Neoplasia: Invasion and Metastasis (complete)

Question 1

Define metastasis

Answer 1

Transfer of malignant cells from primary site to non-connected (secondary) site

• Metastases are tumors discontinuous w/ primary tumor

uh oh

Question 2

What are the different mechanisms of metastasis?

Answer 2

1) Direct seeding of body cavities or surfaces
2) Lymphatic spread
3) Hematogenous spread

Question 3

Why do tumors metastasized?

Answer 3

• Becomes advantageous to move beyond basement membrane

- Conditions around primary tumor get crowded/harsh (hypoxia due to limited blood supply/lack of nutrients)

Question 4

What are the general steps of the metastasis cascade?

Answer 4

1) Invasion
2) Intravasation
3) Extravasation
4) Colonization

Question 5

What are the steps involved in invasion?

Answer 5

1) changes “loosening up” of tumor cell-cell interactions
2) Degradation of ECM
3) Attachment of ECM components
4) Migration of tumor cells

Question 6

Describe step 1 of the invasion stage

Answer 6

Normal: epithelial cells held together by E-cadherin and Beta-catenin

Cancer: E-cadherin is down-regulated —» reduces cells ability to adhere to each other —» detachment from primary tumor and invasion begins

Question 7

Describe step 2 of the invasion stage

Answer 7

• local degradation of basement membrane/CT

- tumors secrete proteolytic enzymes or induce stromal cells to do so

Question 8

Describe step 3 of the invasion stage

Answer 8

• Changes in attachment of tumor cells to ECM proteins
• Loss of adhesion in normal cells leads to apoptosis (tumor cells are resistant)
• Anoikis (death by detachment)

Question 9

Describe step 4 of the invasion stage

Answer 9

• LOCOMOTION
• Propelling tumor cells through degraded membrane and zones of matrix proteolysis
• Process directed by tumor cell-derived cytokines

Question 10

Describe stage 2, intravasation, of metastasis

Answer 10

• Getting into vasculature
• once in circulation, tumor cells vulnerable to destruction by mechanical stress, apoptosis, immune defenses
• that’s why they aggregate in clumps w/ RBCs, platelets

Question 11

Describe stage 3, extravasion, of metastasis

Answer 11

• Getting tumor cells out of the blood vessels
• Tumor emboli involve adhesion (CD44) to endothelium followed by basement membrane distruction
• Most of the time happens at 1st cap bed available to the tumor
• However, natural pathways don’t always predict the placement

Question 12

Describe stage 4, colonization, of metastasis

Answer 12

• Tumor cells secrete cytokines, GFs, and ECM molecules that act on stromal cells —-»> make metastatic site habitable for cancer cells
• Tumor cells inefficent in colonizing distant organs — lead to dormancy

Question 13

What is dormancy?

Answer 13

Prolong survival of micrometastases w/o progression

• often seen in melanoma, breast/prostate cancer

Question 14

Discuss the role of metastasis in death by cancer: what are the ultimate effects of metastasis? what are some of the ultimate causes of mortality due to cancer?

Answer 14

Direct: invasive masses which interfere w/ normal function

Indirect: “Paraneoplastic Syndrome” —> paracrine/endocrine effects

Question 15

What is Paraneoplastic Syndrome?

Answer 15

• Consequence of the presence of cancer but not due to the local presence of cancer cells
• Thought to be due to hormones/cytokines excreted by tumor cells and/or immune response triggered by tumor

Question 16

What are some symptoms of Paraneoplastic Syndrome?

Answer 16

• Ectopic hormone production
• Cutaneous lesions
• Joint/muscle pain
• Neuropathies
• Thromboses
• Nephrosis
• Wasting
• DIC

Question 17

What are some of the ways E-cadherin expression can be lost during invasion?

Answer 17

1) Loss of herterozygosity
2) Inactivation mutation
3) Silencing of gene (hypermethylation)
4) Transcriptional repressors

Alllll the ways cancer can manipulate the basement membrane

Question 18

Describe some theories that explain the bias of metastasis of certain types of cancer towards certain organs

Answer 18

1) Seed and soil theory

2) Mechanical arrest theory

Question 19

Describe the seed and soil theory by Paget

Answer 19

• organ-specific patters explained by needs of the cancer cell —- SEEEEEDD
• causes them to move to a specific environment (SOIL) and initiate and maintain growth

Question 20

Describe Ewing’s mechanical arrest theory

Answer 20

• Cells mechanically arrest in the first cap bed encountered