From an MD, PhD researcher at Stanford...

I never heard of Targesomes before and I don't know the Stanford docs
involved, but I think it is basically a very good idea. But there is one
angle you might not be aware of, which is kind of a weakness in the approach
(or lets not call it a weakness but a limitation), but which may also be a
potential handle for a targeosome 2 idea. If you listen to the Judah
Folkman lecture that I mentioned you can hear him tell it to you directly.
Judah discovered something really really interesting. It started with a
clinical observation. He said, as a young surgeon he was amazed to find
that when patients present with what appears to be a single large cancer
focus that has not spread yet based on a typical metastatic work up of bone
scan, blood work, and liver scan), that often to his great surprise within
weeks after supposedly curative surgery, the patient would explode with many
metastatic tumors all over the body. This sucked me in because I observed
this also again and again and again as a resident at Memorial Sloan
Kettering Cancer Hospital. What he finally figured out, after many years of
research, was the explanation. The cancer had in fact often already spread
before the surgery, but the sites of spread were very tiny tumor foci that
were 1 mm or less in size so could not be detected by the usual tests. But
he went further and figured out why they were only 1 mm in size. What he
discovered is that many tumors, either early in the development of the
primary tumor, or after spread of the tumor, are not yet vascularized.
Tumors, in order to be vascularlized, have to make a stimulator of
angiogenesis (the identities of these stimulators have only recently been
discovered and tell blood vessel cells to migrate into the tumor and to
divide). Early on in tumor development, when the tumors are under 1 mm in
size, they are not making these stimulators or, if they are, are making them
in only low levels or levels insufficient to overcome the also present
angiogenic inhibitors. These inhibitors, which Folkman discovered, can
actually be made by the primary (large) tumor and secreted into the
circulation. So in a way this helps the primary tumor to preferentially grow
and inhibit competing tumors that it sheds off; when the primary tumor is
removed, the small tumors are now free to start growing in the absence of
the circulating inhibitor.

So this work raised an interesting question, which is how can these small
cancers stay so small if the cancer cells are growing uncontrollably.
Folkman figured out the reason why. Because in the center of the tumors
there are lots of cancer cells that are growing quickly, but these new cells
get pushed out to the edges of the tumor where they are far away from blood
circulation and therefore they die. And therefore these small tumors are in
a kind of steady state with the rapid massive cell division being balanced
by an equal and opposite cell death. The tumors might stay 1 mm in size
forever, unless one of two things happens. First, the primary tumor is
removed, removing the angiostatin blood vessel growth inhibitors. Or, even
in the continued presence of the primary tumor, while these cells in the 1
mm tumors are dividing so quickly they have a chance to undergo new
mutations; eventually these mutations allow the cancer cells to secrete more
stimulators of blood growth, allowing them to vascularize and start getting
bigger than 1 mm quickly.

The implication is that all tumors, not just metastasis, have to go
through different stages of evolution. THere is much other evidence to
support this. So if you really want to develop a method to pick up tumors
early while they are 1 mm or less in size (either new primary tumors or
metastases), you need to develop a method that doesn't depend on the the
presence of blood vessels (I gather for the Targesome method you need blood
vessels). So here's a strategy for a Targesome 2. Develop a Targesome that
is concentrated in dying cells. It is highly unusual in a normal body to
have many dying cells. There are always occassional dying cells in any
tissue. But it is very rare to have hotspots where many cells are dying. Of
course many people have previously tried to develop ways of imaging cancers
by imaging cells that are dividing quickly, but it is only in the last few
years that biologists have learned about the kind of cell death (called
apoptosis) that is going on in tumors and in neurodegenerative diseases.
ANd therefore there has been an explosion of recent information about the
molecules involved in this death process, which might suggest new methods of
imaging them. One obvious thing is that the dying cells have fragmenting
DNA, so indicators that bind to fragmenting DNA might be used, for instance.

Being able to detect tumors before they vascularize is a really important
issue. Because small tumors may be sitting in your body (in fact people
think they are) for years and years at the 1 mm unvascularized stage. But
once they mutate to the point that they can vascularize, they grow
exponentially and double in size daily so--you can do the math--annual
targesome exams could miss most of them. (Something thats kind of scary
though, is that it seems possible that if you could develop such a method,
you might find that all of us have lots of 1 mm unvascularlized tumors.)

Note that the Targesome group had already thought of this, but this e-mail is a good explanation of why this may be important (there is still some debate on this). Also, using Targesome, you can detect endothelial, not interstitial (cancer) apoptosis. There is no observation that pre-angiogenic cancers cause endothelial apoptosis. If these cancers themselves undergo apoptosis, they can't detect it because it is not intravascular.