Metastasis and angiogenesis

Question 1

What is epigenetics? Give examples.

Answer 1

The study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.

The addition of chemical groups to DNA or histone proteins which affect DNA structure and gene transcription. Most common are DNA methylation and histone acetylation. The level of methylation or acetyation can control transcription. Changes in levels occurs in cancer.

Question 2

What is metastasis?

Answer 2

Defined as the ability of cancer cells to break away from its site of origin, travel to and recolonise a distant site.

Question 3

What % of solid tumors will have metastasized at the time of diagnosis?

Answer 3

> 50%

Question 4

Outline the mechanism of metastasis

Answer 4

1. Requires break down in cell-cell adhesion and degradation of basal lamina - overexpression of Scr causes cells to round up and this causes less membrane adhesion.
2. Mutations in E-cadherins relax cell to cell adhesion
3. Changes in expression of integrins allows cell movement through ECM
4. Tumors induce surrounding stromal cells to produce MMPs to digest the ECM
5. Intravasation by degradation of basal lamina
6. Transported through the blood vessels and extravasates into new tissues.

Question 5

What are the two hypothesis regarding where a tumor will metastasise to?

Answer 5

1. First pass organ - carried through the blood stream and recolonise in the next organ they encounter (as blood slows down as it approaches the next organ)
2. Premetastatic niche - cancer cells release or induce the release of growth factors to develop a pre-metastatic niche where the tumor will metastasize to. (the secondary site is prepared to receive the cells)

Question 6

What is the purpose of angiogenesis for tumor cells?

Answer 6

Tumor cells need a good blood supply to be provided with oxygen and nutrients and to remove waste. The second purpose is to allow a route for metastasis.

Question 7

What is angiogenesis?

Answer 7

The growth of new blood vessels. It occurs naturally during embryogenesis, wound healing, menstrual cycle.

Question 8

Why could targeting angiogenesis be a potential specific target for cancer?

Answer 8

Angiogenesis is rare in mature healthy cells (it is usually suppressed by an excess of inhibitors) so possible specificity due to lack of normal occurrence.

Question 9

Outline the angiogenic process

Answer 9

1. Surrounding cells release angiogenic factors e.g. VEGF
2. These bind to receptors on nearby endothelial cell
3. The endothelial cells are activated and produce enzymes
4. The enzymes digest the basement membrane
5. The endothelial cells proliferate and migrate out of the vessel
6. Adhesion molecules and MMPs aid the formation of the growing blood vessel
7. The new vessels are stabilized by smooth muscle cells and pericytes

Question 10

What is VEGF? how is it produced?

Answer 10

There are five forms of VEGF, best characterised is VEGF-A
It is an angiogenic factor.
Its production is triggered by oncogenes and by hypoxia. When a cell is deficient in oxygen it produces hypoxia inducible factor (HIF), a transcription factor, HIF stimulates the release of VEGF-A.

Question 11

What is avastin?

Answer 11

Bevacizumab
Humananised monoclonal antibody
Anti VEGFA - binds ligand.

Question 12

What are the problems with avastin efficacy?

Answer 12

Approx. 10-15% of patients benefit from Avastin, however biomarkers for its efficacy are not yet known so we don’t know which patients will benefit until we give it to them.

Avastin is ineffective against tumours with an established blood supply - only prevents new blood vessels forming.

Long term administration could impair natural wound healing.

Question 13

When is avastin used?

Answer 13

First-line treatment of metastatic breast cancer in combination with paclitaxel when treatment with other chemotherapy, including taxanes or anthracyclines is not appropriate

First-line treatment of metastatic breast cancer in combination with capecitabine when treatment with other chemotherapy, including taxanes or anthracyclines is not appropriate (patients who have received adjuvant taxane or anthracycline-containing regimens in the previous 12 months should not be treated with bevacizumab in combination with capecitabine)

Advanced or metastatic renal cell carcinoma in combination with interferon alfa-2a

First-line treatment of unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology (In combination with platinum-based chemotherapy)

First-line treatment of advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (in combination with carboplatin and paclitaxel)

First recurrence of platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have not been treated previously with bevacizumab or other drugs that target vascular endothelial growth factor (in combination with carboplatin and gemcitabine)

Question 14

How could vascular gene therapy be used to treat cancer?

Answer 14

The concept of vascular gene therapy is to correct or alleviate disease by delivery of genes. It requires the identification of an appropriate gene AND the specific delivery of this gene to required area.

Example - target E selectin (adhesion molecules) as only produced by endothelial cells, and use retroviruses which specifically target rapidly proliferating cells. Links this with a gene encoding for a dominant negative form of VEGFR