W2 8 Neoplasia Flashcards
What is a neoplasm?
Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.
What does benign mean?
Neoplasm which is localised and cannot spread
What does malignant mean?
A neoplasm that can invade and destroy adjacent structures and spread to distant sites
What is cancer?
A malignant neoplasm
What is metastasis?
Spread of cancer to a distant site
What is dysplasia?
Pre-malignant change characterised by disordered cell growth due to the accumulation of non-lethal mutations.
How is cancer formed?
Cancer is formed by the clonal expansion of a single mutated precursor cell that has a survival advantage over its neighbours
What genetic alterations can happen in cancer?
Point mutations, translocations, amplifications, deletions, aneuploidy, epigenetic changes
What are the risk factors for cancer?
Inherited genetic predisposition
Age
Environmental
Chronic inflammation
Link between chronic inflammation and metaplasia?
Inflammation provides a permissive environment for cancer growth eg H pylori gastritis or IBD etc
Chronic inflammation at some epithelial sites may cause metaplasia (adaptive response of cells) which is a risk factor for neoplastic transformation.
What are the 3 main pathways for neoplasia?
- Genetic alterations produce benign neoplasm that never progresses to cancer (eg mole on skin)
- Accumulation of further mutations in a benign neoplasm leads to cancer (eg colorectal cancer)
- Genetic alterations produce a cancer in the absence of a pre-existing benign neoplasm (eg most melanomas)
What are proto-oncogenes?
They promote regulated cell growth and proliferation eg growth factors
What are oncogenes?
Constitutively active conferring cells self-sufficiency in growth
What are some hallmarks for cancer?
Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastasis
Tumour promoting inflammation
Avoiding immune destruction
What gene is frequently mutated in human cancer?
RAS is the most frequently mutated proto-oncogene
Give some examples of oncogenes
TGFa, RAS, BRAF
How can evading growth suppressors lead to cancer?
Mutations in tumour suppressor genes (can stop cells from dividing). Mutations in both alleles needed (unlike one allele for proto-oncogenes).
Examples of tumour suppressor genes
p53, RB1
How does a loss of p53 cause cancer?
When DNA becomes damaged, p53 detects this and with either repair the defect or marks the cell foR senescence or target cell for apoptosis or destruction. So if p53 is mutated, p53 dependent genes are not activated following DNA damage, allowing mutations to accumulate.
(This still is not enough to make a cell malignant)
How does a lesion metastasise? (PG73)
Tumour cells break through the basement membrane. Cells migrate through the ECM. Reach a blood vessel and invade through the wall into the lumen. Then embolism to a distant site. They lodge onto an endothelium in a distant region and traverse through the endothelial barrier. Form a metastic deposit in the target organ, distant from the primary site. Complex process requiring mutations in a few different pathways for this to happen.
What pathways can be mutated to facilitate a lesion metastasising?
Loosening of cell junctions
Degradation of ECM
Migration of tumour cells
How can inflammation promote cancer growth?
The innate immune response to cancer promotes tumour development
Give some mechanisms of how the innate immune responds to cancer promoting tumour development and give an example of how
Release of growth factors - eg EGF produced by inflammatory cells stimulated tumour growth
Removal of growth suppressors - proteases released from inflammatory cells degrade the extracellular matrix promoting cancer invasion
Resistance to cell death - integrins expressed on macrophages bind to cancer cells and prevent apoptosis
Angiogenesis - VEGF released by inflammatory cells
Evading immune destruction - TGF-b produced by macrophages suppress anti cancer CD8+ cytotoxic T-cell response
How do tumour cells avoid immune destruction?
Tumour cells express a host of abnormal proteins, potentially capable of eliciting a host immunological response.
What is the most potent immune response to tumour cells?
CD8+ cytotoxic T cells
How does the immune system try and destroy tumour cells?
Tumour antigens are recognised and phagocytosed and processed by dendritic cells (APCs). Antigens are then expressed on MHC class I and II molecules, activating T-cells to lead to immune-mediated destruction of tumour cells.
Limited by tumour cells protecting themselves from immune destruction.
How can cancer cells avoid immune evasion?
Immune system fails to recognise tumour antigens
Production of immunosuppressive proteins (cytokines like TGF-b, IL10, PG-E) or expression of inhibitory cell-surface proteins by tumour inhibits T-cell activation
Compare the gross morphology: shape, size, haemorrhage, ulceration, necrosis of a benign vs malignant neoplasm
Benign: well circumscribed shape, generally smaller (but can be enormous), unusual to have haemorrhage ulceration or necrosis
Malignant: irregular shape, generally larger, common to have haemorrhage ulceration or necrosis
Compare the cytological features: nuclear size, nucleoli, pleomorphism, mitoses, and differentiation of benign vs malignant neoplasms (image pg76)
Benign: normal nuclear size, small/inconspicuous nucleoli, absent pleomorphism, mitoses are infrequent, good differentiation
Malignant: enlarged nuclear size, prominent nucleoli, often marked pleomorphism, frequent (maybe atypical) mitoses, variable differentiaton
Patterns of cancer invasion and metastasis
Go read Pg77/78/79 and look at the images on the page for histology
Pre-invasive stromal invasion, perineural invasion, metastasis, venous invasion, satellite metastases, colorectal cancer metastases
What are the local effects of neoplasia?
Compression of adjacent structures (or obstruct a lumen)
Bleeding
Rupture
Infection
Pain
Systemic effects of neoplasia
Cachexia
Paraneoplastic syndromes
How does cachexia occur systemically from neoplasm?
Marked weight loss
TNF produced suppressed appetite
What paraneoplastic syndromes could arise from neoplasm? (Table pg80)
Cushing syndrome
SIADH
Hypercalcaemia
Nephrotic syndrome
(Associated tumours for each and different pathogenesis)
