4. Neoplasia IV- Tumor Microenvironment And Signaling

Question 1

Describe the mechanisms of invasion and metastasis: the metastatic cascade; interactions of tumor cells with the extracellular matrix (objective)

Answer 1

Answer later

Question 2

Describe interactions of tumor cells with host cells in the tumor microenvironment (objective)

Answer 2

Answer later

Question 3

Describe Epithelial-Mesenchymal Transition- EMT (objective)

Answer 3

Answer later

Question 4

Mechanisms of invasion and metastasis (overview)

Answer 4

• Metastatic cascade

- “Seed and Soil” Hypothesis

Question 5

Tumor cells in their microenvironment (overview)

Answer 5

• Carcinoma cells interact with other cells in their microenvironment
• Tumor cells induce angiogenesis
• Epithelial-Mesenchymal Transition (EMT)

Question 6

Metastatic Cascade is a model of tumor dissemination: hematogenous spread (steps)

Answer 6

1. Transformed cell: clonal expansion, growth, diversification, angiogenesis
2. Metastatic subclone adhesion to and invasion of basement membrane
3. Passage through extracellular matrix
4. Intravasation
5. Interaction with host lymphoid cells (in blood stream)
6. Tumor cell embolus (+platelets bind)
7. Adhesion to basement membrane
8. Extravasation
9. Metastatic deposit
10. Angiogenesis+growth

Question 7

How cells interact with ECM

Answer 7

Integrins

• mediate cell adhesion and migration
• connected to cytoskeleton
• involved in signal transduction

*** Integrins are Heterodimers composed of alpha and beta chain

Question 8

A. Loosening of intercellular junctions (1/3)

Answer 8

• Loosening of cell-cell adhesion mediated by cadherins (E-cadherins)
• Integrins mediate interactions with ECM proteins (collagens, laminin, fibronectin)

Question 9

B. Degradation of ECM (2/3)

Answer 9

Proteases (MMPs, collagenases) degrade ECM proteins

Question 10

C. Migration and Invasion (3/3)

Answer 10

Degraded ECM may release growth factors bound in ECM (bFGF-complexed with heparan sulfate of heparan sulfate proteoglycan in matrix and interacts with FGF receptor)

Question 11

“Seed and Soil” Hypothesis (what goes where)

Answer 11

Many tumors arrest in first capillary bed they encounter (lung, liver)

Primary tumors preferentially metastasize to certain sites (Seed and Soil Hypothesis):

• Colon carcinoma to liver
• Prostate carcinoma to bone
• Lung cancer to adrenal glands

Question 12

“Seed and Soil” Hypothesis (why)

Answer 12

Organ tropism of cancer:

• endothelial cells at metastatic sites may express adhesion molecules or chemokines
• microenvironment may express chemokines that attract cancer cells

Question 13

Old view of cancer

Answer 13

Tumors as random collections of cancer cells

Question 14

Modern view of cancer

Answer 14

Tumor cells have complex interactions with their microenvironment

Question 15

Components of Tumor Microenvironment

Answer 15

Cancer cells
Tumor-promoting inflammatory cells
Extracellular matrix (sequestered growth factors)
Cancer-associated fibroblasts
Endothelial cells
Pericytes

Question 16

Epithelial-Mesenchymal Transition (EMT)

Answer 16

• To acquire motility and invasiveness, cancer cells upregulate some genes and downregulate others
• EMT carcinoma cells downregulate epithelial markers and upregulate mesenchymal markers
• Favor pro-migratory phenotype
• SNAIL and TWIST

Question 17

EMT: down-regulated things

Answer 17

Epithelial markers like E-cadherin

*E-cadherin accumulates in nucleus of tumor cells at tumor-host interface

Question 18

EMT: up-regulated things

Answer 18

Mesenchymal markers: vimentin and smooth muscle actin

Question 19

EMT: phenotype

Answer 19

Believed to favor pro-migratory phenotype

Question 20

EMT: SNAIL and TWIST

Answer 20

Transcriptional repressors that down-regulate E-cadherin expression