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Leicester Warwick Medical School
Neoplasia II
Invasion, Metastasis and
Effects of Tumours
Professor Rosemary A [email protected]
Department of Pathology
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WHAT IS INVASION?
Ability of cells to break through basementmembrane and then spread.
• Into surrounding tissueIn-Situ Carcinoma Invasive Carcinoma
• In lymphatic/vascular channels
Characteristic of malignant cells
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HOW DO CELLS INVADE AND SPREAD?
Complex mechanism involving various factors.
• Malignant cells do not adhere (stick) to the same extent as normal cells
• Malignant cells show a change in their interaction with surrounding stroma
• Factors produced that help cells spread (“scatter factor”)
• Altered synthesis of enzymes that breakdown basement membrane and stroma
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ALTERED CELL ADHESION
CADHERINS are calcium dependent glycoproteins present at cell membrane.
They interact between cells, and within each cell with the actin cytoskeleton through catenins, maintaining polarity.
Reduced expression and alterations in interactions in cancer cells, allowing cells to move apart.
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ALTERED CELL ADHESION
INTEGRINS are cell surface glycoproteins composed of two subunits.
They are receptors for different components of the basement membrane eg. fibronectin.
Reduced expression of integrins in malignant cells modifies the contact between the cell and stroma allowing movement.
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ALTERED ENZYME SYNTHESIS AND INTERACTION
Different enzymes can modify stroma allowing cells to break through basement membrane and spread
eg. Metalloproteinases
MMP2 and MMP9 - collagen IV
MMP1 - collagen I
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ALTERED ENZYME SYNTHESIS AND INTERACTION
Malignant cells synthesise factors that stimulate stromal cells (fibroblasts) to synthesise more enzymes. Enzymes eg. MMP2 bind to malignant cell and allow it to break through basement membrane.
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Altered cadherinAltered
integrin
Basement membrane
MMP2 Fibroblas
t
Growth factor
Cancer Cells
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In Situ Cancer
Basement membrane
Invasive cancer
Blood vessel
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WHAT IS METASTASIS?
Ability of malignant cells to invade into lymphatics, blood vessels and cavities and spread to distant sites.
Cells must be able to invade out of channels and grow at distant site.
Not all circulating cancer cells will settle at a distant site and be able to grow.
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WHY DON’T ALL MALIGNANT CELLS METASTASISE?
Cells may invade and circulate.
May get to distant site but environment may notbe appropriate for growth of those cells.
• Incorrect receptors• Metabolic factors• Failure of angiogenesis
“Seed and Soil”
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ANGIOGENESIS
Formation of small new vessels needed to maintain growth of cells.
Due to various growth factors produced by cancer cells.
Can aid invasion – more vessels with thin walls.
Aids growth of metastasis.
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METASTASIS
Primary = the site where the malignant neoplasm arises eg. breast, stomach.
Secondary = metastasis eg. breast carcinoma that has spread to another organ.
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WHAT ARE THE ROUTES OF METASTASIS?
• Lymphatics
• Blood vessels
• Coelemic spaces
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LYMPHATICS
Spread to local and distant lymph nodes
Frequent route of spread of carcinomas
Can involve lymphatics of lung
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VASCULAR SPREAD
Spread through capillaries and veins to various organs.
Common sites are lung, liver, bone and brain.
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VASCULAR SPREAD
To Lung
Can occur with a wide range of malignant neoplasms.
Sarcomas eg. Osteosarcoma
Carcinomas eg. breast, stomach, large intestine
Kidney (cannonball)
Testis eg. malignant teratoma
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VASCULAR SPREAD
To Liver
Common site for carcinomas of large intestine (portal vein).
Bronchial carcinoma.
Breast Carcinoma.
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VASCULAR SPREAD
To BoneCan cause destruction of bone• Bronchial carcinoma• Breast carcinoma• Thyroid carcinoma• Renal carcinomaCause production of dense bone (osteosclerosis)• Prostate
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VASCULAR SPREAD
To BrainCan cause problems within the brain and themeningesMetastasis from eg.• Bronchial carcinoma• Breast carcinoma• Testicular carcinoma• Malignant melanoma
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WHAT EFFECTS DO TUMOURS HAVE?
Depends on: site of tumour
extent of local spread
site of metastasis
extent of metastatic spread
functional effects
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WHAT EFFECTS DO TUMOURS HAVE?
In certain sites a small tumour can have devastating effects
People can survive for some time with very extensive metastatic spread
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LOCAL EFFECTS OF NEOPLASMS
BENIGN
Cause compression - pressure atrophy
- altered function eg. pituitary
In a hollow viscus cause partial or complete obstruction.
Ulceration of surface mucosa.
Space occupying lesion – brain.
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LOCAL EFFECTS OF NEOPLASMS
MALIGNANT
Tend to destroy surrounding tissue.
In a hollow viscus cause partial or complete obstruction, constriction.
Ulceration.
Infiltration around and into nerves, blood vessels, lymphatics.
Space occupying lesion - brain
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SYSTEMIC EFFECTS OF NEOPLASMS
HaematologicalAnaemia
– due to ulceration (benign and malignant )– infiltration of bone marrow (leukaemia, metastasis)– haemolysis
Low white cell and platelets– infiltration of bone marrow, treatment
Thrombosis– carcinoma of pancreas
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SYSTEMIC EFFECTS OF NEOPLASMS
Endocrine
Excessive secretion of hormones -
benign and malignant neoplasms of endocrine glands e.g.parathyroid hormone, corticosteroids
Ectopic hormone secretion -
ACTH by small cell carcinoma of bronchus
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SYSTEMIC EFFECTS OF NEOPLASMS
Increased pigmentation
Pruritis (itching)
Herpes zoster
Deratomyositis
many carcinomas
jaundice, Hodgkin’s disease
lymphoma
bronchial carcinoma
Skin
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SYSTEMIC EFFECTS OF NEOPLASMS
Neuromuscular
Problems with balance.
Sensory/sensorimotor neuropathies.
Myopathy and myasthenia.
Progressive multifocal leucoencephalopathy.
Not due to metastasis to brain.
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SYSTEMIC EFFECTS OF NEOPLASMS
Cachexia
Malaise
Pyrexia
Mechanisms unknown
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WHY DO NEOPLASMS KILL PEOPLE?
Local effect e.g. brain, perforation, haemorrhage
Benign or malignant
Replacement of essential body organs
Malignant