IMM2022 Lecture Notes - Lecture 2: Immunosuppression, Sarcoma, B Cell
30 May 2018
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Department
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CANCER AND TUMOR
Cancer arises from the uncontrolled proliferation and spread of clones of transformed cells and does
not conform to the normal growth constraints.
Cancer is a disease of multiple genetic mutations.
Causes:
• Random somatic mutations
• Environmental factors (eg. UV radiation)
• Infections
• Errors in DNA recombination/chromosomal translocation (eg, HPV -> cervical cancer)
• Inherited genetic alleles
The ability of a tumour cell population to expand is determined not only by rate of cell proliferation
but also by the rate of cell attrition (cell death)
Hallmark 1
• Self-sufficiency in growth signals
• Cells require signals to move to a proliferative state;
transmembrane receptors -> bind to extracellular ligands -> transduce signals
into the cytoplasm of the cell
• Eg. IL-2
Hallmark 2
• Insensitivity to antigrowth signals
• Normal cells have antiproliferative signals to operate to maintain homeostasis
• Tumour suppressor genes; operate recessively ie. Loss of function mutations
(both alleles must be mutated)
• DNA repair genes can also be classified as tumour suppressor genes
• Eg. BCRA-1; inherited genetic allele which is a tumour suppressor gene, it
repairs ds breaks in DNA, mutations in this gene have up to 60% increased risk
of developing breast cancer
Hallmark 3
• Evading apoptosis
• Normal cells respond to apoptotic stimuli
• Eg. Over-expression of the prosurvival gene Bcl-2 which is found in many
cancers. A mistake is made in VDJ recombination, gene is translocated from
chromosome 18 into heavy chain locus in chromosome 14
Hallmark 4
• Acquisition of limitless proliferative capacity
• Dysregulation of the enzyme telomerase (telomerase overexpression ensures
telomerase stability)
Hallmark 5
(does’t apply
much to
immune cells)
• Sustained angiogenesis
• Tumours require a blood supply if they are to grow to a significant size
• Tumours secrete pro-angiogenic factors to regulate their microenvironment
Hallmark 6
(does’t apply
much to
immune cells
• Tissue invasion and metastasis
• Ability to migrate to new sites where nutrients and space may not be limiting
• Metastases causes 90% of deaths
Hallmark 7 ?
• Ability to evade immunesurveillance
find more resources at oneclass.com
find more resources at oneclass.com
• (Proto) Oncogenes are normal genes which are converted by mutation into oncogenes (genes
that generally cause self-sufficiency from growth signals, over 100 identified)
o C-myc oncogene; transcription factor normally associated with cell division, when expression
pattern is altered it can result in unrestricted growth of cells.
o Involved in many tumours such as lung carcinoma, sarcoma, leukaemia
o Eg. Error in DNA recombination/chromosomal translocation that leads to activation of
oncogene which leads to Burkitts lymphoma: B cell receptor gene recombines with c-myc
gene on chromosome 8 (heavy chain promoter -> truckloads produced -> drive B cell
proliferation), expression of c-myc in cell is increased 2-10 fold, B cell proliferation is
dysregulated), hyper proliferation of B cells leads to lymphoma.
Leukemia
• Malignant proliferation of bone marrow derived cells whose mature
forms are normally found in blood or bone marrow
• May be lymphoid, myeloid or monocyte origin
• Lymphadenopathy (inflamed lymph nodes), bone marrow infiltrates
or meningeal lesions
• Destroying niches for immune cells, causing immunodeficiency
Lymphoma
• Tumours or non-recirculating lymphoid cells generally in the lymph
nodes
• Overspill of malignant cells from a lymphoma and enter circulation
-> leukemic state
(not much difference to leukemia)
Myeloma
• Malignancy of plasma cells forming lesions in the bone marrow
• Myeloma cells secrete paraproteins (monoclonal antibodies)
• Specific symptoms include bone destruction and kidney damage (s
much protein/antibody in kidney forming complexes)
• Different malignancies arise at different stages of differentiation eg. Cancer of mature or
premature B cells
• Lymphoma and lymphoid leukemias are monoclonal (can tell from receptors)
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Cancer arises from the uncontrolled proliferation and spread of clones of transformed cells and does not conform to the normal growth constraints. Cancer is a disease of multiple genetic mutations. Causes: random somatic mutations, environmental factors (eg. uv radiation, errors in dna recombination/chromosomal translocation (eg, hpv -> cervical cancer) The ability of a tumour cell population to expand is determined not only by rate of cell proliferation but also by the rate of cell attrition (cell death) Infections: self-sufficiency in growth signals, cells require signals to move to a proliferative state; transmembrane receptors -> bind to extracellular ligands -> transduce signals into the cytoplasm of the cell. Il-2: normal cells have antiproliferative signals to operate to maintain homeostasis, tumour suppressor genes; operate recessively ie. loss of function mutations (both alleles must be mutated, dna repair genes can also be classified as tumour suppressor genes, eg. Over-expression of the prosurvival gene bcl-2 which is found in many cancers.
