Summary of scientific papers by leading
scientists
Through the arrangement of capillaries in the circulatory system, nearly every
healthy cell has a continual supply of fresh blood that provides oxygen and
nutrients and removes waste products. During embryogenesis, capillaries develop
in the fetus by neovascularization, where endothelial cells arise from
progenitor cells; and angiogenesis, in which new blood vessels sprout from old
ones. By adulthood, under most conditions these processes have stopped
occurring, as blood vessels do not normally increase in size or number. It has
been reported that only 0.01% of endothelial cells are undergoing cell division
at any time, in comparison to 14% of intestinal epithelial cells (cited in
Hanahan and Folkman, 1996). However, in response to angiogenic proteins released
during pregnancy, wound healing, and tumor growth, capillaries in this quiescent
vasculature can be triggered to proliferate.
Without a blood supply, tumors can grow no more than the size of a pea (Folkman,
1996). These mutated cells are harmless and pose no significant threat because
they are limited by the diffusion capacity of oxygens and nutrients in the
preexisting capillary network. Solid tumor masses cannot expand past a diameter
of 1-2mm without depriving cells in the interior from access to blood vessels.
If spheroid tumors can activate angiogenesis and recruit the formation of new
blood vessels, rapid expansion can occur. Not only are new capillaries critical
for the survival of cells in the interior of the tumor, they also provide a
route for cancerous cells to exit the primary tumor site and spread to other
parts of the body. The following diagram shows how the process of angiogenesis
allows metastases.
From Varner, J., Brooks, P., Cheresh, D. 1995. The integrin av?:
Angiogenesis and Apoptosis. Cell Adhesion and Communication. 3:367-374
A major area of research is to identify angiogenic factors, and how to
antagonize their function. Since antiangiogenic drugs presumably would prevent
the growth of new blood vessels without affecting healthy tissue, they represent
a non-cytotoxic class of anticancer drugs. Current cancer treatment often
involves a multi-modality approach of surgery, radiation, chemotherapy, hormone
therapy, and immunotherapy (Current Treatments). If the tumor is detected early,
surgical removal and/or irradiation offers the greatest probability for curing
the cancer. If portions of the primary tumor cannot be removed or if it is
believed to have metastasized, systemic drug therapy is given to kill residual
cancerous cells through the targeting of actively dividing cells. Chemotherapy
has the unfortunate side-effect of causing bone marrow suppression, hair loss,
and gastrointestinal symptoms Side-effects of chemotherapy. Since cancerous
cells are genetically unstable and incur a high mutation rate, drug resistance
is also a major problem.
Unlike the aim of most conventional treatments, angiogenic inhibitors do not
attempt to completely eliminate all cancerous cells. Rather the intention of
antiangiogenic therapy is to gradually shrink existing tumors and
prophylatically inhibit the formation of new metastatic lesions. Since
antiangiogenesis drugs affect normal endothelial cells, which are genetically
stable, drug resistance is less likely to develop Side-effects of
antiangioangesis drugs. In comparison to standard therapies, their side-effects
appear to be mild, only interfering with wound repair and menstruation.
In the early 1970s, Judah Folkman described the principle of capillary growth at
the primary tumor site and proposed that this process was crucial for metastasis
(Folkman, 1971). Most colleagues disregarded his claims as specious, and it was
not until 1983, when two of his postdoctoral fellows purified a protein, basic
fibroblast growth factor (bFGF) from a rat tumor that his views were
substantiated (Shing et al., 1984). bFGF induced the growth of new blood
vessels. Later, members of the vascular endothelial growth factor (VEGF) family
were also found to promote angiogenesis (Dvorak et al., 1995).
The next step was to look for angiogenesis inhibitors and elucidate whether they
could slow tumor growth. By chance, blood vessels growing in vitro in Folkman's
lab were contaminated by a yeast that inhibited their growth without resulting
in necrosis. The compound was isolated from yeast and called fumigillin. In
animals, it was found to cause regression of tumor growth. Searching for
angiogenesis inhibitors in the urine of mice bearing Lewis lung carcinomas
resulted in the discovery of angiostatin (O'Reilly et al., 1994) and endostatin
(O'Reilly et al., 1997).
Interestingly, angiostatin and endostatin are not released by neighboring,
healthy tissue, rather they are secreted by the primary tumor. Although
scientists have not elucidated the functionality or mechanism for
auto-inhibition of tumor growth, this phenomenon explains the rapid expansion of
remote, metastatic tumors. Following elimination of a primary tumor, levels of
angiogenic inhibitors fall. Without circulating angiogenesis inhibitors,
metastatic colonies are no longer suppressed, and can rapidly grow (Folkman,
1994). Microscopic metastases that have not undergone neovascularization are
present at the periphery of a primary lung tumor. After surgical removal of the
primary tumor, metastases appear large and vascularized, indicating that primary
tumors may inhibit neovascularization and growth of metastases (O'Reilly et al.,
1994).
From O'Reilly, M., Homgren, L., Shing, Y., Chen, C., Rosenthal, R., Moses,
M., Lane, W., Cao, Y., Sage, E., Folkman, J. 1994. Angiostatin: a novel
angiogenesis inhibitor that mediates the suppression of metastases by a Lewis
lung carcinoma. Cell 79:315-328
To determine whether the primary tumor inhibited angiogenesis directly or
indirectly, a sustained-release pellet containing bFGF was implanted into the
corneal micropocket of normal mice and mice carrying Lewis lung carcinomas. New
capillary vessels grew in normal mice, whereas neovascularization was completely
inhibited in mice with a primary tumor (Folkman, 1994). Thus, a primary tumor
can suppress bFGF-induced angiogenesis at a distant site.
From O'Reilly, M., Homgren, L., Shing, Y., Chen, C., Rosenthal, R., Moses,
M., Lane, W., Cao, Y., Sage, E., Folkman, J. 1994. Angiostatin: a novel
angiogenesis inhibitor that mediates the suppression of metastases by a Lewis
lung carcinoma. Cell 79:315-328
To see if angiostatin could inhibit the growth of metastases, mice were treated
with angiostatin or placebos, following primary tumor removal. In contrast to
control mice, angiostatin-treated mice showed a marked reduction in the number
and size of metastases. Metastases in control mice were neovascularized, whereas
metastases in angiostatin-treated mice were microscopic and contained no new
capillaries (Folkman, 1994).
From O'Reilly, M., Homgren, L., Shing, Y., Chen, C., Rosenthal, R., Moses,
M., Lane, W., Cao, Y., Sage, E., Folkman, J. 1994. Angiostatin: a novel
angiogenesis inhibitor that mediates the suppression of metastases by a Lewis
lung carcinoma. Cell 79:315-328
Although such research suggests that it may be
useful for cancer patients to be treated with angiogenesis inhibitors after
surgical removal of the largest tumor, it is far simplified in comparison to
clinical manifestations of the disease in humans, partly because our population
is so outbred. There are four common metastatic patterns. Type I patients
exhibit immediate metastasis growth following removal of a primary tumor. Type
II patients show metastases before removal of the largest tumor. Type III
patients display metastases before detection of the primary tumor. Following
tumor removal type IV patients exhibit metastatic growth many years later, if at
all. Although angiogenesis inhibitors may be useful for all cancer patients,
such data suggests that its efficacy may be greatest for type I patients
following tumor removal.
From Folkman, J. 1995. Angiogenesis in cancer, vascular, rheumatoid and other
disease. Nature Medicine.
1:27-31
As with any promising, but unproven therapy, scientists and reporters must be
careful not to give false hope to patients. A front page article in the New York
Times on
Sunday, May 3, 1998 featured Folkman's research. It described the
effects of angiostatin and endostatin towards the treatment of cancer in mice.
One of the most misleading aspects of the Times article was a quote attributed
to Nobel laureate James D. Watson: "Judah
is going to cure cancer in two years." Over the next few days, media across the
country sensationalized this fact. Folkman's office was bombarded by around
1,000 calls a day, many from cancer patients desperately wanting to try these
new drugs. This media hype was not bioethical and reminds us of the need not
only to be wary of media claims, but also to educate the public to be able to
discern between truth and hype. Although Folkman's research indicates that
angiostatin effective inhibits a certain type of mouse tumor, similar success in
humans is far from guaranteed. Cancer represents over 100 diseases that are due
to many genetic and environmental influences. Certain drugs, such as monoclonal
antibodies, interferon, IL-2, and TNF that were found to cure mouse cancers were
later shown to only have a limited role in the treatment of specifics human
cancers. It is likely that angiogenesis inhibitors will follow the same pattern,
in that they alone will not be a panacea for all cancer patients, rather in
combination with other anticancer agents, they may provide an improved therapy
for some patients.
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