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minimum diameter of capillaries where cancer cells are able to migrate is
approximately 8
m
m.
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6.2. Real-time imaging of trafficking cancer cells in blood
vessels
Dual-color cancer cells were injected by a vascular route in an abdominal
skin flap in nude mice. Nuclear and cytoplasmic behavior of cancer cells
were observed in real time in blood vessels as dual-colored cancer cells traf-
ficking by various means or adhered to the vessel inner surface in the abdom-
inal skin flap. During extravasation, real-time dual-color imaging showed
that cytoplasmic processes of the cancer cells exited the vessels first, with nu-
clei following along the cytoplasmic projections. Both cytoplasm and nuclei
underwent deformation during extravasation.
28
6.3. Imaging the trafficking of cancer cells in lymphatic vessels
Cancer cells labeled with both GFP in the nucleus and RFP in the cytoplasm
were injected into the inguinal lymph node of nude mice. The labeled can-
cer cells trafficked through lymphatic vessels, where they were imaged via a
skin flap in real time at the cellular level until they entered the axillary lymph
node. Using this imaging technology, we investigated the role of pressure on
tumor cell shedding into lymphatic vessels. Pressure was generated by plac-
ing 25- and 250-g weights for 10 s on the bottom surface of a tumor-bearing
footpad. Increasing pressure on the tumor increased the numbers of shed
cancer cells, and emboli. Pressure also deformed the shed emboli, increasing
their maximum major axis.
29
6.4. The role of the intravascular microenvironment
in spontaneous metastasis development
Real-time imaging of cancer cell-endothelium interactions during sponta-
neous metastatic colonization of the liver and lung in live mice was carried
out. We observed that prior to the detection of extravascular metastases,
GFP-expressing PC-3 cancer cells resided initially inside the blood vessels
of the liver and the lung, where they proliferated and expressed Ki-67
and exhibited matrix metalloproteinase (MMP) activity. Thus, the intravas-
cular cancer cells produced their own microenvironment, where they could
continue to proliferate. Extravasation occurred earlier in the lung than in the
liver. These results demonstrate that the intravascular microenvironment is a
critical staging area for the development of metastasis that later can invade
the parenchyma. Intravascular tumor cells may represent a therapeutic target
to inhibit the development of extravascular metastases.
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