What is Cancer?
Cancer is one of the most common diseases in the United States
today. Most people know at least one person that has been affected
with cancer. Because it is so prevalent it has become a common
research topic for scientists. The goal of cancer research is to
determine a cause, the effect, and how to treat the cancer.
Cancer, by definition, is uncontrolled cell division. In other words,
mitosis is occurring in cells where it isn’t needed. Normally, before
mitosis begins a cell has to have a very specific signal in order for
mitosis to occur. Sometimes, this signal gets sent at the wrong
time, or the cell divides before a signal is sent. When something
goes wrong in this process cells usually sense this and decide to
kill themselves in order to prevent further damage to the body.
This process is called apoptosis, meaning the programmed death of
a cell.
Usually you would think a cell dying is a bad thing, but this isn’t
the case in apoptosis. Why would apoptosis be helpful to our
health? What do you think would happen is something blocked
apoptosis?
How Does Hedgehog Cause
Cancer?
After many years of research
a huge connection between sonic
hedgehog and cancer was found.
Basal Cell Carcinoma is one of the
most common types of skin cancer
in humans. It is estimated that there
are about 2.8 million cases of Basal
Cell Carcinoma (BCC) in the US
each year. BCC is a tumor that
grows on your skin. It often starts
out looking like skin irritation or
eczema and then continues to grow.
Luckily, BCC tumors rarely metastasize to vital organs and it is
not usually life threatening. However, the early BCC is caught the
more effective treatment is. If the BCC tumor is left for too long it
can cause damage to surrounding tissues. Scientists discovered
that when hedgehog was expressed at the wrong time, adult stem
cells were transformed into cancer stem cells that grew into a
tumor. This discovery offered a huge promise for a potential
cancer treatment. If scientist could discover a way to inhibit sonic
hedgehog they could possible prevent basal cell carcinoma.
To understand the connection we have to look deeper into the
hedgehog pathway. There are three important proteins in the
hedgehog pathway we need to understand in order to understand
how it promotes cancer. Overall, this pathway controls when and
where cells divide, or undergo mitosis. But how does this cause
cancer?
Smoothened (SMO) is a protein that signals a cell to enter mitosis
and divide. Patched (PTCH) is a protein that inhibits smoothened.
Hedgehog (Hh) inhibits patched.
Here is a graphic describing the normal state in most of your cells.
Here, hedgehog is not active so cells are not
dividing:
If something goes wrong with transcription or translation,
Hedgehog can become active at the incorrect time. This causes
cells to divide. Look at the graphic below to see how activation of
the hedgehog pathway leads to cell division.
In the box below, use your knowledge of protein pathways to
model the relationship between these two proteins.
From your model you can see how if hedgehog is expressed at the
wrong time, cells will begin to divide. The definition of cancer in
unregulated cell division. When hedgehog is activated at the wrong
time, cells begin to divide uncontrollably. Those cells ball up
together and form a tumor. This is what causes cancer. Take a look
at the cell below to see how these proteins work together to affect
your cells and body (Similar to parts of a car!)
Apoptosis
Hedgehog has another important role in causing cancer. Not only
does it promote uncontrolled cell division but it also decreases
apoptosis. Apoptosis is when a cell decides to kill itself. At first
this may seem like a bad thing, but apoptosis is crucial to keeping
the human body healthy. When a cell senses something go wrong it
kills itself before causing any harm. Unfortunately, when hedgehog
is activated apoptosis is blocked. This means the cells divided
uncontrollably cannot kill themselves like they normally would.
This allows even more cells to become cancerous and form a
tumor.
*Images from:http://www.hedgehogpathway.com/home/hedgehogpathway/hedgehog-signalling.html
How Do We Treat Cancer?
Now that we understand how a problem in
the hedgehog pathway can cause cancer,
we can begin to think about possible
treatments. If improper activation of the
hedgehog pathway causes uncontrolled
cell division and decreased apoptosis, then
the logical way to treat that would be to
block that pathway.
This is exactly what scientists thought that
lead them to a treatment for basal cell
carcinoma. Vismodegib is a treatment that
was approved by the FDA in 2012 to treat basal cell carcinoma.
Vismodegib works by blocking the hedgehog pathway. This means
it works with hedgehog, patched, and smoothened to block their
activities and begin to control cell division again. The brand name
of this medication in the US is Erivedge.
To understand the affects Vismodegib has on the proteins in the
hedgehog pathway you have to think back to how these proteins
interact with each other. Look at your model for the hedgehog
pathway. If Vismodegib blocks hedgehog what happens to the
other proteins?
In the data analysis section you will be asked to predict levels of
protein after treatment. Keep your model handy as well as your
knowledge of the Vismodegib treatment.