intro to cancer

Question 1

what is cancer?

Answer 1

the unwanted proliferation of certain cells (unwanted cell growth)
- Not just one disease but a collection of diseases with the shared underlying features of uncontrolled cell growth and invasion

Question 2

what are the types of cancers and where does it effect?

Answer 2

carcinoma - epithelial - breast,lung, liver cancer
sarcoma - connective tissues - bone, muscle, blood vessel
myeloma - bone marrow - plasma cells
leukaemia - bone marrow - WBC, erythrocytes
Lymphoma - lymph nodes/glands - spleen, tonsils, thymus
-oma - benign tumours

Question 3

what is neoplasm?

Answer 3

: new disorganised growth with net increase in numbers of dividing cells (i.e. a tendency to excessive, uncontrolled growth). Synonymous with the more familiar term ‘tumour’ (swelling).
-precancerous tissues

Question 4

what is tumor

Answer 4

: a mass of abnormal cells.

Question 5

what is benign tumors?

Answer 5

these enlarge but do not invade the surrounding tissue, nor spread beyond their initial site.

Question 6

what is malignant tumors?

Answer 6

those that are not benign and spread beyond their initial site. These are the more dangerous tumours.

Question 7

what is metastasis?

Answer 7

invasion of a tumour to its surrounding tissue and spread beyond the original site.

Question 8

what is carcinogenesis?

Answer 8

the process of forming a cancer (via carcinogens).

Question 9

how is cancer cell formed?

Answer 9

Cancer cell is formed when a normal cell undergoes specific changes that allow it to proliferate without normal limit and spread to surrounding and/or distant tissues

Multiple changes are usually required to transform a “normal cell” into a “cancer cell”

Inherited susceptibility and/or lifestyle influences cancer progression

Question 10

what is normal cell proliferation and why?

Answer 10

Ongoing throughout life to allow development, repair or regeneration of tissues

Cell division is regulated at a number of different levels to ensure that it is a tightly regulated process

Question 11

what is the phases of cell cycle?

Answer 11

-M phase: mitosis and cytokinesis phase - prophase, metaphase, anaphase and telophase.
GAP 0 - quiescent (resting) cells
GAP 1 - RNA and protein synthesis req’d for S phase
S phase - DNA synthesis
GAP 2 - RNA and protein synthesis req’d for M phase

Question 12

how is the cell cycle regulated?

Answer 12

The activity of cyclin:CDK complexes is regulated at multiple levels:
- Expression of regulatory cyclin component of complex
i.e. Expression and activity of the factors that control cyclin expression (i.e. E2F transcription factors and pRB proteins)

Regulation of the activivty of the cyclin:CDK complex (i.e. phosphorylation/de-phosphorylation events by CDC25 phosphatases)

Direct inhibition of complex activity cyclin-dependent kinase inhibitors (i.e. p27)

Question 13

cell cycles can be regulated positively and negatively ( cell cycle inhibitors)

Question 14

what are the cell cycle checkpoints

Answer 14

M - anaphase blocked if chromatid are not properly assessmbled on mitosis spindle

G1 - DNA damage checkpoint: entrance into S is blocked if genome is damaged.

S- DNA damage checkpoint : DNA replication is halted if genome is damaged

G2 - entrance into M blocked if DNA replication is not completed.

Question 15

what are the hallmarks of cancer

Answer 15

self sufficiency in growth signals

insensitivity to anti growth signals

evading apoptosis

limitless replicative potential

sustained angiogenesis

tissue invasion and metastasis

Question 16

what is oncogene?

Answer 16

Oncogene is the term given to genes which, when mutated or overexpressed, can cause cancer. Mutations in proto-oncogenes lead to a gain of function.

Many oncogenes are involved in the regulation of cell proliferation and lead to growth signals to be constantly turned on, even in the absence of any actual signal.

Question 17

hallmark 1 - gains growth factor
what is ras

Answer 17

Ras was one of the first oncogenes discovered. In the presence of growth signals, normal Ras (the proto-oncogene) is activated and triggers other signalling events that lead to cell proliferation.

In cancer, Ras is often mutated (and becomes an oncogene) and is switched on all the time.

This leads to constant signalling to promote cell proliferation, even in the absence of a growth factor or other signal.

RAS IS transmitting messages downstream and is a growth factor

Ras is the most common oncogene found
in cancer; 20-30% of all tumours have a mutant version of Ras that is permanently switched on.

Other oncogenes include Bcr-Abl, myc, Src and PI3 kinase. In all cases oncogenes have increased activity and lead to increased cell proliferation in the absence of specific growth signals (i.e. gain independence from growth factors).

Question 18

shy is oncogenes important drug target?

Answer 18

Oncogenes are an important drug target as blocking their function should stop the proliferation of cancer cells.

Question 19

what is imatinib?

Answer 19

Imatinib is a tyrosine
kinase inhibitor that
prevents growth factor
signals promoting cell
proliferation

Question 20

Hallmark 1: gains growth factor independence
what is its role?

Answer 20

Cell loses requirement for growth factors to stimulate cell division (i.e. they gain an oncogene)

This might include:
Secretion of growth factor normally secreted by surrounding tissue
Mutation in growth factor receptor so it is constitutively activated
Mutation of components of signaling pathways or transcription factors activated by growth factors

Question 21

what is Human epidermal growth factor receptor 2 (HER2) amplified in ?

Answer 21

breast cancer
gastric
ovarian
prostate

Question 22

what is the significance of HER2 expression?

Answer 22

Her2 positive cancers are typically more aggressive
It is associated with early progression, recurrence and poor prognosis
Trastuzumab (Herceptin) blocks Her2 receptor

Question 23

Hallmark 2: insensitivity to growth inhibitors
what is its role?

Answer 23

Cell loses ability to control abnormal cell proliferation

Might result from alterations in cell cycle regulation
- Loss of tumour suppressor genes (i.e. pRb)
- Upregulation of positive cell cycle regulators (i.e. CDC25 or cyclins )

Question 24

what is the function of the tumor supressor gene?

Answer 24

Tumour suppressor genes perform the opposite function to oncogenes in that they stop tumours from forming.

In many cases, two-hits are required to inactivate a tumour suppressor gene.

Question 25

what are examples of tumor suppressor genes and what are they involved in?

Answer 25

Examples of tumour suppressor genes include pRB, p53 and BRCA.

In most cases tumour suppressor genes are involved in detecting DNA damage and mutations and then either triggering apoptosis or DNA repair.

Question 26

what does mutation of tumor suppressor genes lead to?

Answer 26

Mutations in tumour suppressor genes lead to loss of function. This makes it hard to develop drugs that target them.

Question 27

what is the most mutated gene in cancer?

Answer 27

p53 is the most common mutated gene in cancer - found in 50% of all human cancers.

Question 28

what is the functions of p53?

Answer 28

blockage of transcription
hypoxia
oncogene signalling
ionizing radiation
UV radiation
lack of nucleotide
apoptosis
block of angiogenesis
DNA repair
cell cycle arrest - return to proliferation or senscenes

Question 29

Hallmark 3: proliferate without limit
what is the role?

Answer 29

Most cells cannot proliferate indefinitely (40-60 cell divisions)

Cell division is limited by telomere length

Telomeres normally shorten with every cell division (with exception stem cells and cancers).

Question 30

how can you rebuild telomeres

Answer 30

Tumour cells are effectively immortal and can rebuild their telomeres using the enzyme telomerase.

Question 31

Hallmark 4: avoid apoptosis
role

Answer 31

Apoptosis can be triggered in cells by DNA damage and viral infection, two things which can lead to the development of cancer. Apoptosis is also the mechanism through which chemotherapy and radiotherapy kills cancer cells.

• dont burst like necrosis, form tiny vesicles which can be taken up by macrophages = no inflammations.

Cancer cell gains ability to “avoid” apoptosis;

Resistance to apoptosis signals can be gained from from:
1. Gain of function (over-expression) of pro-survival factors (i.e. IGF)
2. Loss of function of pro-apoptotic factors (i.e. p53)

Question 32

what doed IGF-1 do?

Answer 32

IGF‐1 is known to promotecancerdevelopment by inhibiting apoptosis and stimulating cell proliferation.

Epidemiological studies have reported a frequent positive association between circulatingIGF‐1 levels and various primarycancers, such as breast, colorectal, and prostatecancer.

Question 33

Hallmark 5: promote angiogenesis
explain this hallmark and its role ?

Answer 33

Tumours stay small until they secure a blood supply (angiogenesis)

Increased blood supply (nutrients) to tumour allows continued growth

Promote new blood vessel formation through secretion of angiogenic factors (i.e. Vascular Endothelial Growth Factor (VEGF) or Fibroblast growth Factor (FGF))

Question 34

Hallmark 6: invasion and metastasis
explain this hallmark and its role

Answer 34

90% of cancer deaths are due to the spread of cancer to distant sites – a process called metastasis.

Additional cellular changes are required for the cancer cell to overcome the normal containment mechanisms.

The acquisition of invasive properties is what distinguishes malignant from benign cells.

In many cases, the metastatic tumours are detected first and it is unknown where the primary tumour is.

Most cells in the body don’t move, except in response to injury.

Malignant cancer cells acquire the ability to move and start to break away from the main tumour.

Cells “crawl” through the extracellular matrix (ECM) until they reach a blood vessel.

These abilities may be acquired through the decreased expression of cell adhesion molecules or secretion of proteases to break down the ECM

A small percentage of cells can survive in the circulation until they reach a new tissue to grow in.

Question 35

Tumours do not spread randomly, but have preferred sites that they metastasise to.
what are the preferred sites of metastasise.

Answer 35

Breast - Lungs, liver, bones
Colon - Liver,peritoneum, lungs
Kidney - Lungs, liver, bones
Lungs - Adrenal gland, liver, brain
Melanoma - Lungs, skin/muscle, liver
Ovary - Peritoneum, liver, lungs
Pancreas - Liver, lungs, peritoneum
Prostate - Bones, lungs, liver
Rectum - Liver, lungs, adrenal gland
Stomach - Liver, peritoneum, lungs
Thyroid - Lungs, liver, bones
Uterus - Liver, lungs, peritoneum