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A Model of Human Tumor Dormancy: An
Angiogenic Switch From the Nonangiogenic Phenotype
George N. Naumov,
Elise Bender, David Zurakowski, Soo-Young
Kang, David Sampson, Evelyn Flynn, Randolph
S. Watnick, Oddbjorn Straume, Lars A. Akslen,
Judah Folkman, Nava Almog
Affiliations of authors: Departments
of Surgery (GNN, EB, DZ, S-YK, DS, EF, RSW, LAA, JF, NA) and
Biostatistics (DZ), Vascular Biology Program (GNN, EB, S-YK, DS, RSW,
LAA, JF, NA), Children's Hospital, and Harvard Medical School, Boston,
MA; The Gade Institute, Section for Pathology, University of Bergen,
Bergen, Norway (OS, LAA). Correspondence to: Judah Folkman, MD, Karp
Family Research Laboratories 12.128, 300 Longwood Ave., Boston, MA
02115 (e-mail: judah.folkman@childrens.harvard.edu
). Manuscript received June 20, 2005; revised December 19, 2005;
accepted January 11, 2006.
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Background.
Microscopic human cancers can remain dormant for life.
Methods. Severe combined
immunodeficient (SCID) mice were inoculated with nonangiogenic human
MDA-MB-436 breast adenocarcinoma, KHOS-24OS osteosarcoma, or
T98G glioblastoma cells.
Most of the resulting tumors
remained microscopic (<1 mm diameter), but some
eventually became angiogenic and enlarged and were used to
isolate angiogenic tumor cells.
Angiogenic and nonangiogenic tumor
cells were inoculated into SCID mice, and time to the
development of palpable tumors was determined.
Cell proliferation was assayed in
vitro by growth curves and in vivo by staining for
proliferating cell nuclear antigen or Ki67.
Microscopic tumors from both tumor
cell populations were examined for histologic evidence of
vascular development 14 days after inoculation in mice.
Expression of the angiogenesis
inhibitor thrombospondin-1 was examined by immunoblotting.
Results. Nonangiogenic
tumors of each tumor type developed palpable tumors after
means of 119 days (range: 53–185 days) for breast cancer,
238 days (184–291 days) for osteosarcoma, and 226 days
(150–301 days) for glioblastoma.
Angiogenic cells developed
palpable tumors within 20 days after inoculation.
However, nonangiogenic and
angiogenic cells of each tumor type had similar
proliferation rates.
Fourteen days after tumor cell
inoculation, tumors from angiogenic cells showed evidence of
functional vasculature.
In contrast, nonangiogenic tumors
remained microscopic in size with absent or nonfunctional
vasculature.
Thrombospondin-1 expression was
statistically significantly lower (by five- to 23-fold,
depending on tumor type) in angiogenic than nonangiogenic
cells.
Conclusions. This model
provides a conceptual framework and a reproducible in vivo
system to study unresolved central questions in cancer
biology regarding the initiation, reversibility, and
molecular regulation of the timing of the angiogenic
switch.
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