Metastases

Question 1

What is anoikis?

Answer 1

apoptosis due to a cell not being adherent to anything. A cancer cell must be able to overcome this to spread hemotagenously

Question 2

Why do tumor cells tend to “clump” in the blood stream?

Answer 2

Once in the bloodstream, tumor cells are in danger of attack by the immune system and of shear forces. They tend to adhere to one another and get clotting factors and platelets involved to make a protective group of cells. Also enhances ability to attach to endothelium and extravasate

Question 3

Why does overexpression of CD44 on a tumor cell favor metastatic spread?

Answer 3

CD44 is a common T-cell adhesion molecule. Since T-cells can adhere to vascular endothelium, it is advantagous for a metastatic seed to express this adhesion molecule to get out of the bloodstream into a new tissue (Dissemination stage of metastatic cascade)

Question 4

A tissue secretes CXCL12 and SDF-1…what cancer cells are likely to metastasize in this tissue and why?

Answer 4

Breast cancer cells express CXCR4, which binds CXCL12/SDF-1. Thus, cancer cells are “chemotactic” for the tissues it commonly metastisizes.

Question 5

How do breast cancer cells, when metastisizing to bone, show the importance of stromal cell activation?

Answer 5

Breast cancer cells stimulate osteoclastic acitvity in bone to “make room” for the new colony. This is done through PTHRP secretion by the tumor cell, which in turn causes the osteoBLASTS to upregulate RANKL on their surface. Recognition of RANKL by osteoCLASTS activate osteolytic activity. Thus, breast cancer is osteolytic, all by tickling neighbors to do it’s dirty-work.

Question 6

What (in general) are the four competing theories for the generation of a metastatic phenotype?

Answer 6

1) Tumor cell population needs to be big enough and messed up enough to eventually allow for metastatic seed to genetically reach the “ability” to metastasize.
2) Tumor cells early on generate genetic “ability” to metastasize but they do/don’t use that capability based on some other factor
3) the background genetics of the host are ultimately responsible for providing a hospitable (or inhospitable) environment for a given cancer’s metastatic spread
4) Combo theory, where microenvironment and chronic inflammation play a large role

Question 7

What are the affects of metastasis on the body?

Answer 7

Tissue/organ dysfunction due to the physical presence of an infiltrate. Also, 7-15% of population develops paraneoplastic syndrome (systemic effects that arise from the cancer’s production of paracrine/endocrine secretions)

Question 8

What are the 9 classic Carcinoma-Associated Paraneoplastic Syndromes?

Answer 8

1) Ectopic hormone production (adenocarcinoma)
2) Cutatneous lesions
3) Arthropathies
4) myopathies
5) neuropathies
6) multiple thromboses
7) nephrosis
8) cachexia (wasting away)
9) D.I.C

Question 9

What are the three most common ULTIMATE causes of death due to cancer (non-leukemia)?

Answer 9

1) Infection (42%)
2) Organ Failure (19%)
3) Thromboembolism (12%)

Question 10

If a lymphocyte encounters a metastatic tumor in the blood, and perhaps marks it for coagulation, or for precipitation, how might that actually help the tumor?

Answer 10

• Part of metastasis is intravasation, or breaking through the tissues into a blood stream that has enough flow to move it somewhere
  
  • It, like a rolling lymphocyte, almost wants something to slow it down, and platelets globbing onto it seems to do just the thing
  • If it can adhere once again to endothelial cells and then invade a new space, that’s good for it!

Question 11

Why is there selective pressure to metastasize?

Answer 11

• A tumor cell can get overcrowded, and the middle of a tumor microenvironment might be hypoxic
• Thowing off some metastatic “seeds” will reduce that overcrowding and allow the cells themselves to have a better chance off on their own
○ Think overcrowding, nutrient depravation, and hypoxic environment

Question 12

A carnioma is a tumor made of of what cells?

Answer 12

• Well, cancer cells, but they are epithelial in nature/origin
  
  • Carcinoma = epithelial cancer

Question 13

If a tumor cell didn’t/couldn’t express collagenase, what could it never do?

Answer 13

• Metastisize. Think of a carcinoma…it has to chew through connective tissue, adventitia, basement membranes, into the blood
  
  • From the blood it needs to chew back out through another basement membrane to seed itself in a new environment

Question 14

What is the first step in the metastatic cascade?

Answer 14

Invasion is the first step. But invasion can be separated into several different stages

• First the cells need to dissociate from each other (changes in adhesion molecule expression) - CADHERINS
• E-Cadherins are normal epithelial adhesion molecules and are anchored to actin cytoskelaton through Beta-catenin

Question 15

How is messing with the E-cadherin gene part of a tumor’s progression?

Answer 15

• You need to depart from the mother ship at some point
  
  • Messing with E-cadherin expression will allow the metastatic seeds to break off the main/primary tumor
  • This provides an efficient EPITHELIAL TO MESENCHYMAL transition

Question 16

What are some changes that are associated with EMT (epithelial to mesenchymal transition)? - DOWNREGULATION

Answer 16

• Downregulation of epithelial proteins
○ These are ones that mediate cell-cell adhesions and probably keep the cells “in check” as far as numbers go when they are in a group (contact inhibiton)
* E-cadherins
* Cytokeratins (don’t get keratinized, so they don’t die and get overly epithelialized)
* Epithelial cell polarity (remember, they are like going backwards from epithelia to be able to move a bit better

Question 17

What are some changes that are associated with EMT (epithelial to mesenchymal transition)? - UPREGULATION

Answer 17

Upregulation of mesenchymal proteins
○ Vimentin
○ Fibronectin
○ N-cadherin
○ Motility and invasiveness
○ Increased protease secretion (they have a lot of stuff to chew through to get out of their original tissue)
○ Fibroblast like morphology (more moveable cells)

Question 18

How would you characterize the 2nd stage of invasion?

Answer 18

• Local degradation of the basement membrane and interstitial connective tissue
○ They have to increase proteolytic enzyme secretion to be able to move anywhere

Question 19

Secreted MMPs eventually regulate tumor invasion how?

Answer 19

Remodeling insoluble components of the basement membrane

• Releasing ECM-sequestered growth factors
• Cleavage of collagen and proteoglycans (ECM stuff) have chemotactic, angiogenic, and growth-promoting effects

Question 20

Is the use of MMPs to chew their way through ECM the only way tumor cells move?

Answer 20

• No, they are able to switch into ameboid migration, which doesn’t use MMP’s and uses collagen as a network to pull itself along.
  
  • MMP inhibition doesn’t work well in cancer treatment

Question 21

What is an example of a tumor cell chewing up the ECM to it’s own growth advantage?

Answer 21

• MMP9 is a gelatinase that cleaves type IV collagen of epithelial and vascular basement membrane and stimulates release of VEGF from ECM-sequestered pools

Question 22

Normally, epithelial cells, when they are removed from whateve surface they are anchored/adhered to, will undergo apoptosis (anikoisis). Will a carcinoma do the same?

Answer 22

• No, they have achieved anchorage independence, and they do not need to be anchored to other tissues or ECM

Question 23

How do cancer cells seem to fuel/direct their efforts at movement?

Answer 23

• They secrete (in autocrine fashion) chemotactic molecules at the actin leading edge
• Essentially, they dangle a carrot on a stick in front of them, directing movement in a certain direction by autocrine signaling
○ Tumor-cell derived cytokines (motility factors)