Here are various articles on angiogenesis. I couldn't believe THE MAN
(Folkman) was 15 minutes away from us at the Minneapolis Club, last
Thursday. I am posting an article for our research from today's Minneapolis
Star Tribune. After the MPLS article are a few older articles on
angiogenesis but I find them fascinating. The BUZZ is Folkman is going to
win the Nobel Prize on October 12th. Mark my words, THE MAN is going to
win!!! Every where I turn, the momentum is continuing and people are
excited. Do some of your own research and you will see. I have been
corresponding with the Web Editor at NCI giving her praise for her work on
the new web pages you have to check them out:
One page thoroughly walks through many of the antiangiogenic drugs in
trials. Here is an excerpt of what NCI has on their website: (It echos my
upgraded condition from 'cautiously optimistic.')
Remember, this is NCI making this statement:
Also, because anti-angiogenic drugs are designed to prevent
the further growth of tumors, but do not necessarily kill tumors,
anti-angiogenic therapy may prove useful in combination with
therapy aimed at tumor cells. Early trials using marimastat and
another angiogenesis inhibitor, TNP-470, in combination with
standard cytotoxic drugs have begun.
For some researchers, however, not even cautious optimism
seems appropriate. "All the information we have is that the drug
is working," said Rasmussen. "We have treated 2,500 patients
and we haven't seen any problems yet. I would be stunned if
the drug doesn't work."
p.s. - thanks for the notes today. There were many, however, confused about
results from Phase I trials of Rituxan. I posted that a YEAR ago, Rituxan
was has since been approved (November 1997) and can be recommended by any
oncologist in America, so ask your oncologist and maybe take the PROMISING
PROTOCOLS post with you to discuss options. I am not sure how Rituxan is
marketed around the world but rights have been purchased for it under the
name of MABTHERA and THERAMAB.
From (for research purposes):
Published Wednesday, September 23, 1998
The Observatory: A peek into the future of the war on cancer?
(The subhead, missing from the web but in the paper read:
"The reports from Judah Folkman's lab and case studies are electrifying the
Jim Dawson / Star Tribune
After showing his last slide and making his final point, Dr. Judah Folkman
stepped back from the lectern at the Minneapolis Club last Thursday night
and waited for questions from his audience of surgeons.
A couple of doctors asked for a few more details about his research, but
most of the hundred or so physicians, many of them cancer specialists, just
sat quietly at their tables. When he stepped down from the podium, the room
erupted in loud applause.
"Do you realize who this is?" a surgeon said to me. "This is the man who is
going to put us out of business."
Folkman is the Harvard Medical School professor who won national acclaim
earlier this year for his discoveries of two experimental cancer drugs,
which, so far, have wiped out a host of cancer tumors in mice.
The drugs, angiostatin and endostatin, seem almost too good to be true. The
tumors die, the mice get better, and life goes on. There don't seem to be
any side effects, and the mice don't build up a resistance to the drugs. If
the tumors come back, the scientists give them more drugs, and the cancer
goes away again.
In May a controversial New York Times story described Folkman as the man
who would cure cancer within a couple of years. Nobel laureate James
Watson, the biochemist who helped discover the structure of DNA, was quoted
as making that prediction. But he quickly backed away from it a few days
later, saying he didn't actually say, or at least mean, "cure" cancer.
Still, stories about Folkman filled newspapers and magazines throughout the
country. Many urged caution, and quoted Folkman as saying that he hadn't
found a cure for cancer, except maybe in mice. The promising new drugs
hadn't been tested in humans, and it was too early to get excited, experts
Caution is a good thing, but after listening to Folkman speak to the
Minneapolis Surgical Society last week, many in the room seemed in awe of
what they had heard. Although the two newest drugs from Folkman's lab
haven't been tested in humans, other, less powerful versions have, all
designed to cut off the blood supply to tumors. The results, as he
presented them last week, have been remarkable.
There was the little girl with the tumor on her face at Children's Hospital
in Boston, where Folkman practices. Traditional treatment failed, and the
girl faced traumatic surgery that would disfigure her face. He stepped in
with an early version of one of his anti-cancer drugs. The tumor went away.
That was a few years ago. It hasn't come back.
"Never listen to a physician who talks to you about success on one case,"
Folkman said after telling her story. "But now we have five, and they've
all been successful."
So the night went. There was the woman with cancer of the cervix that had
spread to her lungs. All the traditional treatments had failed. She started
taking the first drug that Folkman helped develop, called TNP-470, through
blood infusion three days a week. The cancer lesions in her lungs stopped
growing, Folkman said, then they went away. The woman gained 11 pounds.
More than two years later, he said, she "continues to be tumor free."
"And if the tumor recurs, she can do it again [take the drug] any time,
because she doesn't have drug resistance."
None of these drugs has been tested long enough to win approval from the
U.S. Food and Drug Administration. And Folkman is the first to issue words
"Have you cured cancer?" a medical student from the Mayo Clinic asked him.
"I think this is an improvement, a step in the right direction," he
replied. The real cure for cancer may come a couple of decades from now,
when "you have a simple molecular cure."
He avoids the word "cure." After the New York Times piece ran, his office
received a thousand phone calls a day from people suffering from cancer.
More stories will trigger more calls. And there isn't much Folkman can do
for the callers. The drugs, which are natural proteins, are proving
difficult to replicate, but pharmaceutical companies are working overtime
to understand and develop them. Human testing of the latest drugs will
start in February or March, and if the history of medicine is a guide,
there will problems to overcome.
'A paradigm shift'
When pressed, Folkman acknowledges that his work may be more than just a
step in the fight against cancer. It might be a "paradigm shift," he said
-- a fundamental change in the way we approach the disease.
He foresees a time when there will be "cancer without disease." In other
words, you have cancer, but it is controlled, and you aren't sick.
When today's children are adults, will they fear cancer the same way their
parents do? Folkman answered with a bit of history. Before antibiotics,
people were terrified of pneumonia because it killed so many, he said. "Now
we treat it on an outpatient basis. In the future we'll treat cancer on an
The surgeons who listened to Folkman seemed to think the future isn't far
-- Jim Dawson is a Star Tribune science writer.
© Copyright 1998 Star Tribune. All rights reserved.
(Dated but I use these for quotes and reference)
They called his theory ridiculous
Now it's revolutionizing cancer treatment
Every few years, Dr. Judah Folkman delivers a lecture to Harvard medical
students on the difference between obstinacy and persistence. "It's a fine
line," he says. "If your idea succeeds, everybody says you're persistent.
If it doesn't succeed, you're obstinate." Folkman should know. He has
endured the ridicule of critics, who have called him a clown--and worse.
And he once watched an auditorium empty when he stood up to give a
scientific talk. But the surgeon and cell biologist at Children's Hospital
in Boston has never wavered from the deceptively simple-sounding theory he
first outlined 25 years ago, a theory that is having profound implications
for the treatment of cancer: Tumors need a blood supply in order to grow.
As it turns out, Folkman is likely to go down in history as persistent, not
merely pigheaded. Over the past decade, the scientist not only has proved
his basic premise but in the process has opened a portal on some of
cancer's most perplexing secrets. Researchers now understand, for example,
that tumors use tricks to induce nearby blood vessels into providing that
blood supply by sprouting tiny branches called capillaries. The tumor then
uses these capillaries as highways to spread--or metastasize--to far-flung
sites in the body.
Now, Folkman's lab has produced the most spectacular finding yet: two
substances that can cut off a tumor's blood supply, stopping cancer in its
tracks. If these drugs work in people as well as they do in mice, they
could reverse the deadly odds cancer patients face once their tumors have
Folkman's idea rests on the observation that once a tumor grows beyond a
few hundred thousand cells--a mass no bigger than a BB--the cells at its
center don't get enough blood. To nourish them, the tumor must send out
chemical signals that induce capillaries to grow--a process known as
angiogenesis, from the Greek angos, for vessel.
Finding the switch. Folkman's theory led him to search for biochemical
messengers that tumors use to turn on blood vessel cells. In 1983, his lab
found the first of these angiogenesis growth factors. Two years later, his
team fished out another substance: This one turned off blood vessel cells,
slowing the growth of capillaries and--Folkman hoped--some tumors as well.
The discoveries turned his critics into competitors. Today, over two dozen
pharmaceutical firms are racing to complete clinical trials of nine
so-called angiogenesis inhibitors in human patients with a variety of
tumors, including cancer of the colon and breast. The drugs are not strong
enough to battle cancer alone. Instead, they provide a one-two punch when
combined with standard radiation and chemotherapy. The angiogenesis
inhibitors starve the tumor by shrinking its blood vessels, while the
standard treatment attacks the cancer itself.
Recently, Folkman's lab isolated two new factors, called angiostatin and
endostatin, which are the most powerful growth inhibitors by far. They also
hold out the promise of an entirely new means of battling cancer. Unlike
chemotherapy, which can make patients quite ill at high doses, the new
factors produce only the mildest of side effects. Indeed, standard
chemotherapy makes cancer-ridden mice listless and easy to catch for their
daily injections. Those treated with angiostatin and endostatin feel frisky
enough to put up a fight. "And I've got the bite marks to prove it," says
Dr. Michael O'Reilly, the postdoctoral fellow who discovered the new
factors. Drugs based on the new factors also are more likely to keep on
working: Cancer cells easily develop resistance to chemotherapy; blood
vessel cells, which reproduce more slowly, are more apt to remain
susceptible to drugs.
For all their promise, these newest angiogenesis inhibitors will not be
widely available for human cancer patients anytime soon. For one thing,
they are hard to come by. O'Reilly had to collect nearly 3 gallons of mouse
urine to purify enough angiostatin to treat a dozen mice. And even when
pharmaceutical companies figure out how to make large quantities of the
compounds, the drugs must still be tested in human patients, who may not
respond as well as mice.
None of which can blunt Folkman's excitement. "I've been waiting for
results like these my whole life," he says. Last month, Folkman reported
that a combination of angiostatin and endostatin eradicated lung tumors in
mice for more than five months--the equivalent of 10 years in a human. "The
importance of angiogenesis is so obvious when you think about it," says
Isaiah Fidler of the M. D. Anderson Cancer Center in Houston. "The world
owes Judah Folkman a debt of gratitude."
BY SHANNON BROWNLEE
(really dated but has terrific, fascinating history, note the reference to
(Kaposi's sarcoma) and Diabetes(Retinopathies), so angiogenesis factors are
in Cancer, Heart Disease, and blindness. Folkman is the 'FATHER OF
ANGIOGENESIS,' so could the Nobel Prize be a long shot? NOPE! This is they
type of thing my Dad would call a 'no brainer.' )
ANGIOGENESIS FACTORS IN CANCER, AIDS , AND DIABETES
Judah Folkman (1974) has estimated that as many as 350 billion mitoses
occur in each human every day. With each cell division comes the potential
that the resulting cells will be malignant. Yet very few tumors actually do
develop in any individual. Folkman has suggested that cells capable of
forming tumors develop at a certain frequency but that a large majority are
never able to form observable tumors. The reason is that solid tumor, like
any other rapidly dividing tissue, needs oxygen and nutrients to survive.
Without a blood supply, potential tumors either die or remain dormant. Such
"microtumors" remain as a stable cell population wherein dying cells are
replaced by new cells.
The critical point at which this node of tumorous cells becomes a rapidly
growing tumor occurs when the pocket of cells becomes vascularized. The
microtumor can expand to 16,000 times its original volume in 2 weeks after
vascularization. Without the blood supply, no growth is seen (Folkman,
1974; Ausprunk and Folkman, 1977). To accomplish this vascularization, the
original microtumor elaborates substances called tumor angiogenesis factors
(TAF). One such TAF, called angiogenin, has been isolated from a human
tumor cell population and has been shown to be a single chain protein of
around 14.4 kDa (Fett et al., 1985). Some tumors, such as many gliomas,
secrete the VEGF that normally is produced by kidneys and brain cells
(Plate et al., 1992; Shweiki et al., 1992), and the inhibition of VEGF
induced angiogenesis suppresses tumor growth in mice (Kim et al., 1993).
When host endothelial cells are infected with a virus producing a dominant
negative form of the VEGF receptor, the mice become resistant to
VEGF-secreting glioblastomas (Millauer et al., 1994).
TAFs stimulate mitosis in endothelial cells and direct the cells' formation
into blood vessels in the direction of the tumor. This phenomenon can be
demonstrated by implanting a piece of tumor tissue within the layers of a
rabbit or mouse cornea. The cornea itself is not vascularized, but it is
surrounded by a vascular border, or limbus. Tumor tissue induces blood
vessels to form and come toward the tumor (Figure 1; Muthukkaruppan et al.,
1979). Most other adult tissues will not induce these vessels to form. (The
exceptions are antigen stimulated lymphocytes and macrophages, which
secrete angiogenesis factors that are probably involved in wound repair.)
As little as 3.5 pmol of purified angiogenin can induce extensive capillary
formation in the rabbit cornea. Once the blood vessels enter the tumor, the
tumor cells undergo explosive growth, eventually bursting the eye.
FIGURE 1. New blood vessel growth to the site of a tumor in the cornea of
an albino mouse. (A) Sequence of events leading to the vascularization of a
mammary adenocarcinoma tumor on days 2, 6, 8, and 12. The veins and
arteries of the limbus surrounding the cornea both provide vessels. (B)
Photograph of living cornea of an albino mouse, with new vessels being
constructed to enter the tumor graft. (A from Muthukkaruppan and Auerbach,
1979; B courtesy of R. Auerbach.)
Angiogenesis inhibitors: Possible treatments for cancer Folkman and co
workers (1983) have shown that certain natural substances inhibit tumor
induced angiogenesis. Heparin, a complex polysaccharide found in the
matrices of numerous connective tissues, is a potent inhibitor of
angiogenesis, especially if administered in the presence of the steroid
hormone cortisone. When mice with established tumors received injections of
heparin and cortisone, their tumors markedly regressed. The same
combination of heparin and cortisone also inhibited normal embryonic
angiogenesis in chick embryos. A naturally occurring angiogenesis inhibitor
is also produced by cartilage. This 27,600 Da protein keeps cartilage
avascular (hence its white, rather than pink, appearance) and is able to
inhibit angiogenesis in vivo (Moses et al., 1990). Another angiogenesis
inhibitor, angiostatin, was found to be made by the primary tumors,
themselves. This protein can act in both paracrine and endocrine fashions.
It is thought that the presence of this factor actually suppresses the
growth of smaller metastases. When the primary tumor is removed, these
secondary, metastatic, growths can then proliferate. Angiostatin turns out
to be the plasminogen protein with its N-terminal third chopped off. It can
block angiogenesis and metastases growth when administered to mice
(O'Reilly et al., 1994). Systemic therapy of mice with angiostatin shows
that this compound can keep metastatic tumors dormant and can inhibit the
growth of at least three types of human primary tumors in mice (O'Reilly et
al., 1996). A third anti-angiogenesis factor, endostatin, has recently been
isolated. This factor is also made by tumor cells and is the 20 kDa
C-terminal fragment of collagen XVIII. This compound can stop tumors and
cause their regression (O'Reilly et al., 1997). Other naturally occuring
anti-angiogenesis factors include interferons alpha and beta, thrombospondin.
In recent experiments, Boehm and colleagues (1997) show that
anti-angiogenic drugs may be extremely useful in combatting tumors. Many
cancers are able to kill people because the tumor cells are genetically
unstable and can develop resistance to the drugs used against them.
Endothelial cells, however, are more stable targets. Boehm and colleagues
administered endostatin to mice that bore one of three types of tumors.
They then stopped the treatment when the tumors regressed but had not yet
been fully eliminated. When the tumor regrew, endostatin therapy was
resumed. The tumor regressed. The ability of endostatin to cause tumor
regression was undiminished even after multiple cycles of growth and
regression. In fact, after several cycles, the tumors remained dormant
longer. Therefore, anti-angiogenic drugs such as endostatin may be useful
in long-term maintenance therapy.
Another approach to blocking tumor-induced angiogenesis involves antibodies
against integrin proteins. In a series of experiments wherein human tumors
placed on chick chorioallantoic membranes induced vessels from the CAM to
enter into the tumor, Brooks and colleagues (1994) showed that the
maintainance of these new vessels depended on their being bound to the
substrate by avb3 integrin. Antibodies against this integrin disrupted its
function and caused the apoptosis of the new blood vessels. The previously
established blood vessels remained unaffected by the antibodies.
Hanahan and Folkman (1996) have hypothesized that tumor angiogenesis is
mediated by a change in the balance between angiogenesis factors (such as
FGF1, FGF2, and VEGF) and angiogenic inhibitors (such as thrombospondin-1,
interferons, platelet factor-4, endostatin, and angiostatin). Observations
on human tumor progression and gene knockout mutations in mice suggest that
tumor angiogenesis may occur either by a decrease in the amount of
inhibitor or an increase in the production of angiogenesis factors. The
signal for new VEGF synthesis in tumor cells might even be the hypoxia the
cells experience in the center of a pre-malignant cell mass.
Angiogenesis and metastasis In addition to supplying the tumor with
nutrients and oxygen, the new blood vessels also provide a route that
enables tumor cells to migrate to new places, thereby forming secondary
tumors. This process is called metastasis. Indeed, most victims of cancer
do not die from the original tumor but from the numerous secondary tumors
spread by metastasis. To enter a blood vessel, a tumor cell has to lyse the
collagenous matrix surrounding the new capillaries. This is thought to be
done by the secretion of a proteolytic enzyme called plasminogen activator.
This enzyme is important in the implantation of the blastocyst into the
uterus (Gilbert, 1997, Chapter 5). Tumor cells use this same enzyme to lyse
a hole in the extracellular matrix surrounding the blood vessels. The
synthesis of plasminogen activator has been correlated with the metastatic
ability of tumors, and antibodies to this enzyme have been found to inhibit
human tumor metastasis (Ossowski and Reich, 1983). Once on the capillary
endothelial cells, the metastatic tumor cell can squeeze between them and
enter the bloodstream (Kramer and Nicolson, 1979). Figure 2 shows a
metastatic melanoma cell squeezing its way between capillary endothelial
FIGURE 2. (A) Attachment, (B) invasion, and (C) migration of a melanoma
tumor cell (T) under a vascular endothelial cell (e). The melanoma cells
were placed on the endothelial cells in culture, and photographs were taken
at intervals of 0.5, 1, and 3 hours. (From Kramer and Nicolson, 1979,
courtesy of G. Nicolson.)
Metastasis requires the ability to travel from one site to another. Like
embryonic cells, many tumor cells need a surface upon which to migrate, and
some of these cells travel along the extracellular matrix of the blood
vessel endothelial cells (Nicolson et al., 1981). This migration, like that
of many embryonic cells, appears to be mediated by components of the
extracellular basal lamina. When mice are injected with a certain strain of
melanoma tumor cells, the cells migrate specifically to the lung, where
they form secondary tumors (Figure 3). When the cells are inhibited from
binding fibronectin or laminin, over 90 percent of the cells fail to reach
the lungs (Humphries et al., 1986).
FIGURE 3. Metastasis of melanoma cells. The ability of particular melanoma
cells to metastasize to the lung is inhibited by the cell binding regions
of fibronectin and laminin. Melanoma cells were injected into the tail vein
of mice. Fourteen days later, the animals were killed with ether and the
lung metastases were counted. Each point is the average of eight mice.
(From Humphries et al., 1986, courtesy of K. M. Yamada.)
In their rapid division and their secretion of plasminogen activator and
angiogenesis factor and in their migration patterns, tumor cells act like
normal embryonic cells. There are numerous cases in which tumor cells
represent adult cells that have reverted to an embryonic stage of their
existence. This finding suggests new approaches to cancer therapy,
including the administration of agents that prevent angiogenesis or that
actually promote the "differentiation" of the "embryonic" tumor cell back
into a normal, "adult" cell (Sachs, 1978; Jimenez and Yunis, 1987).
Retinopathies and Kaposi's sarcoma
One of the symptoms of AIDS is Kaposi's sarcoma, a tumor of blood vessels.
Usually, this type of tumor is ony found in elderly men of Mediterranean
ancestry, and it is normally a slow growing and nonlethal cancer. In
patients with AIDS, this cancer is fast-growing and is seen in young
adults. Ensoli and colleagues (1994) in Robert Gallo's laboratory have
shown that vasculogenesis factor FGF2 synergises with the TAT angiogenesis
inducer of HIV. In "classical" Kaposi's sarcoma, only FGF2 is inducing the
growth of blood vessels. In the Kaposi's sarcoma of AIDS, both factors are
Another disease characterized by excessive blood vessel growth is diabetic
retinopathy. About 60,000 diabetic persons each year suffer some degree of
retinal damage that can lead to blindness. Recent evidence (summarized in
Barinaga, 1995) suggests that this overproduction of blood vessels is due
to VEGF. The retina is the most metabolically active tissue in the body,
and it has an enormous demand for oxygen. In diabetes, it is thought that
the capillaries supplying blood to the retina get clogged. When this
happens, oxygen deprivation results. The new studies suggest that this
oxygen deprivaton stimulates the retina to produce VEGF in an attempt to
produce more capillaries. However, the vessels do not grow with the proper
archetecture, nor do they form in an ordered manner. VEGF was found in the
retina whenever there was oxygen deprivation. This implies that VEGF may
also be responsible for the retinopathy found in premature infants. When
babies are born before the blood vessels that supply the retina have been
completed, the retina lacks the oxygen it needs. About 10,000 premature
infants each year have proliferative vascular retinopathy wherein abnormal
blood vessels cross the retina, sometimes destroying vision. If this
abnormal development could be stopped or redirected, it might be possible
to prevent the blindess that often results from these proliferative
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Another site that I haven't checked out but want to: