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Flashcards in Neoplasia 3 Deck (13):
1

Mechanisms of Invasion & Metastasis

Invasion:

Increased net protease activity --> active degradation of basement membrane and ECM. 
 

Migration:
Mediated by coordinated changes in cytoskeleton and adhesion strcutures. 

Stimulated by autocrine growht factors and ECM cleavage products (e.g. collagen fragments) 

2

Tumor Metastasis Pathways: 

Name the different pathways and give examples of tumors that use those pathways. 

  1. Transcoelomic: 
    - ( Kissing metastasis) 
    - Thoracic / abdominal surface tumors
    - few barriers to spread
    - ex: mesothelioma, ovarian adenocarcinoma. 
     
  2. Hematogenous:
    - ex: sarcomas   
     
  3. Lymphatic:
    - Carcinomas
    - regional lymph node involvement is suggestive of widespread disease. 


    Note: These are not absolute rules especially in severe malignant tumors.  

3

What do we know about mesotheliomas? 

They are a type of tumor which utilizes the trancoelomic pathway. 

They DO NOT metastasize by lymphatic or hematogenous spread. They will only spread to all available surfaces and will invade locally. 

4

The metastatic cascade: 

Describe the steps involved in the hematogenous spread of a tumor. 

  1. Clonal expansion
     
  2. Metastasis of subclonal population. 
     
  3. Intravasation
     
  4. Tumor cell emboli in the veins. 
    - tumor cells form small emboli in vessels
    - they are recognized and attacked by host lymphocytes.
    - surrounded by platelets (hidden from IS) 

     
  5. Extravasation.
    - exit site is dependent on: 
    a. pattern of drainage of primary tumor. 
    b. tumor cell/ endothelial cell adhesion molecule interaction. 
    c. suitable microenvironment. 

     
  6. Metastatic deposit. 
     
  7. Angiogenesis
     
  8. Growth. 

5

Hematogenous spread characteristics:

How can we differentiate between Hematogenous spread and Transcoelomic spread? 

Possible routes of spread? 

Spread is more likely to occur via veins over arteries because veins are thin walled and arteries are thicker walled therefore arteriole walls are more difficult for intravasation. 
 

Hematogenous spread will metastasize therefore will see masses through the organ belly and surface. 

In transcoelomic spread, they do not metastasize throughout the belly of the organ, only via the SURFACES.   

Routes of spread: 

1. Vena cava --> lungs --> arteries

2. Portal system --> Liver

3. Adrenal tumors --> vena cava

-- Adrenal tumors grow out into the vena cava, can cause blockage or rupture of the vena cava.  

6

When checking for metastatic disease what are the areas you want to check first? 

Regional LN

Lungs

Liver 

7

Adenocarcinomas: 

Will likely see polygonal cells surrounding glands. Possibly epithelial cells in lymphatic vessels.

In cats with pulmonary adenocarcinomas, this can metastatsize to the toes and cause nodular masses. 

8

Suppression of Metastasis: 

Small number of identified genes: 

Gene encoding E-cadherin. E-cadherin is a component of adherens junctions:  (suppresses metastasis- and stops cells from separating & metastasizing) 

9

Necessities for successful tumor growth: 

  1. solid tumors > 1-2 mm diameter
     
  2. Angiogenic switch must be ON: allows tumors to sustain new tumor vasculature. 
     
  3. RECRUITMENT OF ENDOTHELIAL CELLS FROM PRE EXISITNG VESSLES. 
     
  4. Endothelial cell proliferation
     
  5. directed migration through the ECM
     
  6. Maturation & differentiation of the capillary sprout. 
     
  7. ANGIOGENESIS.  

10

Angiogenesis: 

1. Stimulation of host blood vessel growth. 

2. Solid tumors > 1-2 mm

3. Oxygen and Nutrients:
a. Vascular endothelial growth factor 
b. acidic and basic fibroblast growth factors. 

Control: 

Balance of angiogenesis- stimulating (VEGF) and angiogenesis- inhibiting (thrombospondin) factors. 

11

Stages in tumor angiogenesis: 

  1. Endothelial cell recruitment
     
  2. Enthelial cell prolfieration
     
  3. Directed migrations through ECM
     
  4. Maturation and dfferentiation of the capillary sprout. (Differentiate into random leaky vessles, not well organized, accounting for fluid leakage and stroma formation) 
     

12

Tumor vasculature vs. Normal vasculature 

Tumor: 

  • Evolving network
  • Unstable
  • Abnromal structure
  • Abnormal function 
  • Inapporopraite to location 


    Normal: 
     
  • Stable
  • Normal structure
  • Normal function
  • Appropriate to location 

13

Characteristics and functions of tumor vasculature: 

Dilated, tortuous, permeable. 

Vessel leakiness --> perivascular fibrin--> tumor stroma formation. 

Endothelial cells produce growth factors--> platelet derviced growth factor (PDGF), IL-1 --> stimulate tumor cell growth