Metastasis

Question 1

Cancer spread

Answer 1

Direct extension; lymphatics (most common initial dissemination of carcinoma); Hematogenous (vasc invasions: venous, angiogen, lymph to vein connections)

Question 2

Heamatogenous Metastasis

Answer 2

To first cap beds it encounters. Lung (most body organs), Liver (blood from digestive organs)

Question 3

Metastatic cascade

Answer 3

Primary tumor to Invasion and migration to Intravasation (into vessels) where it transports. Once it reaches a site it extravasasation to become a secondary tumor (must stimulate angiogenesis in new tissues)

Question 4

Invasion steps

Answer 4

loosening of intracell junctions
Attachment
Degradation
Migration

Question 5

Loosening of intracell junctions

Answer 5

Attached by cadherins normally, must be downregulated so that metastatic cell can detach. Loss of E-cadherin fx via mutation, proteolysis or catenin mutation

Question 6

Attachment

Answer 6

Change in integrin expression profiles leading to addition of laminin and fibronectin receptor. Increased CD44 Hyaluronan-binding protein (binds MMP)

Question 7

Degradation

Answer 7

Type 4 collagenase and plasminogen activator. Secretes MMPs. Serine proteases (uPA and tPA) secreted by stromal cells: plasminogen (act by PA’s) leads to plasmin activates MMP, digests ECM, digests clots. MMP:TIMP unbalanced at leading edge of tumor.

Question 8

MMP and Degradation

Answer 8

MMP leads to degradation of matrix barrier, degradation to reveal cryptic sites = laminin 5 and angiostatin, disrupts E-cadherin, releases GFs, disrupts cell matrix adhesion (by bind to MMP=CD44)

Question 9

Migration

Answer 9

AMF stimulates RHO-GTPase which changes the cytoskeleton and causes migration. ECM cleavage products: growth promoting, angiogen, chemotactic. TMF: AMF = chemokine, increased in many cancers, motilitic; HGF=chemokine HGFR activation; EGF

Question 10

Common signals

Answer 10

RHO = migration
MAPK = proliferation
PI3K = survival
VEGF = angiogen

Question 11

TMF pathway

Answer 11

Signal via RHO GTPases; rho, rac, CD42 leads to changes in cytoskeleton leading to movement

Question 12

Transport

Answer 12

Tumor-platlet emboli. Express receptors that bind to platlets and travel as an embolism (protects from sheer forces). Down regs MHC1

Question 13

Tumor arrest

Answer 13

By chance or specific interactions. Tissue tropism: in addition to anatomy, some have increased affinity for certain tissue. Expressed cell adhesion molecules can also determine where they bind. CAMs bind to target organ endo cells (CD44 binds endo VCAM)

Question 14

Chemokine reg of breast cancer metastasis

Answer 14

Increased CXCR4 and CCR7. CXCR4 (BC) binds CXCL12 (lung, liv, bone) while CCR7 binds CCLR21.

Question 15

Extravasation

Answer 15

Invadopodia: Integrin interaction with endothelial BM and with proteases burrow into tissue. Proteolysis of BM and ECM localized to leading edge

Question 16

VEGF inhib

Answer 16

Bevazizumab (Avastin), Sunitinab, Serafenib

Question 17

EGFR (HER1) inhib

Answer 17

Cetuximab, Panitumumab, gefitinib, Erolinib

Question 18

HER2 inhib

Answer 18

Trastuzumab (herceptin), Petuzumab (dimer inhib)