A Harvard University researcher,
Dr. Judah Folkman, worked on a familiar observation:
Removing a primary tumor often leads to more rapid growth of secondary tumors.
Perhaps the primary tumor is produces some substance that inhibits the growth of the other tumors.
Such a substance could be a powerful weapon against cancer.
Folkman found two candidate substances/ proteins.
Angiostatin and Endostatin.
How do they work?
A tumor needs a lot of food & nutrients to grow more cancer cells.
To help its feeding, a tumor leaks out substances that enable the growth of small vessels & capillaries. This growth of blood vessels is called angiogenesis,
Having new vessels achieves a greater flow of blood to the tumor as it grows larger.
Folkman's two cancer inhibitors are angiogenesis inhibitors.
Angiostatin and endostatin kill a tumor by cutting off its blood supply.
Cutting of cancer cells' supply of food & nutrients literally starves them to death.
So, in order to prevent the growth of competitive tumors, the primary tumor produces angiostatin and endostatin to keep all the resource flow for itself.
In laboratory tests the angiogenesis inhibitors shrinked mice tumors to microscopic.
That was astonishing!
Other scientists tried replicate this exciting result. Some
have succeeded, others not.
Five major laboratories have isolated their own angiogenesis inhibitors and published findings of antitumor activity.
The National Cancer Institute does experiments with angiogenesis inhibitors to human cells.
Preliminary results are encouraging.
While not a cure-all for all cancers, angiogenesis inhibitors seem very effective against some, particularly solid-tumor cancers.
We avidly try to understand how tumors induce angiogenesis.
When a solid tumor grows faster than its blood supply can support, its interior becomes hypoxic (oxygen depleted).
In hypoxia, genes that promote survival under low oxygen pressure are turned on.
Some of these genes increase blood flow to the tumor by promoting angiogenesis.
So how does lowering oxygen pressure in a tumor promote blood vessel formation?
Dr. Randall Johnson of the University of California, San Diego, is studyies the induction of a gene-specific transcription factor (that is, a protein that
activates the transcription of a particular gene) that promotes angiogenesis under hypoxia.
The transcription factor is called HIF-1, for hypoxia inducible
factor-1.
HIF-1 indices the transcription of genes necessary for blood vessel formation.
Molecular Genetics
Primary tumors kill off the competition.
Tumors require an ample blood supply to grow.
The growth of new blood vessels is called angiogenesis.
Inhibiting angiogenesis may block tumor growth.
The Experiment
A problem for Johnson and his co-workers was that HIF-1 has many other effects on cell growth.
To get a clear look, the researchers used embryonic stem cells.
Embryonic stem cells are cells harvested from early embryos, before they have differentiated, so they are still capable of unlimited division.
Such stem cells can form tumors when injected into mice.
That all is a good natural laboratory to study how
HIF-1 can influence cancer growth.
The research team prepared a mutant HIF-1 embryonic stem cell line where the function of the transcription factor encoded by HIF-1 was completely destroyed(null).
Then, grew these HIF-1 null stem cells under hypoxic conditions.
If HIF-1 genes indeed promote angiogenesis and help normal cells grow, these null cells -and so the tumor- wouldn't grow.
The researchers injected HIF-1α null cancer cells into
laboratory mice, wildtype stem cells into a control group of mice.
The injected cells were allowed to grow and form tumors in both null and control hosts (mice).
The tumors that formed were then examined and measured
for differences.
To compare the null and wild-type cells' ability to form new blood vessels. They examined the mRNA amount of a basic for the vessels formation growth factor.
This factor is a protein called vascular endothelial growth factor (VEGF).
In parallel studies, antibodies were used to determine levels of VEGF protein.
The Results
The researchers found that the null cells formed much smaller tumors than the wildtype cells.
The effects were more significant over time.
Tumors were five times larger in wildtype cells than in the HIF-1 null cells after 21 days.
Clearly knocking out HIF-1 prevented tumor growth.
This decrease in the size of tumors produced by null
cells is further supported by the results of the VEGF protein analysis (see graph b above).
Under hypoxia, we have more VEGF in wild-type cells
which promote capillary formation to bring more oxygen to the tumor
VEGF protein was much less in null cell tumors, and responded to hypoxia at a lower rate.
Both the decrease in tumor size and the lower level of
VEGF in the HIF-1 null cells support the hypothesis that
HIF-1 plays an essential role in promoting angiogenesis in
a tumor, responding to a hypoxic condition by increasing
the levels of VEGF.
Do the angiogenesis inhibitors like angiostatin, in fact inhibit VEGF? Are they good candidates for cancer cures?
Exciting findings coming soon, keep pursuing science and leave psychology to the pussies. (kiddin')
