Neoplasia: Invasion and Metastasis

Question 1

What is the definition of metastases?

Answer 1

tumors discontinuous with the primary tumor.

or the transfer of malignant cells from the primary site to non-connected secondary site

Question 2

Invasion and metastasis are characteristics of _______

Answer 2

malignant tumors. Benign tumors don’t invade or metastasize.

Question 3

What are the three mechanisms of metastasis?

Answer 3

1. lymphatogenous
2. hematogenous
3. cavitary

Question 4

What is the pre-invasive stage and what does it mean?

Answer 4

this is called “carcinoma in situ”. In this stage epithelial cells have all the cytologic features of malignancy, but the cancer hasn’t invaded the basement membrane yet.

Question 5

What is cavitary dissemination and what is one example?

Answer 5

the cancer breaks away from the original tumor and seeds in body cavities.
Eg.-ovarian cancer

Question 6

what is extravasation?

Answer 6

cancer cells exiting capillaries and entering organs (in the case of metastasis)

Question 7

What is intravasation?

Answer 7

The invasion of cancer cells through the basal membrane into the blood or a lymph vessel.

Question 8

What is lymphatogenous dissemination? what is the mechanism?

Answer 8

Intravasation and extravasation occur in the lymph.

primary tumor–>lymph node–>other parts of body–>drain into systemic venous system–>can spread hematogenously

Question 9

what is hematogenous dissemination? what is the mechanism?

Answer 9

Intra and extravasation occur in the blood.
primary tumor penetrate blood vessels–>passively transported in the blood vessels to distant sites–> penetrate vessel–>build new tumor

Question 10

What is the most common route of metastasis for sarcomas?

Answer 10

hematogenous dissemination

Question 11

What is the most common route of metastasis for carcinomas?

Answer 11

lymphatogenous dissemination

Question 12

whats the difference between a carcinoma and a sarcoma?

Answer 12

carcinoma arises from epithelial cells, sarcoma arises from mesenchymal cells (like bone)

Question 13

Malignant tumors still recognize anatomic boundaries T or F?

Answer 13

F

Question 14

explain some theories about why tumors metastasize

Answer 14

selection pressure- the cells are proliferating faster than they can make vasculature for itself. With increasing size of tumor hypoxia occurs because of limited blood supply and nutrients. Cells want to move out. Thus it is advantageous for primary tumors to metastasize

Question 15

Increasing tumor size usually correlates with ______ risk of developing metastases.

Answer 15

increased

Question 16

How does metastasis occur?

Answer 16

carcinoma cells must first invade the ECM by
1. breeching the underlying basement membrane
2. traversing the interstitial connective tissue
3. gaining access to circulation by inravasation (must breech the vascular basement membrane)
extravasation is the same in reverse

Question 17

what does the inflammatory response do to cancer?

Answer 17

it is meant to heal but instead supports tumor growth

Question 18

Cancer cells have the ability to ______ which allows them to most effectively support neoplastic proliferation.

Answer 18

modify cellular metabolism

Question 19

modifying cellular metabolism allows cancer cells to evade_____

Answer 19

immunological destruction

Question 20

What are the 4 steps of invasion (as in intravasation of cancer cells)?

Answer 20

1. loosen up cell-cell interactions (i.e. loss of E-cadherin) cells begin to dissociate
2. degradation of ECM (basement membrane and interstitial CT)
3. attachment to ECM components
4. migration of tumor cells

for extravasation the process is reversed.

Question 21

What are the four major theories to describe the bias of certain cancers for certain organs?

Answer 21

1. metastasis is caused by rare variant clones that develop in the primary tumor.
2. metastasis is caused by the gene expression pattern of most cells of the primary tumor (they have a metastatic signature)
3. combo of 1 and 2– metastatic variants appear in a tumor with metastatic gene signature
4. metastasis is greatly affected by the microenvironment (angiogenesis, local invasiveness, resistance to immune elimination).

Question 22

epithelial cells are held together by ____

Answer 22

E-cadherin

Question 23

overexpression of _____ may favor metastatic spread.

Answer 23

CD44

Question 24

What are the four steps of the metastatic cascade?

Answer 24

1. invasion- through the basement membrane and ECM
2. Intravasation- getting into a blood or lymph vessel
3. extravasation- getting out of a vessel at new site
4. Colonization- ability to grow in new site

Question 25

On the intracellular side what does E-cadherin connect to?

Answer 25

Beta-catenin-alpha-catenin actin complex forms dynamic link to cytoskeleton.

Question 26

loss of heterozygosity can cause _____

Answer 26

E-cadherin expression to be lost.

Question 27

SNAIL, SLUG, TWIST, ZEB1/2 are transcriptional repressors that promote _______ by repressing _______.

Answer 27

EMT (epithelial to mesenchymal transition)

E-cadherin

Question 28

How do MMPs regulate tumor invasion?

Answer 28

1. remodeling insoluble components of basement membrane

2. releasing ECM-sequestered growth factors

Question 29

Tumor cells can make proteolytic enzymes themselves or induce ______ to make them.

Answer 29

stromal cells

Question 30

what are MMPs?

Answer 30

proteolytic enzymes. Matrix metalloproteinases

Question 31

what is ameboid migration?

Answer 31

a 2nd type of invasion that tumor cells can possess which allows them to squeeze through spaces in the ECM instead of cutting through it with proteolytic enzymes like MMP (this is why MMP inhibitors don’t work on cancer).

Question 32

Lots of adhesion in normal cells leads to _____

Answer 32

apoptosis. Normal cells are resistant to this.

Question 33

What is a secondary problem of cancer cells modifying the ECM?

Answer 33

it can lead ECM to further promoting invasion and metastasis.

Question 34

what is anoikis?

Answer 34

death by detachment (happens in normal epithelial cells)

Question 35

Movement of tumors can be potentiated and directed by what things?

Answer 35

1. tumor cell-derived cytokines (autocrine)
2. cleavage products of matrix components (collagen, laminin)
3. growth factors which have chemotactic activity for tumor cells (IGFI and II)
4. Paracrine effectors of cell motility secreted by stromal cells.

Question 36

Once in circulation, tumor cells are vulnerable to destruction from what?

Answer 36

mechanical shear stress and immune defenses

Question 37

Tumor overexpression of _____ favors metastatic spread.

Answer 37

CD44

Question 38

In extravasation tumor emboli adhere to endothelium of distant sites and egress through basement membranes. This involves what molecules?

Answer 38

adhesion molecules, such as integrins, laminin receptors, and proteolytic enzymes.

Question 39

CD44 adhesion molecule expressed on normal ______ is used by cancer cells to migrate to selective sites in _______

Answer 39

T lymphocytes

lymphoid tissue

Question 40

What are the direct effects of metastasis?

Answer 40

invasive masses directly interfere with normal function.

Question 41

What are the indirect effects of metastasis?

Answer 41

paraneoplastic syndrome (paracrine, endocrine effects). A disease that involves hormones and cytokines. It is the consequence of cancer but not due to local presence of cancer cells

Question 42

Basement membrane=

Answer 42

lamina, collagen

Question 43

E-cadherin is a ____

Answer 43

transmembrane glycoprotein.