Cancer Mechanisms Flashcards
Which cells are stromal cells, and what do they do?
FAMES
Fibroblasts, adipocytes, macrophages, endothelial cells, smooth muscle cells
They create a suitable *microenvironment for the cancer cells, including things like cytokines, hormones, and enzymes involved in ECM degeneration.
Melanoma with Stromal cell example?
Melanoma cells release GF (growth factor).
This GF stimulates fibroblasts to secrete insulin-like GF-2 (IGF-2), which enhances the survival of the melanoma cell.
Explain the steps of the angiogenic switch
- Hypoxia results in activation of H1F1α transcription factor
- H1F1α binds stimulates expression of VEGF
- VEGF stimulates proliferation of endothelial cells
- Stromal cells can help by releasing chemoattractants
- Chemoattractants stimulate migration of the growing endothelial cells to the tumor site
* Leads to abnormal leaky vessels
In a condition of normoxia, what happens with the angiogenic switch?
Normoxia:
1. Proline hydroxylase oxidizes H1F1α
2. H1F1α then binds to a ubiquitin ligase called VHL
3. VHL polyubiquitinates H1F1α, which then goes through proteasome-mediated degradation.
Thus, H1F1α can never cause the release of VEGF.
VHL is considered what/
A key tumor suppressor.
Cancers with the ability to undergo angiogenic shifts have what clinical importance?
More likely to metastasize, and higher chance of reoccurence.
The type of blood vessels tumors manage to grow contribute to metastasis. How are they different? What is the main thing that makes them better at metastasizing?
They are larger in diameter.
Pericytes are more loosely attached.
Their capillaries often dead-end or double-back.
The main thing helping them is the gaps between the endothelial cells, making them “leaky.”
What percentage of cancer deaths are attributed to metastasis?
90%
explain the first 2 steps required for a tumor to metastasize
- Localized invasion into surrounding tissue
- E-M transformations makes cells resemble fibroblasts, and causes disruption of cell-cell adhesion. Increased *mobility and invasiveness. More vimentin. Loss of polarity
- Changes in cytoskeleton (such as WASP proteins), allowing cell to form *invadopodia
- Invadopodia initiate through focal adhesions (integrins-ECM)
- Production of matrix metalloproteinases *(MMP) degrade BM and ECM, causing disruption of cell-ECM interaction (and so overcome anoikis as well)— makes cell more mobile and invasive, and allows them to gain receptors for PDGF - *Intravasation into blood vessels— all of the above contribute.
- “Leaky” vessels allow cells to enter circulation, as well as help from MMP.. into blood and lymph
If you lose TGF-beta, you will lose what?
the MMP inhibitor. Thus, cells can metastasize easier.
Explain the 3rd step in tumor metastasis
- Extravasation- becomes trapped in capillaries
- Cancer cell forms a microthrombus
- Cancer cell forces its way through endothelium till it reaches BM—MET
- Cancer begins to grow and divide, forcing its way through blood vessel and into new environment. Called a micrometastasis
* This does not necessarily indicate a clinically significant tumor! Depends also on its new environment*
- then can go to macrometastasis
Most breast and prostate cancer metastasizes where?
Colon cancer often invades to?
To bone marrow.
Colon cancer often to the liver.
What is a macrometastasis? What makes it different from a micrometastasis? How does this have to do where different metastases are found?
Macrometastasis develops from a micrometastasis, in the right stromal environment. These are clinically significant.
Often times, metastasis doesn’t follow normal circulation. Tumors end up growing in the right stromal environment–regardless of where it might be.
Pancreatic cancer often spreads to?
The liver.
What is the difference in a metastasized tumor recruiting stromal cells versus invading stromal cells?
When they recruit stromal cells, they create things for the tumor that are reminiscent of where they came from– easier to recognize.
When they invade stromal cells, they simply take over the new organ and displace old cells…and end up looking a lot like the organ they are then in. Makes it hard to tell where the cancer started versus ended.
