Arimidex belongs to a class of drugs called aromatase inhibitors. It works by inhibiting the enzyme aromatase, which is responsible for converting androgens into oestrogen in postmenopausal woman. By reducing oestrogen levels, aromidex helps slow down or stop the growth of hormone receptor positive breast cancer cells.
How is arimidex administered?
Typically taken orally in the form of tablets. 1 tablet (1mg) a day. Can be taken with or without food. Important to take its at the same time each day to maintain consistent levels of the drug in your body. Take the medication whole, don’t crush or chew as it will change the way the drug is absorbs
What is arimidex indicated for?
Primarily indicated for the treatment of hormone receptor positive breast cancers in postmenopausal woman
What are the side effects of arimidex?
- hot flush
- alopecia
- appetite decrease
- arthritis
- fatigue
- nausea and vomiting
- headache
What is femara and what is it used for?
Femara is the brand name for the generic drug letrozole. It is a aromatase inhibitor so also treats hormone receptor positive breast cancer in postmenopausal woman
How is fermara administered?
Oral tablet form. Usual dose is 2.5mg tablets once a day. It can be taken with or without food. It should be swallowed whole and not chewed or crushed.
What is aromasin and what is it used for?
Aromasin is the brand name for the generic drug exemestane. It is an aromatase inhibitor used in the treatment of hormone receptor positive breast cancer.
How is aromasin administered?
Taken orally as a 25mg tablet. To be taken after a meal.
what are the side effects of aromasin?
- alopecia
- decreased appetite
- bone fracture
- depression
- GI upset
What is Estrogen receptor negative breast cancer
Cells have evolved, so they have become self sufficient in growth signalling. They don’t require a growth factor to bind to the receptor to drive cell division. So tamoxifen and aromatase inhibitors would be no use in these estrogen receptors.
What is the difference between tamoxifen and aromatase?
Aromatase inhibitors tend to be used when tamoxifen fails
tamoxifen acts by inhibiting oestrogen binding to the oestrogen receptor ands stopping the signal transduction process that caused cells to proliferate, whereas aromatase inhibitors act earlier in the pathway to inhibit the production of oestrogens.
What are the breast cancer subtypes?
- oestrogen receptor positive
- HER2 positive
- Triple negative: don’t express the oestrogen receptors so cant be targeted by targeted therapies
What is Herseptin (trastuzumab) and how does it work?
One of the first personalised medicines for cancer. Herceptin works by binding to the monomers of the receptor and prevents them from dimerizing and sending the growth signals. Herceptin binding to cells also shows an anti tumour response through the immune system.
What is HER2 breast/ stomach cancer?
HER2 protein is a growth factor with binds to HER3 receptors and the receptor dimerizes. The dimersation causes the activation of a signal which tells cells to grow. In HER2 breast/ stomach cancer cells, there is over expression of HER 2 proteins, causing cells to grow too quickly.
What is the mechnism of action of herseptin?
Herceptin is a monoclonic antibody. It is a chimeric antibody, this means it has some part of human proteins and some parts of mouse antibodies. This is partly why the drug has 2 actions. The immune mechanism of herspetin occurs through antibody dependant cell mediated cytotoxicity and through lysis of HER2 expressing cells through complement activation.
What are the side effects of herseptin?
An infusion reaction since the drug is administered through IV administration – itching, flushing, nausea, headaches and abdominal pain
Sometimes patients will develop immunogenicity against subsequent administration of Herceptin – they develeop HAMA human antimouse antibodies towards herceptin
What is triple negative breast cancer
These cancers lack the oestrogen receptor, progesterone receptor and Herceptin receptor so there is no targeted therapies. This type of cancer is much more aggressive, they tend to occur at a younger age, a higher grade, larger tumour, they aggressively relapse. They have high proliferation, poor differentiation, basal marker cytokeratin 5/6 expression, and aggreaive clinical course with early relapse and decreased survival. Triple negative tumours have specific morphologic characteristics: elevated mitotic count, tumour necrosis, pushing margin of invasion, and stromal lympmhocytic response and higher nuclear-cytoplasmic ratio
What are the treatment options for hormone receptor positive cancers?
- Surgery
- Chemotherapy
- Radiotherapy
- Targeted: tamofxifen and other anti-endocrine therapy
What is the treament options for HER2 and hormone receptor positive tumouts:
- Surgery
- Chemotherapy
- Radiotherapy
- Targeted: Herceptin and other anti-HER2 therapy
What are the treatment options for Triple negative breast cancer?
- Surgery
- Radiothetrapy
- Chemothrepay
- No targeted therapy
Why is chemotherapy given before surgery?
to shrink a larger cancer enough to make an operation possible. Or it might mean that you can have an area of the breast removed, instead of needing a mastectomy
Why is chemotherapy given after surgery?
to reduce the risk of breast cancer coming back
What is prostate cancer
Prostate cancer is a hormonally driven cancer. In the first instance prostate cancers grow in the prostate gland locally and are locally invasive. These tumours are androgen dependant, they require androgen to grow. Usually 100% survival rate, however if the cancer is not detected due t similar symptoms to aging, you get recurring metastatic cancer and this is called castration resistant prostate cancer. This means the cancer no longer relies upon male hormones to drive their growth – this is incurable
What is the endocrine control of the prostate?
The testis produce testosterone, this activates cell growth in the prostate. The hypothalamus also produces hormones which activated the pituitaries to produce adrenal androgens, and these all. Normally will have very controlled growth in the normal prostate, but these can also derive cancers in this area.
What are the treatment strategies for prostate cancer?
- All strategies are couples with active surveillance – monitoring the levels of prostate specific antigen
- Surgery – radical prostatectomy
- Radiotherapy – brachytherapy
- Chemotherapy
- Androgen depravation therapy: androgen receptor antagonists eg chlormadinone acetate or flutmide. Also inhibitors of androgen synthesis eg abiraterone
What is the role of androgens in promoting prostate cell growth
The major androgen in males is testosterone. Other androgens include DHT. Androgens are also the precursor to estrogen in males and females. In normal prostate, androgen regulates the expression of genes that will result in cell division. In prostate cancer tumour cells, the androgen receptor will drive the proliferation and drugs such as abiraterone is a partial agonist of the androgen receptor
What are the principles of androgen deprivation therapy?
- Prostate cells normal and malignant are physiologically dependent on androgens to grow function and proliferate
- Testosterone is the primary male androgen the testes are the major source of testosterone the adrenal glands also produce a week and regions this can be converted into more potent testosterone overall though their effect is negligible in comparison to testosterone production in the testes
- Dihydrotesterone DHT is a metabolite of testosterone and is a more potent underline testosterone doesn’t cause prostate cancer but promotes and encourages growth 100 and deprivation can help in just a pop ptosis or at the very least prevent further growth it can be achieved in two main ways 1. surgical or medical castration. This stops the production of testosterone 2. antiandrogen therapy less inhabits the action of testosterone and prevents the interaction with the receptors on the prostate cancer cells
What are the 2 classes of anti-androgen therapy?
- Androgen biosynthesis: inhibit androgen biosynthesis
- Androgen receptor blockers
What is the mechanism of action of enzalutamide?
the drug inhibits androgen binding to the androgen receptor, which stops the growth and translocation to the nucleus.
What is the mechanism of action of abiraterone?
Abiraterone prevents the synthesis of androgens. The androgen cant bind to the receptor and drive growth.
