Neoplasia (IAS40-43) Flashcards by Josh Ho

name the four characteristics of neoplasia

abnormal mass of tissue,

growth exceeds that of normal tissue, uncoordinated with normal tissue

persists in the same excessive manner after cessation of the stimuli which evoked the change.

irreversible.

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Cancer formation?

Mutations of genes in cell cycle checkpoints: cause UNCONTROLLED cell proliferation

cells pile on top of each other to form tumor

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Name 5 neoplastic phenotypes

1.Loss of response to normal growth control mechanisms

2.Continued proliferation even without a recognizable stimulus

3.Loss of differentiation

4.Aberrant differentiation function

5.Expression of ‘embryonal’ characteristics

3, 4, 5 (especially for malignant neoplasm)

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Compare benign and malignant neoplasms in terms of: ability of invasion and ability of metastasis

Benign: cannot invade nor metastasize

Malignant: can both invade and metastasize

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Compare and contrast a benign and malignant neoplasm in terms of growth:

1) mode of growth and ability to invade beyond basement membrane

2) growth rate

1) Mode of growth
Benign: expansive, limited by basement membrane

Malignant: Infiltrative and expansive, invades beyond basement membrane

2) Growth rate
Benign: slow and may cease
Malignant: Fast, commonly outgrows blood supply (causing irregular necrosis)

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Compare benign and malignant neoplasms in terms of morphology:

1) Gross appearance,
2) Degree of differentiation,
3) nuclear to cytoplasm ratio,
4) size and shape of cells
5) nuclear staining (chromaticity)
6) mitosis

1) Gross appearance:
Benign: circumscribed, encapsulated
Malignant: poorly defined margins

2) Degree of differentiation
Benign: Well differentiated, resembles tissue of origin
Malignant: varying degree of differentiation

3) Nuclear: cytoplasm ratio:
Benign: low nuclear to cytoplasm ratio
Malignant: High nuclear-to-cytoplasm ratio

4) size, shape of cells:
Benign: Cell regularly shaped
Malignant: Cellular pleomorphism (different variations in nuclear and cellular size, shape)

5) Nuclear staining:
Benign: normochromatic nuclei
Malignant: hyperchromatic nuclei (dark, irregularly shaped)

6) Mitosis
Benign: absent/scanty mitosis
Malignant: Increased/abnormal mitosis (tripolar/multipolar spindles)

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Compare benign and malignant neoplasms in terms of:

architecture disturbance
polarity retention

Benign: Mild architectural disturbance, maintained polarity
Malignant: Severe architectural disturbance, loss of polarity

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Compare benign and malignant neoplasms in terms of:

clinical effects
fatality

Clinical effects:
Benign: mechanical or hormonal
Malignant: mechanical or hormonal, destructive and systemic

fatality:
benign: rarely fatal
Malignant: usually fatal

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What can metastasis of malignant neoplasm to lungs lead to

Cannonball lesion

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How can malignant neoplasms invade beyond basement membrane

type IV collagen cleavage by type IV collagenase

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Define differentiation of neoplasm

degree of morphological and functional similarity to origin tissue

neoplastic cells still retain epigenetic memory during growth

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What architectural structures do benign neoplasms form

Papillary foldings (papillary lesions) or invaginating glands (to increae surface area)

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Nomenclature of tumors check Kihiro notes

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Most common type of malignant tumor?

Carcinoma

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Tendencies of adenocarcinoma spread and malignant neoplasia of connective tissue?

Adenocarcinoma: lymphatic system
Malignant neoplasia of connective tissue: blood

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Know that:
1) most benign tumors remain benign and never become malignant
2) malignant tumors often arise de novo without recognizable benign phase

3) other benign tumors can undergo progressive malignant transformations and become malignant

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Define dysplasia:

Cells undergo changes similar to malignant ones (increasingly reluctant to differentiate + gain cytological features of malignant cells) BUT no evidence of invasion AND NO ACTUAL tumor mass formation

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Grading system of dysplasia?

Mild, moderate, severe

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Define carcinoma in situ

Dysplasia spanning entire thickness of surface epithelial membrane

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Know that:
dysplasia increases risk of malignant tumor but can be REVERSIBLE in early stages

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Borderline lesion definition

has ability to invade but NOT the ability to metastasize

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difference between neoplasia and hyperplasia/ hypertrophy

neoplasia: uncoordinated, irreversible
hypertrophy/ hyperplasia: coordinated, reversible

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examples of hypertrophy and hyperplasia

hypertrophy: hypertrophy of skeletal muscle in response to exercise
hyperplasia: uterine smooth muscle in response to pregnancy

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Name 3 genetic drivers of cancer

Proto-oncogenes (when they become activated to oncogenes), tumor suppressor genes (when they become inactivated), DNA repair genes

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Between proto-oncogenes and tumor suppressor genes which needs only 1 allele to be tweaked for the gene to be cancer-causing

proto-oncogene tumor suppressor genes require BOTH alleles to be inactivated for cancer

Know that: when TS genes are INACTIVATED they cause cancers when oncogenes are ACTIVATED they overstimulate cell proliferation and cause cancer

Proto-oncogene function tumor suppressor gene function DNA repair gene function

Proto-oncogene: Stimulate normal cell proliferation and differentiation TS gene: control (like a brake) normal cell proliferation and differentiation DNA repair gene: repair damaged DNA

1 example of a proto-oncogene and its action? Action of mutant KRAS without growth factor? what fraction of cancers in humans are caused by RAS genes

RAS gene includes KRAS, HRAS, NRAS when growth factor binds onto receptor KRAS binds to GTP and promotes cell division mutant KRAS remains active and promotes cell division even without growth factor 1/3

Name genetic changes that can lead to conversion of proto-oncogene to oncogene:

1) promoter insertion 2) Mutation in coding sequences - hyperactive proteins produced in normal amounts 3) Gene amplification: overproduction of normal proteins 4) Chromosomal rearrangements: nearby regulatory gene sequence: normal protein overproduced Fusion to actively transcribed gene: hyperactive fusion protein

Name some examples of tumor suppressor genes

p53, p21, Rb, BRCA1/2

Name the type of mutation that inactivates tumor suppressor genes and examples of the category of mutation

Homozygous mutations deletion, truncating mutations, point mutations, promoter methylation

Cancer related epigenetic modifications on tumor suppressor genes?

1) histone modification - alters chromatin structure, transcription factors cannot access gene 2) DNA methylation - silences the gene

Know that: when DNA is damaged p53 protein is phosphorylated, stabilized and activated then active p53 protein binds to regulatory region of p21 gene, p21 protein transcribed p21 protein (CDK inhibitor protein) binds to G1/S-Cdk and S-Cdk to inactivate the cyclin-Cdk complex to prevent faulty DNA replication acts as a checkpoint in cell cycle

Impact of mutation in DNA repair genes?

Cell tends to acquire mutation in other genes and becomes cancerous

Know that for the concepts of clonality and heterogeneity in malignant neoplasia: 1) Random DNA mutations may confer a growth advantage to certain cells, the cells with mutation outcompete other cells and become the DOMINANT clone 2) Further DNA mutations create more growth advantages, cells accumulating enough mutations to become malignant dominate the whole population 3) In malignant tumours, the malignant cells are usually clonal in origin but have developed heterogeneity (e.g. invasiveness, metastatic ability, response to treatment) to increase the fitness of the tumour

Steps in process of tumor development?

1) MULTIPLE mutations in somatic stem cell genome eg: Activation of oncogenes - Mutations of cell cycle genes / apoptotic genes / DNA repair genes - Inactivation of tumour suppressor genes 2) expression of altered gene products and loss of regulatory gene products 3) Clonal expansion of cells with selective growth advantages 4) Additional genetic alterations → tumour formation under selection pressure 5) Additional genetic alterations → increased genome instability → formation of malignant neoplasm

Define: driver mutations and passenger mutations

Driver: gene mutations that DIRECTLY contribute to cancer development/progression passenger gene: incidental mutations, do not confer growth advantages to mutated cells

Multi-step tumor development model?

stepwise molecular changes and morphological changes during malignant transformation Mutations accumulate (in all 3 of: oncogenes, TSGs and mutator genes) that lead to tumorigenesis

Know that: multistep tumor model is considered to be OVERSIMPLIFIED We also need to account for heterogeneity in tumors - explained by the clonal evolution and CSC models (BOTH MODELS ARE NOT MUTUALLY EXCLUSIVE)

Causes of heterogeneity in tumor cells:

Genetic mutations, epigenetic changes Microenvironmental changes, eg: nutrient, oxygen levels, immune responses, ECM, signals for survival, proliferation, epithelial-mesenchymal transition (EMT involved in metastasis)

Clonal evolutional model?

From the cancer founder cell gives multiple subclones (linear or branched evolution both possible BUT branched evolution is much more likely - branched evolution explains heterogeneity) Tumor cell subclones compete for survival microenvironment exerts selective pressure on cancer cells

Hierarchical model: tumors arise from cancer stem cells (CSCs) - the origin of CSCs? KNOW THAT: CSCs drive tumor growth, recurrence, and treatment resistance (SPECIFICALLY CSCs) for clonal evolutional model can be any cell that generates a tumor

Mutated adult stem cells, progenitor cells, or differentiated cells (through epigenetic rejuvenation)

Know that: 1) CSCs have ability to self-renew and give rise to different cell types in tumor (thus heterogeneity) 2) can undergo symmetric division (produce 2 CSCs) or asymmetric division (1 progenitor cell, 1 CSC) 3) progenitor cells can further differentiate into mature cells OR become new type of CSC 4) subclones need to compete for survival advantages 5) CSCs reside in their own niche to sustain their stemness 6) Can resist conventional therapies by hiding in quiescent state or slow-cycling states

Compare CSC model and the clonal model in terms of: 1) frequency of cells with tumorigenic potential: CSC: rare/moderate Clonal: high 2) ability to seed tumors in different locations CSC: only CSCs can seed tumors Clonal: ALL tumor cells 3) phenotype of cancer cells: CSC: MUST be heterogenic Clonal: homogeneous or heterogeneous 4) tumor organization: CSC: MUST be hierarchical (stem cells > progenitor > terminally differentiated cells) Clonal: not necessarily hierarchical

hallmarks of cancer, their effects and their relevance to therapy: Know that when a tumor becomes malignant ALL hallmarks are usually expressed Hallmarks include:

Deregulating cell energetics, sustaining proliferative signalling, evading growth suppressors, avoiding immune destruction, enabling replicative immortality, Tumor-promoting inflammation, Activating invasion and metastasis, inducing angiogenesis, genome instability and mutation, resisting cell death

Know some drugs that target each hallmark: Deregulating cell energetics - treated by aerobic glycolysis inhibitors Sustained proliferative signaling - treated by EGFR inhibitors Growth suppressor evasion - treated by CDK inhibitors avoidance of immune destruction - treated by immune-activating anti-CTLA4 mAb enabling of replicative immortality - treated by telomerase inhibitors tumor-promoting inflammation - treated by selective anti-inflammatory drugs activation of invasion and metastasis - treated by HGF/c-Met inhibitors Induce angiogenesis - treated by VEGF signalling inhibitors Genome instability/mutation - treated by PARP inhibitors Cell death resistant - treated by Proapoptotic BH3 mimetics

Know factors of carcinogenesis and methods of carcinogenesis: List out some causes/factors of carcinogenesis:

Age, gender environmental factors (chemical carcinogens, radiation, viruses), Hereditary neoplasia (genetic risk) Ethnic associations Other factors eg hormones, chronic irritation/trauma, immunological defects

On age as a factor in carcinogenesis: name the most common types of tumors in children and adults

Adults: carcinoma children: leukemia/lymphoma (more common), CNS tumors

Name the most common types of cancers by gender

Male: colorectum, lung, prostate, liver stomach female: breast, colorectum, lung, corpus uteri, thyroid

Know some examples of chemical carcinogens: Alkylating agents, aromatic hydrocarbons/amines, asbestos, chloroethene, arsenical compounds, soot Know that they need prolonged exposure for carcinogenesis and have long latent period Susceptibility highly variable between individuals Can be directly carcinogenic or indirect (eg need metabolic activation) QUESTION: define initiating agents and promoting agents

Initiating: cause irreversible damage to DNA in isolated cells to form adducts, electrophilic Promoting: do not cause DNA alteration but promote cell proliferation in initiated cells

Radiation: know that it damages DNA by linear energy transfer (UV weaker, gamma stronger) can lead to leukemia, osteogenic sarcoma in atomic bomb survivors and radiotherapy patients

Virus causing cancer: what is the mechanism

Viral oncoproteins bind to + modify functions of growth-modulating cellular proteins Further mutations on top of viral oncoprotein binding needed to cause cancer

Know that: for viruses causing cancer viral DNA is found in cancerous cells, BUT the site of viral integration is variable and mutant cells show CLONAL expansion

Name some examples of cancer-causing viruses and the viruses they cause

HPV: cervical/oropharyngeal/anal cancer (know that vaccine is available) Epstein Barr virus: nasopharyngeal carcinoma/Burkitt lymphoma Hepatitis B virus: hepatocellular carcinoma

Hepatitis B virus mechanism that increases cancer risk?

Hep B virus increases risk of hepatocellular carcinoma because: 1) HBV induces chronic injury, increases cellular proliferation 2) viral HBx protein may activate host proto-oncogenes and protein kinase C > cause cancer BUT KNOW THAT VACCINE AND ANTIVIRAL TREATMENT IS AVAILABLE

Causes of hereditary neoplasia?

inheritance of defective TSGs patients have early cancer onset and can develop multiple cancers, higher chance of 2nd-hit inactivation of TSGs during lifetime may also have familial cancer clustering

Know some forms of hereditary neoplasia: 1) Familial adenomatous polyposis (FAP) 2) Lynch syndrome 3) BRCA1 and BRCA2 associated hereditary breast and ovarian cancer 4) Xeroderma pigmentosum

FAP: Inheritance pattern? Know that: there is germline inactivation of APC gene in chromosome 5 - so there is increased risk of 2nd inactivation as there is inheritance of 1 inactivated APC gene Hundreds of adenomas form starting from 2nd to 3rd decades of life (bc of 2nd inactivation) if untreated leads to colon carcinoma by 4th decade of life

Autosomal dominant

Lynch syndrome: inheritance pattern? Know that: Microsatellites in patients (small DNA repeat sequence in coding regions of important growth proteins, eg TGFβRII) are error-prone in replication > frameshift mutation > cannot synthesize intact protein Patients carry defective MLH1 gene (DNA mismatch repair gene) - in heterozygous carriers 2nd inactivation makes patients unable to repair DNA replication errors Predisposed to colon, endometrium, urinary tract cancer from young age

Autosomal dominant

How to diagnose Lynch syndrome:

1) Measure satellite length (displacement/unequal lengths of cancer and normal bands implies microsatellite instability) 2) DNA sequencing (c.1452-1455delAATG in MSH2)

BRCA1 and 2: the type of cancer? Inheritance pattern?

Breast and ovarian cancer, autosomal dominant

Xeroderma pigmentosum: inheritance pattern? Causes inability to repair UV-damaged skin when both alleles inactivated high risk of cancer in sun-exposed skin

Autosomal recessive

Know that: Southern Chinese people associated with nasopharyngeal carcinoma, Japanese with stomach cancer High estrogen levels associated with endometrial, breast carcinoma High androgen levels associated with prostatic carcinoma

Know intrinsic and extrinsic factors affecting tumor growth: Intrinsic: cell proliferation rate/death/maturation and stop of division Extrinsic: host immune response, adequacy of blood supply, availability of hormonal and growth factors

Routes of tumor spread:

1) Local invasion 2) metastasis: by lymphatic, by blood (haematogenous), transcoelomic, pagetoid spread 3) perineural spread

Lymphatic spread: The route?

Tumor spread from primary organs to regional lymph nodes then to central lymph nodes Know that when the tumor reaches central lymph nodes it is harder to treat

Haematogenous spread: the route?

1) subclone invades beyond basement membrane and passes thru ECM 2) metastatic cells undergo intravasation and reach destination 3) metastatic cells adhere to basement membrane of destination tissues, undergo extravasation to form micrometastasis (deposit) 4) angiogenesis leads to full blown metastasis (Tumor growth)

Know some haematogenous spread examples: systemic venous system to lungs: osteosarcoma Portal venous system to liver: adenocarcinoma of colon also know that very few cells escaping from a 1st tumor can form a stable metastasis

Transcoelomic spread through where or where?

pleural or peritoneal cavity

Pagetoid spread: Know that it is a kind of intra-epithelial spread Individual glandular cells may grow into a layer of stratified squamous epithelium eg in adenocarcinoma of breast

Know about the staging system: derived from route of spread for each cancer type elements: 1) T: extent of local invasion 2) N: extent of lymph node metastasis 3) extent of distant metastasis informs: 1) extent of surgical resection, 2) need for additional local/systemic therapies and 3) chance of recurrence and prognosis