Lecture #22 & #23| Tumor Growth and Metastasis

Metastasis

The ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and the invade and grow in normal tissues everywhere else

lethality of benign tumors

Do not kill host

• well organized and differentiated

• - have fewer “luxury molecules” normal cells but sometimes they have too many

• even a large benign tumor in most places will not kill you

• exceptions: blocking airways

Lethality of metastases

Do kill the host

• its what’s the tumor cells do to the body

  • organ failure

  • cachexia (wasting away)

  • infections: most common cause of death in cancer patients

  • Hemorrhage: rare, excessive bleeding

  • Heart failure: even rarer, rarely has tumors

• hard to treat, not amendable by surgery

Comparison between metatstes and original tissues

Retain some properties of original tissue

• metastatic tumors cells look different from their new surrounding

• retain some of the characteristics of the original tissues that helps to determine the origin of the primary tumor

Effect of metastases on organ function

• typically organs have a lot of excess capacity

  • 2 lungs, 2 kidneys; so metastases can be present for a long time before symptoms arise

• Metastic tumor cells destroy the architecture of the organs

• when pts starts to show symptoms it is often too late

  • leukemias often have symptoms earlier

Steps of metaastasis

1. Hypoxia → angiogenesis (growth of new blood vessels)

2. Invasion of circulatory system

3. Migration to a new site

4. Establishment in a new tissue

5. Rapid proliferation of tumor cells

Step #1 Hypoxia and angiogenesis

Tumor cells may not need growth factors but they do need nutrient and oxygen

• they enduce the growth of new blood vessels

• when the tumor is around 10,000 cells, necrosis of center tumor cells occurs

• in order to survive and proliferate, they need to supply more nutrients

Hypoxia increases expression of p53

• so it is trying to avoid hypoxia

• selects for aggressive, unstable p53 -/- cells

Angiogenesis

It is signaled by factors secreted by tumor and normal cells

• local signaling to endothelial cells

• sprouting-extension of pseudopodia

• invasion through basal lamina

• cell division behind sprout

• formation of capillary tube

balance between activators and inhibitors

Activators are growth factors, inhibitors help inhibit formation of new blood vessels

How do tumor cells migrate?

1. Must lose adhesion to neighboring cells

   1. Lose expression of APC and E-cadherin

   2. Instead express N-cadherin that allows them to migrate

2. Escape tissue of origin and burrow thru neighboring tissue through the expression of new genes that allow it to move like integrins

   1. Cells in tissues are surrounded by extracellular matrix made up of proteins

3. Cross basal lamina which is made up of lamina, collagen, integrins

4. Tumor cells must degrade ECM but also make holes (through proteases) in basal lamina → allows invasion of capillaries

   1. EMT=epithelial to mesenchymal transition then MET=mesenchymal to epithelial transition

      

Proteases that degrade basal lamina to make holes

1. Matrix Metalloproteinases

2. Serine proteases

Matrix Metalloproteinases

1. Affect cell migration by degrading ECM and change cell adhesion

2. Alter cell-ECM interaction: regulate cell shape, proliferation, apoptosis

3. Release latent growth factors attached to ECM

4. Directly regulate activity of extracellular enzymes

Notice that around cancer cells there is less ECM

• Expression of MMP results in hyperplasia and invasive metazoic tumors in mouse models

Angiostatin inhibits angiogenesis. What is its connection to basement membrane?

It inhibits the protease that turns inactive plasminogen into active plasmin

ECM/BM is cleaved by processes such as plasmin

VEGF

Pro-angeiogenic factor that binds to endothelial cell receptor kinase and singles cell to proliferate

• released from normal and tumor cells under hypoxia

• can be surpasses by antagonists of receptor

What is HIF

Hypoxia inducible factor which regulates the transcription of VEGF

• so hypoxia stabilizes transcription factor HIF to increase the expression of VEGF

Regulation of proteases

1. Secreted by inactive precursors

2. confined to specific areas by TIMP (tissue inhibitor of MMPs (plasmin activates pro-MMP to MMP) and serpins (serine protease inhibitors)

3. many cells have receptors on their surface that bind protease and limit their range of action

Migration to a new site

1. Follow the circulatory system

   1. Lung get metastases from many tissues because all the blood goes there for oxygenation

   2. Portal vein goes directly to liver

2. Large cancer cells can get stuck in blood vessel causing a blood clot

3. Cancer cells also travel through the lymphatic system → metastases in lymph nodes

4. Homing and coloration of a cancer cell to a distant organ is a complex process that depends on the target tissue as well as the tumor cells and other unknown

Establishment in a new tissue

Proper environment is required that depends on hormones

Rapid proliferation of a new tissue

Takes time to adapt

• genetic instability will accelerate the process

How can knowledge of metastasis be used tonight cancer

1. Diagnostically: determine the stage of the tumor and therefore how to treat it

   1. MMP

   2. Metastatic gene signatures

2. Therapeutically

   1. Target any of the 5 steps of metastasis

Diagnostic applications of metastasis knowledge

1. MMPs are diagnostic of metastatic potential

   1. detection of MMP in tissues indicate whether the tumor has the potential to metastasize, used as a screening tool

2. DNA sequencing to see if there is a metastatic signature which allows staining of the whole genome

   1. Signatures allows prediction of metastasis and survival for many cancers

      

does not work well for lymphoma

Therapeutic application using knowledge of metastasis to fight cancer

1. Direct inhibition of proteases through TIMP

2. Target the cells that produce the proteases, normal cells rather than tumor cells

3. Angiogenesis → a good drug target for cancer

   1. Angiostatin can decrease tumor size but requires repeated treatment

4. Tumor blood vessels are leaky and disorganized

   1. Taken advantage of in treatment

   2. Even hypoxia can be taken advantage of but tumor hypoxia can cause cancer cells to become resistant to standard therapies → solution: bioreductive prodrugs that become activated only in oxygen poor core of solid tumors

Drugs approved by the FDA for good drugs to target cancer

1. Monoclonal antibody for VEGF

   1. anti-angiogenesis drug that slows tumors

   2. Avastin

2. Chemical inhibitor of angiogenesis

   1. given in combo with other drugs

   2. ex: thalidomide inhibits angiogenesis, Ub ligases and generates ROS → impacted babies