Cancer Flashcards
What is atrophy?
Shrunken tissue with reduced cell size (± number),
e.g. all organs in anorexia nervosa/starvation; immobile skeletal muscle; astronaut left ventricle
What is hypertrophy?
Enlargement of a tissue with increased cell size,
e.g. trained muscle, hypertensive heart disease.
What is hyperplasia?
Increased number of otherwise normal cells in a tissue,
e.g. mammary glands in lactation.
What is transdifferentiation?
A switch of differentiation direct from one mature lineage to another which is normally present in that tissue,
e.g. adipocytes to cancer-associated fibroblasts in breast cancer models.
What is metaplasia?
A switch of differentiation from one mature phenotype to another which is not normally present in that tissue, in response to an environmental change - progenitor plasticity from new, stable epigenetic changes,
e.g. bronchial squamous metaplasia from tobacco smoking, intestinal metaplasia in distal oesophagus from acid reflux (Barrett oesophagus).
What is dysplasia?
Disordered microscopic appearance and maturation of cells, implying neoplasia,
e.g. intraepithelial neoplasia, invasive carcinoma.
What is a tumour?
Abnormal lump of no specific cause (often presumptively a neoplasm)?
What is a cyst?
Abnormal fluid-filled lesion lined with epithelium; congenital, retention, implantation, parasitic, neoplastic.
What is a hamartoma?
Disorganised but mature normal tissue elements, lacking autonomous growth.
What is a neoplasm?
Abnormal accumulation of cells derived from a mutated ancestor ‘seed’ cell.
Growth is autonomous of environmental restraining signals and fuelled by epigenetic and genetic lesions affecting ‘driver’ genes in a permissive environment.
What is cancer?
Cancer is a malignant neoplasm.
Invasion: crosses tissue boundaries; e.g. basement membrane, vascular/nerve invasion, serosal breach.
Metastasis: discontinuous spread to survive and grow at remote sites; carriage in blood/lymph/serous cavity fluid/CSF (cerebrospinal fluid); only a minority of circulating cancer cells establish a metastasis.
What is the craniospinal venous system?
2-way venous flow (no valves).
Links cranial and vertebral circulation with intercostal, abdominal and pelvic venous plexuses.
Direct ’back-door’ route for metastasis to spine and brain; skips lungs, lymphatics; e.g. from prostate, breast, thyroid.
What is the staging of cancers?
How far the cancer has progressed from early invasion to widespread dissemination. This is a major predictor of cure, or survival time after diagnosis; requires radiological, pathological and clinical data.
TNM system has criteria for each cancer type and site:
Local Tumour extent - diameter +/ breach of tissue boundaries;
Lymph Node metastasis (regional, distant, number affected);
Metastasis elsewhere (e.g. T2 N1 M0).
Residual tumour status (R) after treatment (R0-R1-R2) includes local and distant cancer, either microscopic (R1) or clinically obvious (R2). This influences further treatment and strongly affects prognosis.
What is cancer grade?
How chaotic the cells look.
Grade often predicts prognosis and treatment response, you need a tissue sample.
If cancer cells look similar and organised, resembling a normal counterpart, the cancer is ‘well’ differentiated, otherwise ‘moderately’ or even ‘poorly’ differentiated. The extreme is undifferentiated malignancy.
Different cancers and intraepithelial neoplasia have their own grading rules, involving:
Differentiation towards a mature phenotype - Glandular (making mucin & forming glands or tubes), or Squamous (making squamous keratins, having desmosomes and showing stratified layering);
Variability (pleomorphism) between cancer cells or between their nuclei;
Proportion of cancer cells proliferating.
How is a neoplasia classified by differentiation (cell type resembled)?
Malignant:
Epithelial - Adenocarcinoma (duct/gland: e.g. breast, prostate, lung, colorectal, etc.), Squamous cell carcinoma (skin, bronchus, oesophagus, cervix, etc.), Basal cell carcinoma, Urothelial carcinoma;
Mesothelial - Mesothelioma;
Melanocytic - Melanoma;
Neuroendocrine - Lung small cell carcinoma.
Benign:
Epithelial - Adenoma (duct/gland: Squamous cell papilloma);
Melanocytic - Melanocytic naevus (benign mole);
Neuroendocrine - Pituitary adenoma.
You need a tissue sample to confirm these diagnoses. Histology features correlate closely with comprehensive molecular profiling (genome, transcriptome, epigenome, proteome).
What are malignant neoplasia classifications based on differentiation (cell type resembled)?
Epithelial:
Adenocarcinoma (duct/gland); e.g. breast, prostate, lung, colorectal, etc.;
Squamous cell carcinoma: skin, bronchus, oesophagus, cervix, etc.;
Basal cell carcinoma;
Urothelial carcinoma.
Mesothelial: Mesothelioma.
Melanocytic: Melanoma.
Neuroendocrine: Lung small cell carcinoma.
Haematolymphoid:
Leukaemia (myeloid/lymphoid),
Lymphoma (lymphocyte),
Myeloma (plasma cell).
Connective tissue = sarcoma:
Osteosarcoma (bone),
Angiosarcoma (endothelium),
Leiomyosarcoma (smooth muscle),
Rhabdomyosarcoma (striated muscle).
Placental: Choriocarcinoma.
Germ cell: Seminoma (testicular).
CNS: Glioma.
Embryonal (‘blastomas’):
Hepatoblastoma (liver),
Medulloblastoma (CNS), etc.
What are benign neoplasia classifications based on differentiation (cell type resembled)?
Epithelial: Adenoma (duct/gland): Squamous cell papilloma.
Melanocytic: Melanocytic naevus (benign mole).
Neuroendocrine: Pituitary adenoma.
Connective tissue/mesenchymal:
Lipoma (adipose),
Leiomyoma (smooth muscle),
Chondroma (cartilage),
Osteoma (bone),
Haemangioma (vascular),
Fibroadenoma (breast: stromal + recruited epithelium).
Mixed (divergent) differentiation:
Mature Teratoma (all 3 germ cell layers),
Pleomorphic adenoma (epithelial + mesenchymal diff’n).
Where should surface neoplasm with an ulcerated appearence be sampled for biopsy?
A worrying ulcer is best sampled at the edge for tissue diagnosis to avoid false negative diagnosis, because non-specific inflammation, fibrin and necrotic debris in an ulcer base can hide an underlying cancer.
What is the difference between a polyp and paillary?
Both are club-shaped lesions covered by epithelium (squamous/urothelial/glandular), either with a connective tissue stalk (pedunculated) or without (sessile).
Polyp: epithelium covers a raised core of connective tissue stroma.
Papilloma/papillary neoplasm: epithelium (squamous/glandular/urothelial) covers long thin branches of connective tissue stroma (papillae); much greater surface area than polyp of similar size, more complex architecture.
How do benign neoplasms cause problems?
Compression (push tissue aside, not invade) - pituitary adenoma on optic chiasm, meningioma on brain.
Obstruction/intussusception - intestinal wall neoplasm.
Haemorrhage ± infarction - very vascular neoplasms.
Secreted products - pituitary adenoma, adrenal cortical adenoma.
Progression to malignancy - colorectal adenomas.
Cosmetic, local trauma/irritation/infection - some benign skin neoplasms.
What are some complications of neoplasms?
Local and metastatic:
Anatomic - Tubes/ducts/surfaces (perforation, occlusion, ulceration), Space-occupying (spinal cord compression), Organ destruction (liver failure from carcinomatosis; CNS invasion), Organ encasement (respiratory failure from pleural mesothelioma);
Hormone excess - Insulinoma, functional pituitary adenoma, etc.
Cachexia:
Progressive muscle dysfunction and lean muscle wasting (+/- adipose loss), not reversible with nutritional support;
80% advanced cancer patients, esp pancreas, liver, lung, GI, head/neck;
Hyperactivation of muscle catabolism - autophagy, ubiquitin-proteasome;
Humoral factors (insulin resistance, TNF, TGFB) - exosomes probably involved (e.g. TLR4 activation);
No effective therapy (complete cancer excision works in early cases).
Paraneoplastic = not attributable to cancer invasion or secretion of indigenous tissue hormone:
Venous thrombosis,
Hypercalcaemia,
Neuropathies,
Dermatomyositis,
Finger clubbing,
Nephrotic syndrome.
What is clonal expansion?
Clonal expansion (clonal mosaicism) occurs in normal healthy tissues. Clonal expansion is normal, increases with age and varies by site.
Some mutated clones expand (positive selection) if the environment is right; some have mutated cancer driver genes but this is not cancer. Normal adult tissues become a patchwork of mutant clones competing for space and survival.
Clonal expansion in quiescent aging epithelium may improve declining fitness to maintain itself; clonal patches in epithelium can outcompete and purge early tumours to maintain tissue integrity.
What is cancerisation field?
Cancerisation field is a tissue with accumulated genetic and epigenetic changes that favour cancer emergence.
Remodelling of chromatin and histone marks determines future susceptibility to specific mutations.
Epigenetic changes (methylation in stem cells) in healthy tissue cells such as chromatin opening allows new transcription in progenitors for migration and plasticity programs to help maintain tissue.
New susceptibility landscapes arise from the environment (e.g. inflammation, smoking), mutations in epigenetic regulators/histones (e.g. silencing of tumour suppressor transcription).
Epigenetic changes reflect life history, changes linger: wound priming, chronic infection/inflammation (H. pylori, HPV, etc.), carcinogens.
Cancer driver changes more likely to escape tissue homeostasis.
How does damage and regeneration facilitate field cancerisation?
Mutation count and clonal patch sizes increase with:
Chronic inflammation (cycles of destruction and regeneration) – ulcerative colitis (majority of epithelium, clones several cm2), cirrhosis (20% nodules have cancer driver mutations);
Carcinogens – sun exposure, smoking, alcohol, etc.; many chemical carcinogens do not mutate, but enable clonal expansion (create a growth-permissive environment, e.g. by effects on nearby cells/stromal cell signals/physical stresses).
Opportunistic clonal expansion at regeneration after extensive tissue damage often favours different clones than steady state tissue conditions, i.e. different cancer drivers. Carcinogens and therapy likewise alter selective pressures to favour different clones than steady state.
What is involved in the tumour microenvironment?
Non-cancer cells: Resident cells, Infiltrating immune cells, Nerves (support & conceal, or suppress), Exosomes from cancer/other cells.
Structural: Interstitial fluid (pressure, shear), Extracellular matrix (mechanosignalling, porosity), Fibroblasts/myofibroblasts.
Irrigation: Blood vessels and lymphatics.
Soluble: nutrients, metabolites, cytokines (IL-1, IL-17), plasma proteins, DAMP.
What are the hydronynamics of cancer?
Cancer depths have poor perfusion and diffusion from surroundings: high interstitial fluid pressure (~10x), solid stress from tumour growth.
This produces a core environment of ischaemia and pressure stress due to:
Sluggish blood flow (leaky angiogenesis increases viscosity),
Few/compressed intra-tumoural lymphatics so no drainage,
Acidic (pH6.7-7), hypoxic, low glucose, DAMP, autolytic enzymes.
Interstitial fluid flows radially from core, past tumour margins then to nearest lymphatics. Steers cell migration toward peri-tumour lymphatics/vessels and impedes drug diffusion within cancer.
What is the perivascular niche inside cancer?
Diffusion limits produce perivascular gradients of nutrients:
Critical ischaemia at 100-180μ from capillaries;
Peri-capillary sleeve of proliferating cells - more distant quiescence and survival - cell cycle-based therapy misses the more distant quiescent cells, hypoxia reduces efficacy of X-rays to generate lethal oxidative radicals, hypoxia-induced transcription regulators (HIF) change the phenotype of cancer cells;
Produces strong selection pressure for angiogenesis in growing cancers - hypoxia-driven gene expression (HIF), angiogenic factors (VEGF, angiopoietins).
What are characteristics of cancer angiogenesis?
Cancer angiogenesis creates chaotic blood flow.
Cancer cell competition for blood resources leads to uncoordinated angiogenesis: haphazard, immature vascular geometry; not hierarchical, unstable haemodynamics - pooling, eddies, flow reversals. So pO2 varies in “waves & tides” (sec/min)-(hrs), causing fluctuating ischaemia, pH, hormone levels, reperfusion injuries, ‘dry streambed’ vessels surrounded by dead cancer cells.
How are regional differences within cancer cells created?
A cancer is an ecosystem of malignant and non-malignant cell types, interacting with each other and surrounding matrix structure.
Growing cancers have selection pressure for an angiogenic switch; but cancer angiogenesis is haphazard, with regional and unpredictable variations in blood flow; so cancer masses have poorly perfused and drained cores, with radial fluid flow into the adjacent tissue and lymph that affects invasive spread and drug access.
These characteristics tend to produce regional differences within a cancer, and shape how sizeable cancers evolve.
What are cancer driver genes?
The causal impact in human cancer: most human cancers have 2-8 mutant drivers [581 genes (solid evidence), 162 genes (strong indication)].
Half of early clonal driver mutations occur in just 9 genes (e.g. TP53, KRAS, TERT).
Later clonally mutated driver genes are more diverse between cancer types: mutation distribution often mirrors the accessible chromatin of the normal cell; suggests cell of origin influences what could be a cancer driver (via available transcriptional landscape).
The typical cancer driver gene affects multiple cancer hallmarks, suppressing some and promoting others [e.g. RAC1: promotes angiogenesis, proliferation and metastasis; but protects from uv-induced skin cancer].
Has opposing roles (or no role) in different cancers, i.e. other factors matter. Role depends on gene defect, cell type, cancer stage [e.g. BRCA1 inactivations: DNA mutations increased (early); metastasis enhanced (late); proliferation may benefit positive selection early, but limit metastasis capacity later].
What are some of the genetic changes in cancers?
Cancer cells are mutationally more similar than random normal cells, due to early clonal sweeps. Key driver mutations are often ubiquitous in untreated cancer and its metastases; new mutations often have no selective impact - neutral passenger mutations in subclones.
Treatment pressures unmask previously neutral or minority but resistant subclones; rapidly relapsed small cell lung cancer after apparently successful cisplatin chemotherapy as it can survive different apparently successful treatments before emerging (ancestral clones from treatment-naïve cancer: not ‘cancer progression’).
Other important genetic changes include:
Chromosome defects (losses often precede gains);
Whole genome duplication is common (30%) and bad news;
Oncogene copies (amplified in >50% cancers), eg glioblastoma; most copies are outside chromosomes in circular extrachromosomal DNA; different inheritance pattern so unequal segregation at mitosis, allows fast (weeks) change in oncogene copy number to new selective pressure - drivers, drug-resistance, immunomodulatory, etc.
What are the 10 features of cancer fitness?
Genome instability and mutation,
Inducing angiogenesis,
Activating invasion and metastisis,
Tumour-promoting inflammation,
Resisting cell death,
Reprogramming energy metabolism,
Enabling replicative immortality,
Avoiding immune distrction,
Evading growth suppressors,
Sustaining proliferative signalling.
What are universal cancer tasks?
Several common cancers share 3-5 distinct gene expression programmes. Different clinical associations but these ‘cancer task’ archetypes incorporate the cancer hallmarks; gene drivers of a task can differ between cancer types.
Cancer tasks:
Cell division (early stage) - cancer hallmark is replicative immortality, growth suppressor escape, proliferation;
Biomass/energy (early stage) - cancer hallmark is metabolic reprogramming (electron transport, glycolysis);
Lipogenesis (early stage) - cancer hallmark is metabolic reprogramming (peroxisome lipid metabolism);
Immune interaction (late stage) - cancer hallmark is immune tolerance, resist cell death, tumour-promoting inflammation;
Invasion and tissue remodelling (late stage) - cancer hallmark is migration, matrix degradation, angiogenesis.
How do cancers alter trade-offs between tasks?
Diversity emerges under pressure to perform several tasks, when you can’t be optimal at everything because of trade-offs between them. Cells adapting within the range of options will better tolerate change (resources, threats).
Plasticity allows cancers to alter trade-offs between tasks.
Proliferation – Survival: metabolically different strategies, trade-off depends on stress level (drug, nutrient);
Proliferation – Invasion.
Driver genes push cells towards a specialisation [p53 in breast cancer: cell division archetype, NRAS in thyroid cancer: biomass/energy archetype];
Cancer cells close to an archetype are sensitive to drugs that disrupt that task [cell division: mitosis inhibitors; biomass/energy: mTOR inhibitors (growth regulator)];
Cells re-prioritise between key tasks by transcriptional adaptation (plasticity) so responses that seem to be cancer ‘evolution’ are cancer cell ‘adaptation’ to circumstance.
What is the benefit of cancer cells being stemness?
Allows for the plasticity of cancer cells.
Many cancer cells move in and out of stemness states, this means:
They can repopulate depleted ‘cancer stem cells’;
Have proximity to niche signals - self-renewing undifferentiated state (WNT factors) e.g. HGF from cancer-associated fibroblasts, blocked differentiation (NOTCH ligands from adjacent cells), proliferation signals (EGFR ligands);
Cancer progression reduces dependence on external niche signals, so easier switch to stemness state when beneficial, stem cell programmes can be activated epigenetically [NOTCH1 in breast & pancreas carcinoma, WNT in leukaemia].
What is Epithelial-mesenchymal plasticity (EMP)?
Epithelial-mesenchymal plasticity (EMP) is reversible mesenchymal properties; development, wound healing program [minority of cancer cells (1-10%), cycling between EMT-MET].
Response to stress: hypoxia, acidity, dense matrix; at invasive front (stromal contact), around necrosis; factors from cancer-associated fibroblasts/macrophages (e.g. TGFb).
Motility (invasiveness)/angiogenesis helps enter the circulation (most circulating solitary cancer cells), doesn’t help establish metastasis, for which epithelial differentiation is important.
Less proliferation resists therapy that targets proliferating cells - metformin reverses EMT: improved survival among diabetic breast cancer patients.
What are features of cancer metabolism?
Cancer metabolism is adaptable between anabolic and survival states.
Anabolic (aerobic glycolysis) depletes nutrients (oxygen, glucose, essential amino acids), toxic metabolites accumulate (H+ , lactate acidity, adenosine).
Gains from non-cancer cells; e.g. cancer cell ammonia (from glutamine metabolism) triggers fibroblast autophagy, yielding protein breakdown products like glutamine to support the cancer cell.
Metastasis requires anti-oxidant strategies; circulation - oxidative stress (pO2 & iron) hinders survival; skeletal muscle is very hostile (++ H2O2).
How does the tumour microenvironment (TME) prevent immune attack?
Anabolic cancer cells and chaotic vasculature produce metabolic stress, which depleted oxygen and nutrients, and metabolites accumulate.
Metabolic stress causes immune dysfunction; antigen signalling under metabolic stress causes CD8 T cell exhaustion, which impairs innate immune cell activation and function.
Metabolic competition induces effector T cell senescence; cancer cells and Treg competitively ‘steal’ limited glucose from effector T cells, triggering senescence, senescent T cell products suppress other immune cells.
Sentinels:
NK, Tc, innate T cells delete new immunogenic clones (immunoediting);
Virus antigen (oncogenic virus e.g. HPV, EBV);
Neoantigens - driver or passenger mutation alters protein, dysregulated enzyme alters carbohydrate side chains (glycoprotein/glycolipid);
NK cells eliminate most circulating cancer cells, but platelets, NET coatings conceal and facilitate metastasis.
Cancer cells subvert immune activation, release immunosuppressive factors [TGFb, IL-10, PG], repress antigen processing and presentation (small cell lung cancer), reduce MHC I and display immune inhibitors (PDL1, CTLA4).
