Chapter 7 - Neoplasia Flashcards
Cancer
Genetic disorder caused by DNA mutations
Often also show epigenetic changes (focal increases in DNA methylation and alterations in histone modifications)
Clonal
genetic alterations a heritable, passed to daughter cell on cell division. At the time of tumour initial the selective advantage are conferred on a single cells -
sub clones can develop and can lead to tumour progression
Some definitions:
Neoplasia = new growth. Cells are transformed - i.e they continue to replicate apparently oblivious to the regulatory influences that control normal cells.
Neoplasm’s enjoy autonomy and tend to increase in size regardless of their local environment (although this is not complete - all neoplasms do depend on their host for nutrition and their blood supply!)
Benign vs. Malignant …
Benign - microscopy and gross characteristics are innocent - remain localised and amenable to surgical removal. Often have “Oma” at the end
Malignanct - invades and destroys and has the ability to metastasise.
Features that delineate BENIGN VS MALIGNANT ?
1) Differentiation and anaplasia (degree to which resemble paenchymal cell of origin, morphologically and functionally. lack of differentiation = anaplasia)
2) LOCAL invasion - often benign tissues (not always) are encapsulated.
3) metastases = spread to sites that are physically discontinuous with the primary tumour AND UNEQUIVOCALLY means the tumour if malignant
in general rapid growth IMPLIES malignancy, but no a reliable descriminator.
LOCAL invasion and mets often go hand in hand but are separable (i.e some tumours are ++ locally invasive BUT do not have mets)
Malignant tumour
Arising in Solid mesenchymal tissues = sarcoma
mesenchymal cells of the blood = leukemia or lymphoma
malignant neoplasms of epithelial cells = carcinomas (regardless of the tissue)
carcinomas of glands = adenocarcinomas
carcinomas that produce squamous cells = SCC
sometimes the cell of origin can be found, but often poorly differentiated “poorly differentiated” “undiferentiated” carcinoma
Most cells in a tumour resemble each other (rare if not - mixed tumour. Mixed tumors are monoclonal but projenitc cell differentiates down more than one lineage)
Examples of “Mixed Tumors”
Salivary gland
Fibroadenoma of the female breast
Teratoma - recognisable mature or immature cells or tissues derived from MORE than ONE germ cell later, and sometimes all three (arise from totipotential germ cells such as those that arise in the ovary or the testis)
Hamartoma
mass of disorganised tissue, indigenous to a particular site. (i.e lung or liver etc)
traditionally development malformations, but they are now actually thought to be clonal and contain chromosomal aberrations acquired due to somatic mutations
DIfferntiation
stroma contains the blood supply - doesn’t delineate benign v malignant
anaphasia reliable indicator of malignant - unclear if de-differnetiation or failure to differentiate
- features of anaplasia
1) pleomorphism (variation in size/shape)
2) nuclear abnormalities (extreme hyperchromatism, variation in size, or prominent single or multiple nucleoli), change in the nuclear to cytoplasmic ratio.
3) atypical mitoses
3) loss of polarity
anapaestic cells don’t really retain their function either
- dysplasia ? disorderly proliferation. loss of uniformity of individual cells and their architectural orientation. dysplastic cells exhibit pleomorphism and often have large hyper chromatic nuclear
mitotic figures are more abundant and frequently appear in abnormal locations - dysplasia involving the entire thickness of an epithelium = carinocoma in situ
- dysplasia does not equal cancer. but marks as increase risk. may degree however
Mechanism of mets
1) seeding body cavities - ovarian, neoplasms of brain may go into CSF and re-deposit on meningeal surfaces
2) haematogenous spread - more common in sarcomas. vein > arteries. (Which is why the liver and lung are the most common sites - all portal blood goes to the liver, all caval bloods flows through lung!)
3) lymphatic spread - more common in carcinomas (sentinel LN = first regional LN that receives lymph flow from a primary tumour)
Environmental factors linked to CANCER:
Diet including obesity
Smoking - mouth, pharynx, larynx, oeophsagus, bladder, lung (90% of lung cancer deaths due to smoking)
alcohol consumption - oropharynx, larynx, oesophagus and liver
reproductive history - unopposed oestrogen - cancers of the endometrium and breast increased +++
Acquired conditions linked to cancer
(insert picture from page 199)
precursor lesions - imply increased risk (examples - squamous metaplasia/dysplasia (smoking), endometrial hyperplasia/dysplasi (unopposed oestrogen stimulation), leukoplakia - SCC, villous adenoma of the colon - risk risk progression to colorectal cancer)
CANCER GENES
Oncogenes - over expression of “protooncogenes”. Only one mutation (dominant) turn on genes, usually transcription factors or pro survival
TSG - need both alleles, knocked out. Loss of function. Usually “Guardian” genes (sense genomic damage) or governors (put breaks on cellular proliferation)
Regulators of apoptosis
Types of genetic lesions in cancer: Driver and Passenger
Driver mutation = mutations that alter the function of cancer genes and therefore directly contribute to the development or progression of a given cancer.
Passenger genes - neutral and do not affect cellular genes ‘come along for the ride’
- passenger genes can provide genetic variation that may provider tumour cells with selective advantage in the setting of therapy.
Types of genetic lesions in cancer
Point mutations - can be either gain of function (proto-oncogene –> oncogene) or loss of function (TSG)
- the TSG most commonly affected by point mutation = TP53
Gene rearrangements: chromosomal translocations or inversion
Deletions: deletions of specific regions of chromosome may result in the loss of a specific tumour suppressor gene (often combined with a loss of function point mutation in the case of TSG knock out)
Gene amplifications: protooncogene -_> oncogenes resulting in over expression of otherwise normal proteins. May produce several hundred copies of the gene or a change in the copy number (can be detected by molecular hybridisation techniques). examples are the MYV and HER-2 genes
Aneuploidy: change in the number of chromosomes. Usually in errors in the mitotic checkpoint. (the major cell cycle control mechanism)
MicroRNA and cancer: microRNAs = noncoding single stranded RNAs, negative regulators of genes. They inhibit gene expression post-transcriptionally by preventing translocation
- if the target of the microRNA is a oncogene or TSG may result in carinogenesis
- examplel is the down regulation or deletion of microRNAs in leukemia/lymphoma lead to over expression of BCL-2 anti-apoptotic gene
THINGS I DONT UNDERSTAND OR SKIPPED
Gene amplification “double minute??”
Look into the stuff on page 202 about lymphoid gene rearrangements etc. etc.
RAS picture - its a G protein coupled receptor
Skipped page 217 to 225
Page 229 - regulators of angiogenesis
Read the ret of the tumour metastases theory - bottom of page 232
EVASION OF THE IMMUNE system - only read the summary portion
Mechanisms of chemical carcinogens (page 239 - got bored!!)
How Gene rearrangement can lead to ONCOGENES
1) REMOVING the oncogene from normal regulator elements and placing them under the control of an inappropriate, highly active promoter or enhancer.
eg BURKITT t(8:14) - over expression of MYC gene of chromosome 8, by juxtaposition with the IgH chain gene regulator elements on chromosome 14
eg FOLLICULAR lymphoma t(14;18) - overexpression of the anti-apoptotic gene BCL-2 on chromosome 18 with the regulator elements of chromosome 14
2) FUSION GENES encoding novel chimeric proteins
- e.g Ph chromosome chromosome 9;22 - fusion of the BCR gene on chronometer 22 with the ABL gene on 9
EPIGENETICS and CANCER
epigenetics = reversible, heritable changes in gene expression which occur without mutations
post translational modifications of histones and DNA methylation
Genoma is silenced by DNA methylation and histone modifications
Cancer cells are characterised by global DNA hypomethylation AND selective promoter localised hypermethylation.
TSG can be silenced by hypermethylation of promoter sequences.
CARCINOGENESIS as a multistep process
genetic evolution over time darwinian selection and leads to more aggressive and less responsive to therapy over time
HALLMARKS OF CANCER (there are eight)
Self sufficiency in growth signals - gain of function mutations protooncogenes to oncogenes. oncogenes encode oncoprotein promote cell growth even in the absence of growth promising signals. Insensitivity to inhibitory signal Altered cellular metabolism Evasion of apoptososi Limitless replicative potential sustain angiogenesis Invasion and metastasis evasion of immune surveillance
TYPES OF ONCOGENES:
involved in the growth factor/cellular signallin/proliferating pathway/signal transduction
GROWTH factors -
Growth factor receptors- often act as oncoprotein when over expressed. i.e the Epidermal growth factor (EGF family) - ERBB1 (EGF receptor) over expression in lung ca, epithelial cancers of the head and neck, ERBB2 (HER2) is amplified in breast Ca. Tyrosine kinases are also affected by point mutations or gene rearrangements - leading to them being constitutively active (i.e leukemia, lymphomas, some sarcomas)
DOWNTREAM signal-transducing proteins - downtream of growth factor receptors - activated by ligand binding to growth factor receptors
example RAS - RAS is commonly mutated in human tutors - (30% of all human tumours)
example ABL
NUCLEAR TRANSCRIPTION FACTORS - A host of oncoprotein - function as transcription factors that regulate the expression of growth promoting genes - MYC being an example
THE RAS oncogene
most commonly mutated oncogene in human tutors
RAS = member of a family of small G proteins that bind GTP and GDP
Normally RAS flips back and forth between an excited and quiescent state. RAS is inactive when bound to GDP, activation by growth factors leads to exchange GDP –> GTP and activation (short-lived recycled back to the inactive star)
Activated RAS stimulates downstream regulators of proliferation by several interconnected pathways that converge on the nucleus and alter expression of genes that regulate growth (i.e MYC)
RAS most commonly activated by points mutations in amino acid residues within the GTP binding pocket or in the enzymatic region involved in GTP hydrolysis
- interfere with the breakdown of GTP which is essential to inactive RAS
- RAS is therefore trapped in it’s activated form.
- continuously proliferating state.
ABL
Non receptor tyrosine kinase.
ABL porto-oncoprotein has TK activity dampened by internal negative regulatory domains
ABL translocates from chromosome 9 to the BCR region of chromosome 22, this fusion gene encodes this BCR-ABL hybrid protein that contains the ABL TK domain and BCR domain that self-associates - leading to the constitutiative TK activity
