Cancer biology Flashcards
What is the percentage of breast cancer cases linked to over-expression of HER 2 gene?
25 %
How does the over-expression of HER 2 result in the development of breast cancer?
HER 2 is a hetero dimer sub-class of EGFR receptors. Over-expression of the receptors amplify the downstream signalling pathway resulting in increased transcription factors for cell proliferation (sustaining proliferative signalling).
What class of chemotherapy is Trastuzumab?
Monoclonal antibody
How does Trastuzumab work?
Binds to the extracellular domain of the receptor, preventing HER2 homodimerisation and hence the downstream signalling pathway.
How do Cetuximab and Panitumumab work and what type of cancer are they commonly used for and why?
Bind to the EGFR portion of the receptor and are commonly used for colorectal cancer. (A high proportion of colorectal cancer is linked to EGFR overexpression).
How do Erlotinib and Gefitinib work?
They inhibit the tyrosine kinase portion of the EGFR, which is often highly expressed or mutated in non-small cell lung cancer in which the drugs are often indicated for. Upon binding to the ATOP site this prevents transphosphorylation of the tyrosine residues and hence the signal cannot be transducted.
How would you define cancer?
Abnormal growth of cells in an uncontrolled way that can spread and metastasis to other tissue.
Describe the difference between benign and malignant tumours.
Whilst both benign and malignant tumours have cell abnormalities and are unregulated within the body, benign tumours grow much more slowly and do not metastasise and therefore are not classified as cancerous.
Malignant tumour cells are cancerous therefore they do have cell abnormalities, they have rapid uncontrolled cell division and they ability to metastasise to other tissue.
Describe the difference in definition between carcinomas and sarcomas.
Firstly both are types of cancer and are merely describing where in the body the cancer develops.
Carcinomas are cancers that originate from epithelial tissue, the tissue covering the internal and external structures and organs in the body.
Sarcomas however originate in the connective and supportive mesenchymal tissue.
What are the four different classifications of carcinomas?
Adenocarcinoma when the cancer develops within an glandular secreting cell keeping the tissue moist.
Squamous cell carcinoma where the cancer develops in the squamous cells which are flat, surface covering cells which line the throat for example.
Transitional cell carcinoma are cells that stretch as the organ expands and they make up the transitional epithelium.
Basal cell carcinomas are cells deepest in the skin.
Which organs are most affected by carcinomas?
Normally organs that are capable of secreting such as the breasts (milk), prostate (semen), colon (gastro-intestinal fluids) and the lungs (mucus).
What are some examples of where sarcomas tend to occur?
Bone
Tendon
Cartilage
Muscle
Fat
What are some examples of sarcomas?
Ewing’s sarcoma (bones or tissue around the bones)
Fibrosarcoma (fibrous connective tissue)
Glioma or astrocytoma (connective tissue in the brain)
What is the difference in demographics that are affected by carcinomas and sarcomas?
Carcinomas tend to affect elderly people more whereas sarcomas are more commonly seen in young people.
Aside from differences in where they occur and the demographics they affect, what are some of the other differences between carcinomas and sarcomas?
There is less vascularity in carcinomas in comparison to sarcomas and therefore sarcomas spread and metastasis more rapidly and therefore have an increasingly high malignancy and lower prognosis compared to carcinomas.
Aside from carcinomas and sarcomas what are the other groups that cancers are divided into?
Myeloma
Leukemia
Lymphoma
Brain and spinal
Mixed type
Describe the development of adenocarcinomas.
Normally a single mutated cell has sustained proliferative signalling, resulting in hyperplasia of cell type forming a benign adenoma before dysplasia occurs, the tumour has acquired a substantial number of mutations resulting in the development of malignancy. Now malignant the tumour cells then invade the basal lamina into the connective tissue by the developing angiogenesis into the bloodstream and are able to metastasise (invasive cancer).
What percentage of cancers are carcinomas?
85%
What percentage of cancers are sarcomas?
1% every year in the UK (on her slides says 12% of cancers are sarcomas)
What are the two types of sarcomas?
Bone sarcomas
Soft tissue sarcomas
What are some examples of soft tissue sarcomas?
Cartilage (Chondrosarcoma)
Muscle (Rhabdomyosarcoma or Leiomyosarcoma)
What percentage of cancer cases are due to leukemia?
3% of all cases each year
What percentage of cancer cases are due to lymphoma?
5% of all cases each year
How is leukaemia defined?
Leukaemia is cancers of the immature white blood cells that proliferate and divide in the bone marrow before accumulating within the bloodstream.
What are the four main types of leukaemia?
Acute myeloid leukaemia
Chronic myeloid leukaemia
Acute lymphoblastic leukaemia
Chronic lymphocytic leukaemia
What is the difference between myeloid and lymphoblastic / lymphocytic types of leukaemia?
Myeloid leukaemia is when the cancer originates from granulocytes or monocytes within the bone marrow whereas lymphoblastic/ lymphocytic leukaemia is when the cancer originates from the lymphocytes.
Where do lymphomas develop?
Cancer that originates in the lymph glands or nodes within the lymphatic tissue.
What is the function of the lymph nodes?
To produce immune cells such as lymphocytes and to purify bodily fluids. The lymphatic system includes nodes, vessels and glands.
Define carcinogenesis.
It is the process in which normal cells evolve into cancerous cells as a result of an accumulation of mutations.
Define tumour progression.
It is defined as the irreversible change in the tumor characteristics reflecting the sequential appearance of a genetically altered subpopulation of cells with the new characteristics.
What is tumour progression driven by? *
Random mutations
Epigenetic alterations (changes in DNA methylation) of DNA that affects proliferation and survival
Increased expression of peptides and other mitogenic peptides*
What are the three main ways that DNA mutations arise?
Mistake during replication
Nucelotides undergoing spontaneous chemical changes
Effect of mutagenic agents
Explain the example of mistakes in DNA replication.
Incorrect base can be added due to miscorporation of nucleotides being added during replication and proofreading enzymes such as DNA polymerases fail to recognise the error.
What is the consequence of nucleotides undergoing spontaneous chemical changes?
Bases can be missed or purines are removed
What are the two types of mutagenic agents?
External mutagenic agents such as industrial chemical agents like vinyl chloride, benzo(a)pyrine- 4,5-epoxide in addition to UV and X-rays which can all cause DNA damage.
Internal mutagenic agents such as reactive oxygen species which are produced as a result of metabolism or inflammation.
How do reactive oxygen species result in DNA damage and hence mutation?
Reactive oxygen species produce reactive free radicals , which can cause a double strand break in the DNA as a result of ROS-conversion of guanine to 8-oxyguanine so it can pair with cytosine and adenonine which can result in double strand breaks and leads to genomic instability.
What mutations arise as a result of exposure chemical agents?
Chemical agents such as Asbestos, Benzo(a)pyrine-4,5-epoxide causes cross linking in the DNA strands or single or double breaks within the DNA.
What mutations arise as a result of exposure to UV or ionising radiation?
Ionising radiation can result in single or double breaks within the DNA strands or UV radiation specifically can cause pyrimidine linking (pyrimidine dimerisation on the intrastrand).
Which type of cancer has pyrimidine linking been associated with?
Melanoma
What is the cause of a bulge in the DNA forming as a result of deletion or insertion of a nucleotide?
Due to an intercalating agent inserting itself into the DNA and which results in the addition or subtraction of a nucleotide during replication or recombination.
What are some examples of an intercalating agents?
They tend to be flat, planar molecules such as benzo(a)pyrene.
To recap, what are the seven mechanisms of mutation?
Incorrect base
Missing base
3’ deoxyribose fragments
Bulge due to the deletion or insertion of a nucleotide
Single or double breaks
Linked pyrimidines
Crossed linked strands
Despite all of these mutations occuring in everybody at times, how does cancer actually occur?
Cancer occurs when there is a fault with the repair enzymes which means the mutation cannot be rectified.
For example, UV induced skin cancer there is a fault with the nucleotide excision repair mechanisms.
Describe the mechanism in which DNA viruses can induce cancer?
The virus has infected cells by inserted their own episome (circular piece of DNA) into the host cell. The viral DNA can code for proteins that will promote cell proliferation (sustaining proliferative signalling) or code for proteins that will inhibit tumour suppressor genes (avoiding growth suppressors).
Describe how the human papillomavirus can lead to cancer?
Two genes human papillomavirus are E7 and E6. Both genes not only encode for onco-proteins (sustaining proliferative signalling) but they also interfere with tumour suppressor genes. E7 oncogene associates with the retinoblastoma inducing its proteosomal degradation. E6 meaning associated with p53 and hence targets its for proteasomal degradation?
In the majority of cervical cancers would you expect there to be a mutation in Rb or p53 or not?
According to WHO 95% of cervical cancers are believed to be linked to HPV. Therefore, it is understood HPV contains two specific oncogenes E6 and E7 which encode for the proteosomal degradation of tumour suppressors genes Rb and p53 respectively, ultimately resulting in their downregulation. Therefore in cervical cancer it is belived that it is the downregulation of the tumour suppressor genes rather than mutations that occur within them that lead to the development of cervical cancer.
Which human herpes viruses have been identified as being oncogenic viruses?
Epistein Barr virus (EBV) and Kaposi sarcoma associated virus (KSHV)
Despite only two types of HHV being identified as oncogenic, can other types of HHV cause cancer?
Yes, for examples herpes simplex 1 and 2 has been linked to prostate cancer and melanoma.
How does EBV cause cancer?
The virus contains genes which encodes for proteins inducing hypermethylation of the tumour suppressor gene RAS (specifically RASSF1A) which cause sustained proliferation as it is downstream of the growth receptor signalling pathway. Furthermore p16 a tumour suppressor protein undergoes homozygous deletion and methylation and hence is downregulated. p16 is a cdk inhibitor, preventing phosphorylation of the Retinoblastoma, with p16 downregulated the cyclin dependent kinase is no longer inhibited and Rb is constantly phosphorylated and inactivated.
How does Kaposi sarcoma associated virus cause cancer?
The virus has two specific genes vIRF3 and ORF73 both of which inhibit p53 activity and therefore p53 cell-induced apoptosis. A third viral gene ORF16 encodes the viral Bcl-2 protein (pro-survival) which also inhibits apoptosis (evading apoptosis).
Describe the two mechanisms in which RNA viruses induce carcinogenesis?
As RNA viruses insert themselves into into the host genome, they can induce carcinogenesis either by:
Providing and inserting an additional proliferative gene that alters the growth in the host cell
Or by insertional mutagenesis where the virus intergrates into the DNA close to a host gene, a proto-oncogene that encodes for cell growth (such as a growth factor), and the virus can then promote or enhance that gene expression.
Describe the direct mechanism of viral carcinogenesis.
The virus is either a DNA virus in which an episome is formed and results in viral oncogene expression or as a RNA virus insertion into the host genome can also lead to viral oncogene expression (either through insertional mutagenesis or additional proliferative genes). Viral oncogene expression then leads to sustained proliferative signalling, avoiding growth suppressors, cell survival, telomerases and increase in genetic instability leading to cancer.
What type is viral carcinogenesis is the virus acting internally and which is it acting externally?
Virus acts internally in direct viral carcinogenesis and acts externally in indirect viral carcinogenesis.
Which type of viral carcinogenesis would you expect the cancer cells to be within the monoclonal form?
Direct viral carcinogenesis as it is acting within and therefore is aiming to maintain the tumour phenotype.
Describe indirect viral carcinogenesis?
Virus infects cells and as a result release chemokines which attracts pro and anti-inflammatory cells to the site of viral infection. As a result of their metabolism pro-inflammatory cells release reactive oxygen species which release free radicals which can induce mutation by a double strand break and others by constant years of inflammation.
Explain how HIV is an example of indirect viral carcinogenesis?
At the beginning of a HIV infection, CD8+ T-cells are able to undergo their normal function but once immuno-suppression has occured there are no T-cells to immuno-suppress tumour growth and the normal defence mechanisms.
What type of cancers do patients with HIV normally get?
Lymphomas associated with EBV or Kaposi associated sarcoma.
Which types of cancer does EBV cause?
Burkitt’s lymphoma
Nasopharyngeal carcinoma
Which type of cancer does Human herpes virus 8 cause?
Kaposi’s sarcoma
Body cavity lymphoma
Which types of cancer does hepatitis B and C cause?
Hepatocellular carcinoma
Define hypertrophy of cells vs hyperplasia.
Hypertrophy is an increase in the size of cells (specifically muscle cells, normally achieved through exercise) whereas hyperplasia is the increase in the number of cells (increase in muscle fibres).
What is atrophy?
Reduction in size of muscle cells (opposite to hypertrophy).
Describe what occurs with dysplasia cells.
Often indicative of an early neoplastic stage, the cell to cell interactions are broken down and there is an expansion of immature cells with a reduction in number and size of mature cells.
Describe metaplasia.
When one cell types changes into another.
What are the four main phases in carcinogenesis?
Initiation
Promotion
Progression
Metastasis
What phase does hyperplasia occur?
In the promotion phase
Describe the process of carcinogenesis development.
Firstly a normal cell undergoes initiation step if it is exposed to a mutagen or there is a breakdown in the repair mechanisms and it becomes an initiated cell. In the promotion stage there are a series of other mutations that occur that gives rise to preneoplastic cells or dysplasia occur. At this point it is reversible however if a series of other mutations then occur neoplasia occurs and the tumour size will rapidly grow and metastasise.
Where does cancer originate from in colon?
In the colonic crypt epithelium
Describe the genetic mutations that arise in colon cells that result in the development of carcinogenesis.
The development from normal, healthy colon cells to the construction of a small benign tubular adenoma is a consequence of inhibition of a tumour suppressor gene (A PC beta catetin), DNA hypomethylation and a mutation in the proto-oncogene Ras. The progression of a small benign adenoma to a larger one is believed to be a result of inhibition of another two tumour suppressor genes including TSG 101. From the progression of a large but benign adenoma to carcinoma, T53 is inhibited.
Define neoplasia.
Neoplasia is a direct result of dysplasia (expansion of immature cells) and metaplasia (when one cell type converts to a less differentiated one). The state of neoplasia, genetically abnormal cells growing at an uncontrolled rate, is one that cannot be returned to normal, regulated one.
What is the mutation that arises in the Ras proto-oncogene?
It is a point mutation, where a guanine is converted to a thymidine (GGC to GTC) meaning that instead of a glycine being coded, a valine is coded instead.
What percentage of cancers are found to contain a mutation in the Ras proto-oncogene?
30%
Would you expect immortalised cancer cells to cause a tumour in a mouse?
No, they are not cancer cells and do not have the ability to metastasise. They most likely have a couple of mutations however they are not capable of causing cancer in a mouse.
Describe the beginning of Weinburg’s experiment.
Took a biopsy of cells from a patient who had bladder cancer, isolated the DNA from the cells and inserted it into the immortalised cells.
What did Weinburg observe once he had injected the immortalised cancer cells?
Most of the cells remained with the same mutations as before the injection and behaved accordingly, however some cells had genetically mutated further and demonstrated neoplasia and had begun to colonise.
After the observations, what did Weinburg do?
Isolated the neoplastic cells and then injected them into the mouse. As a result a tumour did grow inside of the mouse. He then isolated the human genes from the mouse and confirmed the Ras mutation.
What are the four main types of mutations in the GF signalling cascade?
Gene amplification
Gene rearrangements (promoter misplacement results in a weakly expressed gene, becoming strongly expressed)
Large structural deletions
Subtle mutations (Ras)
In reference to the GF signalling pathway, where does gene amplification occur?
Growth factor
Receptor and tyrosine kinase domains
Transcription factor
In reference to the GF signalling pathway, where does gene rearrangements occur?
Transcription factor
In reference to the GF signalling pathway, where does large structural deletions occur?
Receptor and tyrosine kinase domains
