Invasion and Metastasis Flashcards
Define invasion
Ability of cells to break through normal barriers e.g. basement membrane into the surrounding tissue
How to neoplastic cells invade and spread?
Detachment of neoplastic cells from each other (through down-regulation of cadherin expression)
Attachment to ECM via specific receptors
Degradation of the ECM through secretion of collagenases and proteases
Locomotion through the ECM via secretion of motility factors
Cells then spread via vascular system, lymphatics or transcoelomic
How is cell adhesion altered?
Reduced expression and alteration of cadherins. Cadherins are Ca2+ dependent glycoproteins on the cell membrane that interact between cells and maintain cell polarity and structure. Reduction allows cells to move apart
Reduced expression of intergins. Cell surefacec glycoproteins that anchor the cell to the basement membrane. Modifies contact between the malignance cell and stroma, allowing movement.
How doe saltered enzyme synthesis promote metastasis?
Different enzymes can modify stroma allowing cells to break through the basement membrane and spread. e.g. MMPs, gelatinases, stromelysins
Malignant cells produce factors that stimulate stroma (fibroblasts) to synthesise more enzymes.
Remodelling determined by levels of MMPs and TIMPs (tissue inhibitor of MMPs). Can inhibit TIMP activity to alter balance of remodelling
What is metastasis?
Ability of malignant cells to invade lymphatics, blood vessels and cavities, and spread to distant sites.
Cells must be able to invade from channels and grow at a distant site.
What are the steps of metastasis?
Invade basement membrane
Pass through ECM
Intravasation
Immune interaction
Platelet adhesion
Adhesion to endothelium
Extravasation
Angiogenesis
Why don’t all malignant cells metastasise?
Cells may invade and circulate but distal environment may not be appropriate for growth due to:
Incorrect receptors
Metabolic factors
Failure of angiogenesis
What is angiogenesis
Formation of small new vessels needed to maintain the growth of cells.
Produced in response to growth factors.
Name 3 growth factors that promote angiogenesis
VEGF
Basic fibroblast growth factor
Angiopoietins
Anti angiogenic factors: thrombospondin, angiostatin, endostatin
Define primary and secondary metastasis
Primary: site where the malignant neoplasm arises
Secondary: carcioma that has spread to another organ
What are the routes of metastatic spread?
Lymphatics - spread via draining lymphatics to lymph nodes
Vascular - spread by veins draining the lesion. GI tumours metastasise to the liver via portal vein. Cells that enter systemic veins form mets in the lung, BM, brain and adrenals.
Transcoelomic - tumours in the abdomincal cavity or thorax can spread across coelomic spaces - peritoneal or pleural cavities.
Common sites of vascular spread
Liver
Lung
Bone
Brain
Cancers which commonly spread to the lung via the blood
Sarcomas - osteosarcoma
Carcinomas - breast, stomach, large intestine
Kidney
Testis
Cancers which commonly spread to the liver
GI carcinomas via portal vein
Bronchial carcinoma
Breast carcinoma
Cancers which commonly spread to the bone
Bronchial carcinoma
Breast carcinoma
Thyroid carcinoma
Renal carcinoma
All cause the destruction of bone
Cancers which commonly spread to the brain
Bronchial carcinoma
Breast carcinoma
Testicular carcinoma
Malignant melanoma
Maligant neoplasms which spread via transcoelomic route
Ovary
Stomach
Breast
Lung
What factors determine the effect a tumour has ?
Site
Extent of local spread
Sites of metastasis
Extent of metastatic spread
Functional effects
Paraneoplastic effects
What are paraneoplastic effects?
Effects which occur at distal sites due to the effects of tumour growth
e.g. dermatomyositis. Cancer induces autoimmune response
Local effects of benign neoplasms
Compression - leading to pressure atrophy, or altered function
Partial or complete obstruction
Ulceration of surface mucosa
Space occupying lesion
Local effect of malignant neoplasm
Destroys surrounding tissue
Causes partial or complete obstruction
Ulceration
Infiltration into nerves, blood vessels and lymphatics
Space occupying lesion
Name 5 systemic effects of neoplasms
Anaemia
Thrombosis
Myasthenia
Myopathy
Pigementation
Dermatomyositis
Cachexia
Malaise
Pyrexia
What are the haematological effects of neoplasms?
Haematological:
Anaemia - due to ulceration, infiltration of BM or haemolysis
Low WCC and platelets - due to infiltration of BM, chemotherapy
Thrombosis - cancers are pro-thrombotic
What are the endocrine effects of neoplasms?
Excessive secretion of hormones
Ectopic hormone production
What are the effects of neoplasms on the skin?
Pigementation
Pruritis
Dermatomyositis
What are the neuromuscular effects of neoplasms?
Neuromuscular:
Problems with balance
Sensory neupathy
Myopathy and myasthenia
How does local invasion of neoplasms occur?
Secretion of collagenases and elastases by neoplastic cells facilitates growth into surrounding connective tissue, vessels and nerves
Describe the patterns and sites of metastasis
Not all tumours metastasise. Route of metastasis depends on the type of neoplasm.
Carcinomas first metastasise via lymphatics to lymph nodes and only via the bloodstream later in the disease.
Sarcomas metastasise via the bloodstream early, usually to the lung
Cancers of prostate, lung, thyroid, kidney and breast tend to metastasise to the bone
Describe the role of angiogensis in metastasis
Tumours need an adequate blood supply to be able to grow.
A vascular network is required for the metastatic spread.
Tumour cells secrete pro-angiogenic factors (VEGF, FGF) which induce endothelial cell growth, migration and vessel formation.
Tumours also fail to produce anti-angiogenic factors, resulting in uncontrolled growth of vessels.
Vessels anastamose with blood supply
Systemic symptoms assocaited with neoplasms
weight loss
loss of appetite
fever
malaiese
anaemia
