intro to cancer Flashcards
what is cancer?
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
what are the types of cancers and where does it effect?
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
what is neoplasm?
: 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
what is tumor
: a mass of abnormal cells.
what is benign tumors?
these enlarge but do not invade the surrounding tissue, nor spread beyond their initial site.
what is malignant tumors?
those that are not benign and spread beyond their initial site. These are the more dangerous tumours.
what is metastasis?
invasion of a tumour to its surrounding tissue and spread beyond the original site.
what is carcinogenesis?
the process of forming a cancer (via carcinogens).
how is cancer cell formed?
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
what is normal cell proliferation and why?
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
what is the phases of cell cycle?
-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
how is the cell cycle regulated?
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)
cell cycles can be regulated positively and negatively ( cell cycle inhibitors)
what are the cell cycle checkpoints
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.
what are the hallmarks of cancer
self sufficiency in growth signals
insensitivity to anti growth signals
evading apoptosis
limitless replicative potential
sustained angiogenesis
tissue invasion and metastasis
what is oncogene?
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.
hallmark 1 - gains growth factor
what is ras
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).
shy is oncogenes important drug target?
Oncogenes are an important drug target as blocking their function should stop the proliferation of cancer cells.
what is imatinib?
Imatinib is a tyrosine
kinase inhibitor that
prevents growth factor
signals promoting cell
proliferation
Hallmark 1: gains growth factor independence
what is its role?
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
what is Human epidermal growth factor receptor 2 (HER2) amplified in ?
breast cancer
gastric
ovarian
prostate
what is the significance of HER2 expression?
Her2 positive cancers are typically more aggressive
It is associated with early progression, recurrence and poor prognosis
Trastuzumab (Herceptin) blocks Her2 receptor
Hallmark 2: insensitivity to growth inhibitors
what is its role?
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 )
what is the function of the tumor supressor gene?
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.
what are examples of tumor suppressor genes and what are they involved in?
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.
what does mutation of tumor suppressor genes lead to?
Mutations in tumour suppressor genes lead to loss of function. This makes it hard to develop drugs that target them.
what is the most mutated gene in cancer?
p53 is the most common mutated gene in cancer - found in 50% of all human cancers.
what is the functions of p53?
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
Hallmark 3: proliferate without limit
what is the role?
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).
how can you rebuild telomeres
Tumour cells are effectively immortal and can rebuild their telomeres using the enzyme telomerase.
Hallmark 4: avoid apoptosis
role
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)
what doed IGF-1 do?
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.
Hallmark 5: promote angiogenesis
explain this hallmark and its role ?
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))
Hallmark 6: invasion and metastasis
explain this hallmark and its role
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.
Tumours do not spread randomly, but have preferred sites that they metastasise to.
what are the preferred sites of metastasise.
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
